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WO2011016811A1 - Procédés pour réduire l'incidence d'une mucosité induite par chimiothérapie - Google Patents

Procédés pour réduire l'incidence d'une mucosité induite par chimiothérapie Download PDF

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Publication number
WO2011016811A1
WO2011016811A1 PCT/US2009/053115 US2009053115W WO2011016811A1 WO 2011016811 A1 WO2011016811 A1 WO 2011016811A1 US 2009053115 W US2009053115 W US 2009053115W WO 2011016811 A1 WO2011016811 A1 WO 2011016811A1
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Prior art keywords
dose
administered
treatment
galactomannan
chemotherapeutic
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Anatole Klyosov
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Pro Pharmaceuticals Inc
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Pro Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters

Definitions

  • compositions relate to the administration of a toxic agent to a subject in a formulation in which toxicity is substantially reduced, thus resulting in decreased incidence or severity of chemotherapy induced mucositis as well as the ability to deliver an increased dose intensity of chemotherapeutic agents to treat tumors alone or in combination with alternate or complementary therapies.
  • these methods provide a new therapeutic weapon against refractory disease, and provide medical professionals with enhanced options to administer both dose- intensive and metronomic (e.g., low-intensity, prolonged) cancer treatment regimens.
  • The present invention relates to compositions and methods for treating disease.
  • the instant invention relates to compositions comprising a polysaccharide and pharmaceutical agent, wherein the polysaccharide lowers the toxicity profile of the drug as well as increases its efficacy.
  • chemotherapeutic agents have significant therapeutic use limitations relating to their toxic effect on the patient and the efficacy of a particular dosage to target and kill tumor cells. Such limitations are limited by maximum dose and/or dose intensity that can be tolerated by a patient in need of treatment. However, the maximum dose intensity that may be tolerated by a patient may be less than the effective dose and/or dose intensity of a chemotherapeutic agent, especially against refractory disease.
  • chemotherapeutic agents kill cancer cells once they begin to undergo division and replication. Cells are killed by disrupting cell division. For example, a chemotherapeutic agent may prevent the formation of new DNA or block some other essential function within a cell. Some chemotherapeutic agents may work by inducing apoptosis, essentially causing the cells to commit suicide by triggering the cells' programmed death process. Although these agents are effective for treating cancer cells that generally grow rapidly through unregulated cell division, they also kill healthy non-cancerous cells as they undergo ordinary cell division. This toxic effect is particularly apparent in fast-growing normal cells, such as bone marrow cells, those in the digestive tract, hair follicles, and reproductive cells.
  • chemotherapy harms healthy tissue
  • the effectiveness of a treatment is limited by its dosage levels and treatment frequency such that it should not exceed the tolerance levels for noncancerous cells.
  • the chemotherapy regimen often dramatically diminishes the quality of a patient's life through its physical and emotional side effects.
  • chemotherapy dosages must be kept within a range (i.e., the therapeutic index) that healthy tissue can tolerate, thus often reducing the optimal effectiveness of chemotherapy on diseased tissue.
  • chemotherapeutic agents could be reduced, then practitioners would be able to increase the dosage and/or dosage intensity of a drug without the resultant unacceptable side effects.
  • Increasing efficacy in a chemotherapeutic agent can be translated into a decreased dosage of chemotherapeutic agent, which again minimizes the potential harmful effects on a patient while offering maximum benefit.
  • Increasing efficacy of a chemotherapeutic agent together with a reduction in toxic side effects resulting from the administered chemotherapeutic agent would lead to improvement of the patient's quality of life through controlling the tumor and through reducing harmful side effects.
  • a method comprising the steps of administering to a subject a treatment comprising a polysaccharide component, and an effective dose of a chemotherapeutic agent, wherein administration of the treatment results in reduction of toxicity of the chemotherapeutic agent.
  • the chemotherapeutic agent is administered to the subject at a dose intensity of at least 500 mg/m 2 /30 minutes. [0091 ' n another embodiment, the chemotherapeutic agent is administered to the subject at a dose intensity of at least 600 mg/m 2 /22 hours.
  • the polysaccharide component of the treatment is administered prior to administration of the chemotherapeutic component of the treatment.
  • the polysaccharide component of the treatment is administered simultaneously with the chemotherapeutic component of the treatment.
  • the polysaccharide component is a galactose- pronged polysaccharide.
  • the polysaccharide component is DAVANAT® .
  • the chemotherapeutic component is 5-FU.
  • the chemotherapeutic compound is a cell cycle-dependent agent.
  • the polysaccharide component of the treatment is administered at a dose intensity of at least 400 mg/m2/week.
  • the polysaccharide component of the treatment is administered over a dose duration of not more than 30 minutes.
  • the dosage frequency is at least 4 dosages delivered within a 21 day period.
  • a method increasing the therapeutic index of a chemotherapeutic agent comprising co-administering a chemotherapeutic agent at a dose intensity of at least 280 to 500 mg/m 2/ day with a sufficient amount of a polysaccharide to reduce toxicity of said chemotherapeutic agent.
  • a method of preventing grade 3-4 mucositis comprising administering a sufficient amount of polysaccharide to a patient at risk of developing mucositis so as to reduce toxicity of a subsequently-administered chemotherapeutic treatment.
  • the present invention comprises compositions and methods for treating disease, such as cancer.
  • the compositions of the present invention comprise one or more polysaccharides together with one or more chemotherapy agents and/or other treatment modalities.
  • the methods of the instant invention comprise the coadministration of one or more chemotherapy agents and one or more polysaccharides to a subject, wherein the pharmaceutical preparation including the pharmacological agent and polysaccharide has reduced toxicity.
  • the compositions of the present invention has both reduced toxicity and increased efficacy such that a greater amount of the therapeutic agent may be administered (at once or over time) or greater intensity of administration of the therapeutic agent can be achieved without reaching the adjusted LD 50 of the co-administered chemotherapeutic agent.
  • a lower dose of chemotherapy may be utilized in combination with the present invention without "triggering" development of a serious adverse event such as mucositis.
  • the present invention when co-administered with a given chemotherapeutic agent, may increase the therapeutic index of the particular chemotherapeutic agent, and may permit practitioners to use nonstandard chemotherapy dosing regimens that until now have been essentially unusable due to increased incidence of serious adverse events associated with such regimens.
  • a method for treating cancer in a subject comprising administering to the subject a mixture of one or more polysaccharides alone or in combination with an effective dose of a chemotherapeutic agent in a pharmaceutically acceptable formulation, wherein the polysaccharide is selected from group consisting of galactomannans, which are available from a number of plant and microbial sources.
  • This pharmaceutical formulation is then administered to a patient in need thereof in an acceptable manner well known to those skilled in the art.
  • a mixture of one or more polysaccharides and one or more chemotherapeutic agents is administered to a subject in need thereof, wherein the mixture comprises a sufficient amount of polysaccharide and chemotherapeutic agent in a ratio suitable for reducing the toxic side-effects in a subject while being effective against a particular pathology being treated, wherein the polysaccharide is selected from group consisting of galactomannans (from Cyamopsis tetragonoloba), Arabinogalactan (from Larix occidentalis), Rhamnogalacturonan (from potato), Carrageenan (from Eucheuma Seaweed), and the Locust Bean Gum (from Ceratonia siliqua).
  • the toxic side-effects are defined as those physiological effects (symptoms) realized by the subject resulting from the administration of the chemotherapeutic agent absent the polysaccharide.
  • a pharmaceutical formulation that includes a mixture of one or more polysaccharides and an effective dose or dose with increased therapeutic index of one or more chemotherapeutic agents in a pharmaceutically acceptable formulation, wherein the polysaccharide is selected from group consisting of galactomannans (from Cyamopsis tetragonoloba), Arabinogalactan (from Larix occidentalis), Rhamnogalacturonan (from potato), Carrageenan (from Eucheuma Seaweed), and the Locust Bean Gum (from Ceratonia siliqua).
  • galactomannans from Cyamopsis tetragonoloba
  • Arabinogalactan from Larix occidentalis
  • Rhamnogalacturonan from potato
  • Carrageenan from Eucheuma Seaweed
  • Locust Bean Gum from Ceratonia siliqua
  • the mixture in the formulation contains an amount of one or more polysaccharides and one or more chemotherapeutic agents in a ratio suitable for reducing any toxic side-effect in the subject.
  • the polysaccharide to chemotherapy ratio could be in the range from 10:1 up to 1 :10. With the about 50,000 MW modified galactomannan the optimum ratio was in the range from 6:1 to 1 :3.
  • the mixture contains an amount of one or more polysaccharides and one or more chemotherapeutic agents in a ratio suitable for enhancing efficacy of the chemotherapeutic effect for treating the cancer.
  • the mixture contains an amount of one or more polysaccharides and one or more chemotherapeutic agents in a ratio suitable for effectively treating cancer as well as reducing any potential toxic side-effect(s).
  • a method for treating cancer in a subject in need thereof that includes administrating an a mixture of one or more polysaccharides and an effective dose of one or more chemotherapeutic agents formulated so that the chemotherapeutic agent has enhanced therapeutic efficacy in the presence of the polysaccharide component.
  • Active Compound refers to any and all chemotherapeutic agents used herein for the treatment of cancer, and any and all added agents that increase efficacy of the chemotherapeutic agent or decrease toxicity of the chemotherapeutic agent.
  • Adjuvant Therapy means treatment used in addition to main treatment. It usually refers to hormone therapy, chemotherapy, radiation therapy, or immunotherapy given after surgery to increase the chances of curing the disease or keeping it in check.
  • At Risk Of Developing Mucositis means a subject subjected to an environmental or biochemical stressor that increases the likelihood that subject cell trauma will lead to inflammatory cytokine-mediated adverse biochemical processes at a local or systemic level.
  • the likelihood that a subject's DNA replication mechanisms will be interrupted in a particular tissue is increased.
  • the likelihood that a cell cycle dependent chemotherapeutic agent will have an adverse effect on the tissues of a subject represents a risk of developing mucositis.
  • “Chemotherapy” means any chemical treatment intended to be therapeutic with respect to a disease state; chemical treatment to kill or halt the replication or spread of cancerous cells in a patient.
  • 5-fluorouracil is a chemotherapeutic agent.
  • DAVANAT® means a partially hydrolyzed galactomannan polysaccharide having a mannose-to-galactose ratio of 1.7:1 ; comprised of a mannose backbone with galactose singular side residues, having an average molecular weight of 59 ⁇ 10 kD as measured by NMR and/or HPLC/RI-MALLS; and derived from guar gum, e.g. as described in U.S. Patent Application Serial No. 10/657,508, herein incorporated by reference in its entirety.
  • Dose means the amount of a given substance administered to a subject in a single administration. In one embodiment, chemotherapeutic dose is measured in number of milligrams of agent delivered per square meter of body surface area.
  • Dose Intensity means the dose of a given substance delivered per unit time, usually in milligrams per square meter per a specified time period, such as hour, day, or week.
  • Dose Duration means the amount of time (for example, 30 minutes or 22 hours) within which a complete dose is infused into a subject.
  • Dose Frequency means the number of doses separately administered during a given period (for example, three doses infused into a subject within a 28-day period, or 4 doses within a 24 hour period).
  • Duration of Regression refers to the interval during which a tumor classified as a partial or complete regression continues to be below 50 percent of its size at first treatment.
  • Effective Dose is that dose of chemotherapeutic agent required to achieve a predetermined physiological effect, such as tumor size reduction.
  • Effective to Reduce Toxicity means acting so as to reduce toxicity of a chemotherapeutic agent.
  • the toxicity of a given chemotherapeutic treatment is observable in vivo or in an in vitro mucosal cell assay such as the type described below.
  • Enhanced Therapeutic Efficacy means that the effective dose of a given chemotherapeutic agent (alone or as a composition comprising one or more polysaccharides and one or more therapeutic agents) exceeds the effectiveness of a reference chemotherapeutic agent, and/or gives a somparable anti-cancer effect while improving a patient's tolerance for the agent.
  • Efficacy for a toxic therapeutic agent refers to the relationship between a minimum effective dose and the accompanying toxic side-effects. Efficacy of an agent is increased if a therapeutic end point can be achieved by administration of a lower dose or a shorter dosage regimen, and/or if an improved therapeutic endpoint can be reached without an increased risk or probability of occurrence of serious adverse events associated with said treatment, such as, for example, onset and/or exacerbation of mucositis. If toxicity can be decreased, a therapeutic agent can be administered on a longer dosage regimen or even chronically with greater patient compliance and improved quality of life. Further, decreased toxicity of an agent enables the practitioner to increase the dosage to achieve the therapeutic endpoint sooner, or to achieve a higher therapeutic endpoint. "Efficacy" for a non-toxic therapeutic agent relates to improved therapeutic effect for treating a condition.
  • Evaluation Size refers to the tumor mass selected at one or two mass doubling versus beginning with the initial tumor size at the start of treatment.
  • “Increased Effectiveness” means: a higher or lower value of a readout parameter directly related to a curative effect of the drug, e.g. tumor shrinkage
  • Tucositis means the painful inflammation and ulceration of the mucous membranes lining the digestive tract, usually as an adverse effect of chemotherapy and /or radiotherapy treatment for cancer.
  • Parenteral Administration includes administration by bolus injection or infusion, as well as administration by intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular subarachnoid, intraspinal, epidural and intrasternal injection and infusion.
  • Patient refers to a human subject who has presented in a clinical setting with a particular symptom or symptoms consistent with a pathophysiological process.
  • “Pharmaceutically acceptable carrier” refers to any and all solvents, dispersion media, e.g., human albumin or cross-linked gelatin polypeptides, coatings, antibacterial and antifungal agents, isotonic, e.g. sodium chloride or sodium glutamate, and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier is suitable for oral, intravenous, intramuscular, subcutaneous, parenteral, spinal or epidural administration, (e.g., by injection or infusion).
  • the active compound can be coated in a material to protect the compound from the action of acids and other natural conditions that can inactivate the compound.
  • Polysaccharide refers to polymers comprised primarily of monomers of one or more sugars and substituted sugars.
  • the sugar monomers can be modified in ways well known to those in the art.
  • Randomtion means the use of ionising radiation (IR) to maximise damage to malignant tumours while minimising damage to normal tissue. It is one of the mainstays of cancer treatment, often playing either a primary or adjuvant role. Rapidly proliferating cells, including tumour cells, undergo apoptosis in response to IR-induced DNA double strand breaks. Inter-mitotic death is also common in contrast to the consequence when non-dividing and slowly dividing cells are exposed to IR.
  • IR ionising radiation
  • Relative Dose Intensity means the amount of drug administered per unit of time expressed as the fraction of that used in the standard regimen.
  • Subject refers to an animal including a mammal, such as human, dog, cat, pig, cow, sheep, goat, horse, rat, mouse, and alike.
  • “Pharmaceutically Acceptable Carrier” refers to any and all solvents, dispersion media, e.g., human albumin or cross-linked gelatin polypeptides, coatings, antibacterial and antifungal agents, isotonic, e.g. sodium chloride or sodium glutamate, and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier is suitable for oral, intravenous, intramuscular, subcutaneous, parenteral, spinal or epidural administration, (e.g., by injection or infusion).
  • the active compound can be coated in a material to protect the compound from the action of acids and other natural conditions that can inactivate the compound.
  • the diminishment is at least 3%. . In one embodiment, the diminishment is at least 5%. . In one embodiment, the diminishment is at least 10%. . In one embodiment, the diminishment is at least 15%. . In one embodiment, the diminishment is at least 20%.
  • the diminishment is at least 25%.
  • Standard Dose means the dose; dose intensity; dose duration; or dose frequency utilized with respect to a particular chemotherapeutic agent.
  • Representative (but by no means exclusive or recommended) dosages of various chemotherapeutic agents are reproduced below:
  • Therapeutic Index means: a comparison of the amount of a therapeutic agent that causes a desired therapeutic effect to the amount that causes death. Quantitatively, it is the ratio given by the lethal dose divided by the therapeutic dose.
  • a therapeutic index is the lethal dose of a drug for 50% of the population (LD 50 ) divided by the minimum effective dose for 50% of the population (ED 50 ).
  • a high therapeutic index is preferable to a low one: this corresponds to a situation in which one would have to take a much higher dose of a drug to reach the lethal threshold than the dose taken to elicit the therapeutic effect.
  • Time Required for Tumor Mass Doubling is the time to reach the evaluation size, it is used in the calculations of the overall delay in the growth of the median tumor [(T-C)/C.times.100%], where T-C (days) is the difference in the median of times postimplant for tumors of the treated (T) groups to attain an evaluation size compared to the median of the control (C) group.
  • the T-C value is measured excluding non-specific deaths, and any other animal that dies whose tumor failed to attain the evaluation size.
  • Toxic refers to any adverse effect caused by an agent when administered to a subject.
  • Treatment means any administration or formulation of a compound or mixture intended to be administered to an organism and to have a resultant beneficial effect.
  • a treatment is intended to decrease the number of viable cancer cells present in an organism by targeting and disrupting the DNA replication or cellular division process of rapidly -dividing cells.
  • Tuor Regression was scored (excluding nonspecific deaths) as “partial” (less than 50 percent of its size at the beginning of the treatment), or “complete” (tumor becomes unpalpable).
  • FIG. 1 is the stereochemical configuration of galactomannan
  • FIG. 2 is a graphical representation of the results of 1 H-NMR spectrum of the galactomannan of the invention (from guar gum) and galactomannan from carob
  • FIG. 3 is the Fourier transform of the 1 H-NMR results shown in FIG. 2;
  • FIG. 4 is a graphical representation of the results of 13C-NMR spectrum of the galactomannan of the invention (from guar gum) and galactomannan from carob gum;
  • FIG. 5 is a graphical representation of the results of HPLC/RI-MALLS profile of the galactomannan of the present invention.
  • FIG. 6 is a schematic representation of a manufacturing and purification process to produce the galactomannan of the present invention
  • FIG. 7 is a graph summary of the results of the first part of the efficacy study described in Example 3.
  • FIG. 8 is a graph summary of the results of the second part of the efficacy study described in Example 3.
  • FIG. 9 is a graph summary of the results of the efficacy study described in
  • FIG. 10 is a graph summary of the results of the efficacy study described in Example 5.
  • FIG. 11 is a graph summary of the results of the three efficacy studies described in Examples 3, 4, and 5.
  • the present invention provides compositions and methods for treating an individual in need thereof.
  • the compositions of the invention comprise a mixture of one or more polysaccharides and one or more therapeutic agents.
  • the compositions of the present invention are directed toward individuals afflicted with a disease, such as cancer.
  • the polysaccharide/therapeutic agent compositions of the present invention once administered to an individual in need thereof, may, in one embodiment, enhance the therapeutic efficacy of the therapeutic agent while concomitantly reduce its toxic side-effects.
  • the polysaccharide/therapeutic agent compositions of the present invention once administered to an individual in need thereof, may, in one embodiment, enhance the therapeutic efficiency of the therapeutic agent while concomitantly reducing its toxic side-effects, therefore improving the therapeutic index of the composition and facilitating the use of both increased and decreased (but increased duration) intensity chemotherapeutic treatment regimens.
  • the present invention both increases the usable dose intensity (resulting in an increased area under the curve) and increases the resultant therapeutic index with respect to certain chemotherapeutic agents.
  • the increase in therapeutic index or use of increased dose intensity with respect to the chemotherapeutic agent results in the ability to administer an effective dose of a chemotherapeutic agent without significantly increasing relative risk of morbidity or mortality of the subject.
  • the therapeutic agent of the present composition includes all known pharmaceuticals listed in, for example, the Physicians Desk Reference, as well as experimental therapeutic agents, as well as radiation treatments.
  • the therapeutic agents are chemotherapeutic agents, alone or in combination.
  • dosage intensity has been employed to define the amount of drug delivered per unit time, usually in milligrams per square meter per week.
  • dose intensity delivered directly relates to treatment outcome. In most tumors in which cure is possible, this issue becomes critical and less than optimal dosing and/or dose intensity may result in treatment failure.
  • J0077J Drug resistance occurs rapidly when treatment with a single drug is used.
  • a combination of chemotherapeutic agents can be used to treat various cancers. Drugs can be used in combination when the dose-limiting toxicity of one drug is nonoverlapping with the other. When toxicity occurs, it may be difficult to adjust subsequent drug doses, because the major offending agent may not be known.
  • Cycle-active agents are drugs that require a cell to be in cycle, i.e., actively going through the cell cycle preparatory to cell division to be cytotoxic. Some of these drugs are effective primarily against cells in one of the phases of the cell. The importance of this designation is that cell cycle-active agents are usually schedule- dependent, and that duration of exposure is as important and usually more important than dose.
  • cell cycle-active agents are particularly valuable that can be administered over a long period of time, more or less continuously, with minimal or decreased associated serious adverse events.
  • noncell cycle-active agents are usually not schedule-dependent, and effects depend on the total dose administered, regardless of the schedule.
  • Alkylating agents are generally considered to be noncycle active, whereas antimetabolites are prototypes of cycle-active compounds.
  • 5-FU 5- fluorouracil
  • 5-FUdR 5-fluorodeoxyuhdine
  • 5-FU exerts its cytotoxic effects by inhibition of DNA synthesis, or by incorporation into RNA, thus inhibiting RNA processing and function.
  • the active metabolite, of 5-FU that inhibits DNA synthesis through potent inhibition of thymidylate synthase is 5-fluorodeoxyuhdylate (5-FdUMP).
  • 5-FU 5-fluorodeoxyuhdylate
  • 5-FU 5-fluorodeoxyuhdylate
  • Incorporation of 5-FU into DNA can occur also and may contribute to 5-FU cytotoxicity.
  • 5-FU has been used for over forty years in standard chemotherapy regimens for a number of solid tumors including colorectal, breast, non-small cell carcinoma of the lung (NSCCL), gastric, pancreatic, ovarian and head and neck tumors.
  • Schedule modification of 5-FU administration including prolonged intravenous infusion, and pharmacokinetic modulation has produced improved response rates and tolerability, however, this has not always translated well into improved survival rates.
  • agents which, when given with 5-FU, enhance tumor specific delivery, and improve safety and convenience of administration such as what is described herein.
  • 5-FU and 5-FUdR have antitumor activity against several solid tumors, most notably colon cancer, breast cancer, and head and neck cancer.
  • a preparation containing 5-FU is used topically to treat skin hyperkeratosis and superficial basal cell carcinomas.
  • the major limiting toxicities of 5-FU and 5-FUdR include marrow and Gl toxicity, including serious adverse events of mucositis (grades III and IV). Stomatitis and diarrhea usually occur 4-7 days after treatment. Further treatment is usually withheld until recovery from the toxic side-effects occurs. The nadir of leukopenia and of thrombocytopenia usually occurs 7-10 days after a single dose of a 5-day course.
  • the dose-limiting toxicity to infusions of 5-FUdR through the hepatic artery is transient liver toxicity, occasionally resulting in biliary sclerosis. Less common toxicities noted with 5-
  • FU after systemic administration are skin rash, cerebellar symptoms and conjunctivitis.
  • Purine analogs such as 6-mercaptopurine and 6-thioguanine, define drugs that are also employed as a cure against cancer.
  • Hydroxyurea is another drug that is used to treat cancer. Hydroxyurea inhibits ribonucleotide reductase, the enzyme that converts ribonucleotides at the diphosphate level to deoxyhbonucleotides.
  • Vinca alkaloids are also involved in the treatment of cancer. The vinca alkaloids include vinblastine, vincristine and vindesine.
  • Epipodophyllotoxin is a derivative of podophyllotoxin that is used in the treatment of such cancers as leukemia, Hodgkin's, and other cancers.
  • Alkylating agents such as mechlorethamine, phenylalanine mustard, chlorambucil, ethylenimines and methyl melamines, and alkylsulfonates are employed to treat various cancers.
  • Nitrosoureas like carmustine, lomustine, and streptozocin are used to treat various cancers and have the ability to readily cross the blood-brain barrier.
  • Cisplatin (diamino-dichloro-platinum) is a platinum coordination complex that has a broad spectrum antitumor activity. Cisplatin is a reactive molecule and is able to form inter- and intrastrand links with DNA in order to cross-link proteins with the DNA.
  • Carboplatin is another platinum based antitumor drug.
  • Triazenes like dacarbazine and procarbazine are a part of the antitumor arsenal.
  • antibiotics that have antitumor activity such as anthracyclines, such as doxorubicin, daunorubicin, and mitoxantrone.
  • Other antitumor antibiotics include bleomycin, dactinomycin, mitomycin C, and plycamycin.
  • cyclophosphamide Cytoxan
  • melphalan alkeran
  • chlorambucil leukeran
  • carmustine cyclophosphamide
  • BCNU thiotepa
  • busulfan myleran
  • glucocorticoids such as prednisone/prednisolone, triamcinolone (vetalog)
  • DTIC dacarbazine
  • procarbazine matulane
  • therapeutic agents that may be administered with one or more polysaccharides to reduce their toxicity or enhance efficacy include the following: anti- infectives including antibiotics, anti-virals and vaccines, antineoplastics, cardiovascular drugs including antiarrythmics, antihypertensives, etc., central nervous system drugs including analgesics, anorectics, anticonvulsants, anti-inflammatories and tranquilizers, etc.
  • anti- infectives including antibiotics, anti-virals and vaccines, antineoplastics, cardiovascular drugs including antiarrythmics, antihypertensives, etc.
  • central nervous system drugs including analgesics, anorectics, anticonvulsants, anti-inflammatories and tranquilizers, etc.
  • OTICS opthalmics
  • gastrointestinal including anti-ulcer drugs, anticholinergic drugs etc.
  • hormones, respiratory drugs including allergy medications, bronchodilators and decongestants, topical drugs and vitamins and minerals.
  • compositions of the present invention can further include an enhancer.
  • any chemotherapeutic agent known to result in mucositis in a subject subsequent to administration may be utilized.
  • the pathobiology of mucositis has recently been proposed as an overlapping five phase model.
  • the first phase, initiation, occurs immediately with cellular and tissue exposure to cytotoxic agents. DNA and non-DNA damage is initiated and reactive oxygen species (ROS) is generated. Upregulation and message generation is the second phase, where nuclear factor kappa B (NF-jB) is thought to be a key player. DNA strand breaks result in the activation of several transduction pathways that activate transcription factors such as p53 and NF-jB. NF-jB, which is also directly activated by radiation, several chemotherapeutic drugs and ROS, results in upregulation of the transcription of over 200 genes involved in mucositis.
  • ROS reactive oxygen species
  • NF-jB is also thought to have both pro-apoptotic and anti-apoptotic consequences, thus making it a significant factor in determining the fate of normal tissues following radiation or chemotherapy.
  • the upregulation of genes also result in production of pro-inflammatory cytokines including tumour necrosis factor-alpha (TNF- a), interleukin (IL)-I b, and IL-6.
  • cytokines produced earlier amplify the primary signal or may activate NF- jB in other cells, resulting in transcription of genes generating biologically active proteins such as mitogen-activated protein kinase (MAPK) and cyclooxygenase-2 (COX-2).
  • MMPs matrix metalloproteinases
  • the ulcerative phase follows, usually within 1 week of therapy, where the loss of epithelia and increased exudation lead to the formation of pseudomembranes and ulcers.
  • the mucosa is breached and neuronal endings are exposed, creating clinically significant pain.
  • Microbial colonisation of damaged mucosal surfaces by Gram-negative organisms and yeast occurs, and this may be exacerbated by concomitant neutropenia. Sepsis may also result.
  • Mucositis usually clinically appears four to five days after beginning chemotherapeutic treatment, reaching a peak at around day 10, and slowly and gradually reduces over the course of a month or two months. Mucositis makes the mucosal lining of the mouth to become thin, then red, inflamed, ulcerated, it may slough off. It may develop so-called pseudomembrane, which is a yellowish fibrin clot. Ulcers often range from %-inch to 1.5-2.0 inches in length, and they cause a severe pain in the mouth and throat. Due to pain, the patient may experience trouble speaking, eating, or even opening the mouth.
  • mucositis Treatment of mucositis is commonly mainly supportive, and aims at lubrication of the mouth with some water-soluble jellies or using salt mouthwashes. Overall, mucositis associated with chemotherapy, and particularly 5-FU treatment, increases mortality and contributes to rising health care costs.
  • Grade 3 Patients need to be on a liquid diet, as they experience extreme sensitivity swallowing solid food.
  • Grade 4 Patients are not able to swallow. Total parenteral nutrition or tube feeding is necessary.
  • the WHO grading system was the most commonly used one along with [he NCI-CTC grading system.
  • Most researchers employ lhe WHO grading system however, a consensus is not reached as yet.
  • NCi- CTC system which grades orai mucositis differently with respect to conventionai-dose chemotherapy, high-dose chemotherapy with stem cell support, and radiation therapy.
  • radiation oncology groups use specific grading systems, based on combinations of signs, symptoms, and observed functional changes.
  • OMAS Oral Mucositis Assessment Scale
  • Some lectins might contribute to the risk of developing mucositis, since galectins (lectins specific to galactose) play an active role in inflammatory responses, and trigger some inflammatory diseases. Such inflammatory responses may be siowed down and even reversed when the galectins are blocked with specific iigands of carbohydrate nature.
  • galectin-1 through induction of apoptosis and suppression of the T-cell response, and mediation of the T-cell regulatory cell activity via its binding to T-cell surface glycoproteins is immunosuppressive, (b) galectin-1 secreted by tumor cells induces apoptosis of activated human immune cells targeting the cancer cells, thus helping such cancer cells to evade the immune system, and (c) galectin-1 exerts a variety of functions related to inflammatory responses in vivo through its function on cell activation, cell migration, and inhibition of apoptosis, thus prolonging the survival of inflammatory cells.
  • Galectin-1 and galectin-3) null mutant (gal “1" and gal “3” ) mice, as described in Liu et. al, "Galectins in regulation of inflamation and immunity” in: Galectins (Klyosov et al., editors), John Wiley & Sons 2008, pp. 97-1 13. Galectin-1 is also implicated in angiogenesis. See, e.g. Kiss et. al. "Galectin-1 , cancer cell migration, angiogenesis, and chemoresistance” in: Galectins (Klyosov et al., editors), John Wiley & Sons 2008, pp. 157-191.
  • Tumor vasculature is not necessarily derived from endothelial cell, as cancer tissue can acquire vasculature by vasculogenic mimicry, e.g. the generation of microvascular channels by genetically deregulated, aggressive tumor cells.
  • Endothelial and vascular smooth muscle cells express galectin-1.
  • galectin-1 induces angiogenesis in the context of tumor hypoxia.
  • the process is under the control of VEGF and the upstream protein ORP150, also called HYOU1 , a hypoxic stress induced-protein. It is known for almost forty years that tumor growth depends on angiogenesis, however, only within the last several years has galectin-1 been identified as a major player in this process.
  • galectin-1 regulates the formation of the capillary vessels in a tumor, which is critical for its continuous growth and also provides a gateway for the dissemination of malignant cells.
  • Evidence is accumulating that galectin-1 is required for tumor angiogenesis and outgrowth of tumors, and that decreasing the expression of galectin-1 in tumor cells impairs angiogenesis both in vitro and in vivo.
  • galectin-1 was upregulated in capillaries associated with carcinoma cells, that treatment with galectin-1 -specific antisense oligodeoxynucleotides on polyclonal antigalectin-1 antibodies resulted in the inhibition of endothelial cell proliferation and migration, that galectin-1 is a target for the angiogenesis inhibitor anginex, and that tumor growth in galectin-1 -null mice was markedly impaired because of insufficient tumor angiogenesis, and no longer responds to antiangiogenic treatment with anginex.
  • Galectin-1 antagonism or downregulation could constitute a target for a novel treatment of a range of devastating cancers.
  • Galectin-1 can also modulate immune and inflammatory responses and may therefore play a key role in helping tumors to escape immune surveillance.
  • the effectiveness of an agent as ligand to cell-surface galectin-1 receptors may be directly predictive of its effectiveness as an anti-mucositis agent.
  • cancer One disease targeted by the present invention is cancer.
  • the types of cancer envisaged to be within the scope of the present invention include, but are not limited to, chronic leukemia, breast cancer, sarcoma, ovarian carcinoma, rectal cancer, throat cancer, melanoma, colon cancer, bladder cancer, lung cancer, mammary adenocarcinoma, gastrointestinal cancer, stomach cancer, prostate cancer, pancreatic cancer, and Kaposi's sarcoma.
  • treatment regimes are envisaged to be within the scope of this invention include, but not limited to, anti-depressants, anti-inflammatory agents, gastroenterology drugs (for treating ulcers and associated disorders), anti-psychotic drugs, anti-hyperlipidemic agents, etc., as many therapeutic agents must be administered as a chronic medicine, i.e., on a long-term basis, potential reduction in dosage and improvement in quality of life become significant factors in availability, cost of therapeutic agents, and patient compliance.
  • the effective dose is that amount needed to enhance the efficacy of the therapeutic agent. In another aspect, the effective dose is that amount need to minimize or eliminate the toxic side effects of a drug as well as maintain and/or increase the drug's efficacy in treating a subject. In one embodiment, the effective dose is that amount needed to facilitate the use of a higher-intensity chemotherapy regimen without increasing certain concomitant serious adverse events. In one embodiment, the effective dose is that amount needed to facilitate the use of a lower-intensity, higher- frequency chemotherapy regimen without increasing certain concomitant serious adverse events.
  • the polysaccharides of the present invention can have side branches of target specific carbohydrates, such as, galactose, rhamnose, mannose, or arabinose which provides recognition capabilities in targeting specific lectin type receptors on the surface of cells, especially tumor cells.
  • Branches can be a single unit or two or more units of oligosaccharide.
  • a composition comprising one or more polysaccharides and one or more therapeutic agents.
  • the polysaccharides are formed from monomehc units.
  • Modified polysaccharides are also considered to be within the scope of the present invention and can include modification by, for example, limited controlled depolymehzation, or, for example, having lipid, protein, or nucleic acid moieties affixed to the monomehc units of the polysaccharide.
  • the polysaccharide of the composition can be branched or unbranched.
  • the polysaccharides include, but not limited to, galactomannans available from a number of plant and microbial sources, e.g., plants: Gleditsia triacanthos, Medicago falcate, Cyamopsis tetragonoloba, Trigonella Foenum- graecum and microbial like Ceratonia siliqua, Xanthomonas campestris, yeast and mold galactomannan, Arabinogalactan (from Larix occidentalis), Rhamnogalacturonan (from potato), Carrageenan (from Eucheuma Seaweed), and the Locust Bean Gum (from Ceratonia siliqua).
  • galactomannans available from a number of plant and microbial sources, e.g., plants: Gleditsia triacanthos, Medicago falcate, Cyamopsis tetragonoloba, Trigonella Foenum- graecum and microbial like Ceratonia siliqua,
  • the polysaccharide can be ⁇ -1 ,4-D-galactomannan and include a ratio of mannose to galactose in the range of about 1.7.
  • the molecular weight of the galactomannan polysaccharide is in the range of about 4,000 to about 200,000 D.
  • the galactomannan has an average weight of about 40,000 to 60,000 D.
  • the structure of the galactomannans is a poly- ⁇ -1 ,4 mannan backbone, with side substituents affixed via ⁇ - 1 -6-glycoside linkages.
  • the galactomannan polysaccharide can be ⁇ -1 ,4- D-galactomannan.
  • the polysaccharide is (((1 ,4)-linked ( ⁇ -D- mannopyranose)17-((1 ,6)-linked-( ⁇ -D-galactopyranose)10)12)- .
  • the galactomannan can be a derivative of Guar gum from seeds of Cyamopsis tetragonoloba.
  • a polysaccharide like galactomannan in a mixture with a therapeutic drug such as 5-FU.
  • a therapeutic drug such as 5-FU.
  • galactomannan may increase cancer cell membrane fluidity and permeability as a result of galactose-specific interactions at the surface of the target cell.
  • the polysaccharide can thus serve as an effective vehicle for delivery of the drug to the target.
  • galactomannan may act to inhibit aggregation of tumor cells and their adhesion to normal cells so that the cancer fails to metastasize.
  • the polysaccharide may release the anti-cancer drug.
  • the toxicity of a therapeutic agent may be reduced because the drug is inactive as long as it is bound to the polymer.
  • the polysaccharide may release therapeutic agent.
  • polysaccharide like galactomannan may involve its interaction with some regulatory sites in a biological system, for example, if those sites are governed by galactose-specific residues, such as galectins.
  • the polysaccharide of the present invention may interact with any of the family of galectin receptors (including, in one embodiment, galectin-1 ) so as to downregulate nf-KB transcription factor and resultant upregulation of inflammatory cytokines such as TNF- ⁇ or IL-1 ⁇ .
  • Yet another possible mode of action may involve an inhibitory effect of the polysaccharide having a certain chemical structure (a certain Man:Gal ratio) and a certain size (molecular weight) on enzymatic systems responsible for a rapid clearance of therapeutic agent from the body, and therefore may potentially increase the bioavailability and prolong the mean residence time of drug in the body, thus improving the therapeutic profile of a drug in cancer therapy.
  • a certain chemical structure a certain Man:Gal ratio
  • a certain size molecular weight
  • the polysaccharide is galactomannan.
  • Use of a galactomannan-containing composition can have an immediate effect of increasing the responses of patients to chemotherapy.
  • one effect is a decrease in the dosage of the therapeutic agent required for effective chemotherapy. It can have an immediate beneficial effect for the patient by decreasing toxicity of the chemotherapeutic agent, as here exemplified, but not limited to, adramycin, 5-FU, effetotecan and cisplatin.
  • Galactomannan can be obtained from a variety of natural sources such as plants and microbial sources.
  • the polysaccharide can also be synthetically made.
  • Galactomannan can be derived from carob gum (Ceratonia siliqua), guar gum ⁇ Cyamopsis tetragonoloba), and honey locust (Gleditsia triacanthos), are examples of commercial available galactomannans.
  • Galactomannan is a polymer comprising mannose and galactose.
  • the resulting ratio of mannose to galactose in the isolated polysaccharide can vary according to the source of the galactomannan and the isolation procedure used, typically ranging between one and four.
  • the polysaccharide galactomannan is a polymer that can occur in a variety of size ranges.
  • galactomannan can have a molecular weight in the range of about 20,000 to about 600,000 D.
  • the galactomannan can range in size from about 90,000 to about 415,000 D.
  • the galactomannan can be dehvatized or hydrolyzed resulting in fragments of the native molecule for example in the range of 4,000 to 60,000.
  • the molecular weight of the derivatized or hydrolyzed polysaccharide is about 59 KD as determined by HPLC/RI-MALLS (high performance liquid chromatography/refractive index-multi-angle laser light scattering).
  • the molecular weight of the derivatized or hydrolyzed polysaccharide is between about 50 - 55 kD as determined by HPLC/RI-MALLS. In another embodiment, the molecular weight of the derivatized or hydrolyzed polysaccharide is between about 45 - 90 kD as determined by HPLC/RI-MALLS. In another embodiment, the molecular weight of the derivatized or hydrolyzed polysaccharide is between about 40 - 65 kD as determined by HPLC/RI-MALLS. In another embodiment, the molecular weight of the derivatized or hydrolyzed polysaccharide is between about 4- 40 kD as determined by HPLC/RI-MALLS.
  • a method for treating a disease comprising administering to the subject a mixture of one or more polysaccharides and an effective dose of one or more chemotherapeutic agents in a pharmaceutically acceptable formulation, wherein the polysaccharide is selected from a group consisting of galactomannans from various sources.
  • This pharmaceutical formulation is then administered to a patient in need thereof in any acceptable manner known in the art.
  • the components, i.e., the polysaccharide and pharmaceutical can be administered separately to a subject.
  • the polysaccharide component of this embodiment can be prepared using methods articulated herein. If for example hydrolyzed galactomannan is one of the components for the present embodiment, it can be extracted from Guar gum which itself is obtained from seeds of Cyamopsis tetragonoloba.
  • the polysaccharide can be stored as a powder or as an aqueous solution, for example, in physiological saline. Other acceptable physiological solutions can be used as well.
  • a pharmaceutical preparation can be formed using the prepared polysaccharide and one or more pharmaceutical agents.
  • the polysaccharide therapeutics' IV dose in humans can be, for example and without limitation, in the range of 0.5 to 12 mg/kg; 1 -7 mg/kg; 1 -20 mg/kg, which is respectively 20-490, 45-280, and 45-800 mg/m 2 ; and is usually optimized to the optimal therapeutic dose of the chemotherapeutic agent for best therapeutic performance.
  • mice For 5-FU the optimum dose (in mice) has been established at 30 to 150 mg/kg (90 to 450 mg/m 2 ) with best results at about 120 mg/kg (360 mg/m 2 ). For humans, it varies in clinics often between 200 to 600 mg/m 2 /day of 5-FU. However, it could vary with other chemotherapy.
  • the pharmaceutical carriers that can be used for the administration of the present composition are well known to those skilled in the art.
  • the dose intensity of the administration of the polysaccharide may also be varied.
  • dosage intensity of 5-FU administration regimens for example, there is no consensus on the optimum regimen of these drugs: practice ranges from the high toxicity Mayo Clinic schedule to the very low toxicity weekly QUASAR schedule.
  • 5-FU may be administered, for example and without limitation, in doses ranging from 50 mg/m 2 to 2000 mg/ m 2 .
  • a dose of 100 mg/m 2 is administered.
  • a dose of 150 mg/m 2 is administered.
  • a dose of 200 mg/m 2 is administered.
  • a dose of 250 mg/m 2 is administered.
  • a dose of 300 mg/m 2 is administered.
  • a dose of 350 mg/m 2 is administered. In another embodiment, a dose of 400 mg/m 2 is administered. In another embodiment, a dose of 450 mg/m 2 is administered. In another embodiment, a dose of 500 mg/m 2 is administered. In another embodiment, a dose of 550 mg/m 2 is administered. In another embodiment, a dose of 650 mg/m 2 is administered. In another embodiment, a dose of 700 mg/m 2 is administered. In another embodiment, a dose of 750 mg/m 2 is administered. In another embodiment, a dose of 800 mg/m 2 is administered. In another embodiment, a dose of 850 mg/m 2 is administered. In another embodiment, a dose of 900 mg/m 2 is administered.
  • a dose of 950 mg/m 2 is administered. In another embodiment, a dose of 1000 mg/m 2 is administered. In another embodiment, a dose of 1050 mg/m 2 is administered. In another embodiment, a dose of 1100 mg/m 2 is administered. In another embodiment, a dose of 1150 mg/m 2 is administered. In another embodiment, a dose of 1200 mg/m 2 is administered. In another embodiment, a dose of 1250 mg/m 2 is administered. In another embodiment, a dose of 1300 mg/m 2 is administered. In another embodiment, a dose of 1350 mg/m 2 is administered. In another embodiment, a dose of 1400 mg/m 2 is administered. In another embodiment, a dose of 1450 mg/m 2 is administered.
  • a dose of 1500 mg/m 2 is administered. In another embodiment, a dose of 1550 mg/m 2 is administered. In another embodiment, a dose of 1600 mg/m 2 is administered. In another embodiment, a dose of 1650 mg/m 2 is administered. In another embodiment, a dose of 1700 mg/m 2 is administered. In another embodiment, a dose of 1750 mg/m 2 is administered. In another embodiment, a dose of 1800 mg/m 2 is administered. In another embodiment, a dose of 1850 mg/m 2 is administered. In another embodiment, a dose of 1900 mg/m 2 is administered. In another embodiment, a dose of 1950 mg/m 2 is administered. In another embodiment, a dose of 2000 mg/m 2 is administered.
  • a dose of greater than 2000 mg/m 2 is administered.
  • many chemotherapeutic agents are administered in conjunction with one or more adjuvants; for example, 5-FU may be co- adminitered with leucovorin, which acts to disable the enzyme responsible for 5-FU clearance and thus prolongs the bioavailability of a given 5-FU dose.
  • the dose duration of the chemotherapeutic compound may also be varied. In one embodiment and without limitation, the entire dose is given as a single bolus. In another embodiment, the dose is given over about 30 minutes. In another embodiment, the dose is given over about 1 hour. In another embodiment, the dose is given over about 2 hours. In another embodiment, the dose is given over about 3 hours.
  • the dose is given over about 4 hours. In another embodiment, the dose is given over about 5 hours. In another embodiment, the dose is given over about 6 hours. In another embodiment, the dose is given over about 7 hours. In another embodiment, the dose is given over about 8 hours. In another embodiment, the dose is given over about 9 hours. In another embodiment, the dose is given over about 10 hours. In another embodiment, the dose is given over about 11 hours. In another embodiment, the dose is given over about 12 hours. In another embodiment, the dose is given over about 13 hours. In another embodiment, the dose is given over about 14 hours. In another embodiment, the dose is given over about 15 hours. In another embodiment, the dose is given over about 16 hours. In another embodiment, the dose is given over about 17 hours.
  • the dose is given over about 18 hours. In another embodiment, the dose is given over about 19 hours. In another embodiment, the dose is given over about 20 hours. In another embodiment, the dose is given over about 21 hours. In another embodiment, the dose is given over about 22 hours. In another embodiment, the dose is given over about 23 hours. In another embodiment, the dose is given relatively continuously over a number of hours.
  • the dose frequency of the chemotherapeutic compound may also be varied.
  • the dose is infused 1 out of every 28 days. In another embodiment, the dose is infused 2 out of every 28 days. In another embodiment, the dose is infused 3 out of every 28 days. In another embodiment, the dose is infused 4 out of every 28 days. In another embodiment, the dose is infused 5 out of every 28 days. In another embodiment, the dose is infused 6 out of every 28 days. In another embodiment, the dose is infused 7 out of every 28 days. In another embodiment, the dose is infused 8 out of every 28 days. In another embodiment, the dose is infused 9 out of every 28 days. In another embodiment, the dose is infused 10 out of every 28 days. In another embodiment, the dose is infused 11 out of every 28 days.
  • the dose is infused 12 out of every 28 days. In another embodiment, the dose is infused 13 out of every 28 days. In another embodiment, the dose is infused 14 out of every 28 days. In another embodiment, the dose is infused 15 out of every 28 days. In another embodiment, the dose is infused 16 out of every 28 days. In another embodiment, the dose is infused 17 out of every 28 days. In another embodiment, the dose is infused 18 out of every 28 days. In another embodiment, the dose is infused 19 out of every 28 days. In another embodiment, the dose is infused 20 out of every 28 days. In another embodiment, the dose is infused 21 out of every 28 days. In another embodiment, the dose is infused 22 out of every 28 days. In another embodiment, the dose is infused 23 out of every 28 days.
  • the dose is infused 24 out of every 28 days. In another embodiment, the dose is infused 25 out of every 28 days. In another embodiment, the dose is infused 26 out of every 28 days. In another embodiment, the dose is infused 27 out of every 28 days. In another embodiment, the dose is infused every day. In another embodiment, the dose is infused 3 out of every 7 days. In another embodiment, the dose is infused 3 out of every 9 days. In another embodiment, the dose is infused 3 out of every 10 days. In another embodiment, the dose is infused 3 out of every 11 days. In another embodiment, the dose is infused 4 out of every 11 days. In another embodiment, the dose is infused repeatedly on a daily basis over several days. In another embodiment, the dose is administred repeatedly on a majority of the days of the cycle.
  • chemotherapy is given more frequently than usual and in tinier doses, targeting the process by which a new blood supply is created feeding tumor growth, called angiogenesis, and /or a novel process by which tumors develop a highly patterned microcirculation that is independent of angiogenesis: in aggressive primary and metastatic melanomas, the tumor cells generate acellular microcirculatory channels composed of extracellular matrix and lined externally by tumor cells, in a process otherwise known as "metronomic" chemotherapy.
  • treatment is given at the highest possible initial dose so as to kill as many cancer cells as possible before such cells acquire resistance to a particular chemotherapeutic agent.
  • the dose duration of the chemotherapeutic compound may also be varied.
  • the chemotherapeutic compound is administered during a 30 minute infusion.
  • the chemotherapeutic compound is administered during a 1 hour infusion.
  • the chemotherapeutic compound is administered during a 2 hour infusion.
  • the chemotherapeutic compound is administered during a 3 hour infusion.
  • the chemotherapeutic compound is administered during a 4 hour infusion. In one embodiment, the chemotherapeutic compound is administered during a 5 hour infusion. In one embodiment, the chemotherapeutic compound is administered during a 6 hour infusion. In one embodiment, the chemotherapeutic compound is administered during a 7 hour infusion. In one embodiment, the chemotherapeutic compound is administered during an 8 hour infusion. In one embodiment, the chemotherapeutic compound is administered during a 9 hour infusion. In one embodiment, the chemotherapeutic compound is administered during a 10 hour infusion. In one embodiment, the chemotherapeutic compound is administered during an 11 hour infusion. In one embodiment, the chemotherapeutic compound is administered during a 12 hour infusion.
  • the chemotherapeutic compound is administered during a 13 hour infusion. In one embodiment, the chemotherapeutic compound is administered during a 14 hour infusion. In one embodiment, the chemotherapeutic compound is administered during a 15 hour infusion. In one embodiment, the chemotherapeutic compound is administered during a 16 hour infusion. In one embodiment, the chemotherapeutic compound is administered during a 17 hour infusion. In one embodiment, the chemotherapeutic compound is administered during an 18 hour infusion. In one embodiment, the chemotherapeutic compound is administered during a 19 hour infusion. In one embodiment, the chemotherapeutic compound is administered during a 20 hour infusion. In one embodiment, the chemotherapeutic compound is administered during a 21 hour infusion.
  • the chemotherapeutic compound is administered during a 22 hour infusion. In one embodiment, the chemotherapeutic compound is administered during a 23 hour infusion. In one embodiment, the chemotherapeutic compound is administered during a 24 hour infusion. In one embodiment, the chemotherapeutic compound is administered during a substantially continuous infusion.
  • the routes of administration include oral, intravenous, subcutaneous, intraperitoneal, intramuscular, and alike.
  • the route of administration can be any route sufficient to introduce the composition into a subject in a manner consistent with good medical practice. These various routes of administration are well known to those skilled in the art.
  • a mixture of one or more polysaccharides and chemotherapeutic agents are administered to a subject in need thereof, wherein the mixture comprises a sufficient amount of polysaccharide and chemotherapeutic agent in a ratio suitable for reducing the toxic side-effects in a subject while being effective against the particular pathology being addressed, wherein the polysaccharide is selected from a group consisting of galactomannans from different plant sources.
  • Arabinogalactan from Larix occidentalis
  • Rhamnogalacturonan from potato
  • Carrageenan from Eucheuma Seaweed
  • Locust Bean Gum from Ceratonia siliqua
  • the toxic side-effects being defined as those physiological effects (symptoms) realized by the subject resulting from the administration of the chemotherapeutic agent absent the polysaccharide.
  • a sufficient amount of polysaccharide is then understood herein to mean that amount required to minimize or mitigate toxic side-effects resulting from the administration of a pharmaceutical agent.
  • a pharmaceutical formulation in another embodiment, includes a mixture of one or more polysaccharides and an effective dose of a chemotherapeutic agent in a pharmaceutically acceptable formulation, wherein the polysaccharide is selected from group consisting of galactomannans from plant sources.
  • the mixture in the formulation contains an amount of one or more polysaccharides and a chemotherapeutic agent in a ratio suitable for effectively treating cancer as well as for reducing any toxic side-effect in the subject.
  • the mixture contains an amount of one or more polysaccharides and a chemotherapeutic agent in a ratio suitable for enhancing efficacy of chemotherapeutic effect for treating the cancer.
  • a method for treating cancer in a subject in need thereof that includes administrating an a mixture of one or more polysaccharides and an effective dose of a chemotherapeutic agent formulated so that the chemotherapeutic agent has enhanced therapeutic efficacy and reduced toxic effect upon the subject.
  • Any of the identified compounds of the present invention can be administered to a subject, including a human, by itself, or in pharmaceutical compositions where it is mixed with suitable carriers or excipients at doses therapeutically effective to prevent, treat or ameliorate a variety of disorders, including those characterized by that outlined herein.
  • a therapeutically effective dose further refers to that amount of the compound sufficient result in the prevention or amelioration of symptoms associated with such disorders.
  • Techniques for formulation and administration of the compounds of the instant invention may be found in Goodman and Gilman's The Pharmacological Basis of Therapeutics, Pergamon Press, latest edition. I00135J
  • the compounds of the present invention can be targeted to specific sites by direct injection into those sites. Compounds designed for use in the central nervous system should be able to cross the blood-brain barrier or be suitable for administration by localized injection.
  • compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent development of or alleviate the existing symptoms and underlying pathology of the subject being treated. Determination of the effective amounts is well within the capability of those skilled in the art.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC 50 (the dose where 50% of the cells show the desired effects) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans.
  • a therapeutically effective dose refers to that amount of the compound that results in the attenuation of symptoms or a prolongation of survival in a subject.
  • the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage can vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the exact formulation, route of administration and dosage can be chosen by the individual physician in view of a patient's condition. Dosage amount and interval can be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the desired effects.
  • co-administration of the polysaccharide of the instant invention with a chemotherapeutic index may favorably increase that chemotherapeutic's therapeutic index (in other words, decrease the LD 50 as a relative function of the ED 50 .
  • the effective local concentration of the drug may not be related to plasma concentration.
  • composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • compositions of the present invention can be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for use in accordance with the present invention thus can be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the agents of the invention can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barriers to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated.
  • Pharmaceutical preparations for oral use can be obtained solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP).
  • disintegrating agents can be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • filler such as lactose, binders such as starches, or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions can take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, thchlorofluoromethane, dichlorotetrafluoromethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, thchlorofluoromethane, dichlorotetrafluoromethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, thchlorofluoromethane, dichlorotetrafluoromethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, thchlorofluoromethane, dichlorotetrafluoromethane, carbon dioxide or other suitable gas.
  • the compounds can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection can be presented in unit dosage for, e.g., in ampoules or in multidose containers, with an added preservatives.
  • the compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds can be prepared as appropriate oily injection suspension.
  • Suitable lipohilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension can also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds can also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycehdes.
  • the compounds can also be formulated as a depot preparation.
  • Such long acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.
  • a pharmaceutical carrier for the hydrophobic compounds of the invention is a co-solvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • benzyl alcohol a non-polar surfactant
  • a water-miscible organic polymer a water-miscible organic polymer
  • an aqueous phase a co-solvent system
  • the proportions of a co-solvent system can be varied considerably without destroying its solubility and toxicity characteristics.
  • the identity of the co-solvent components can be varied.
  • other delivery systems for hydrophobic pharmaceutical compounds can be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds can be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known to those skilled in the art.
  • Sustained-release capsules can, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization can be employed.
  • compositions also can comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • compositions of the invention can be provided as salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts can be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents that are the corresponding free base forms.
  • Suitable routes of administration can, e.g., include oral, rectal, transmucosal, transdermal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
  • the compound in a targeted drug delivery system, e.g., in a liposome coated with an antibody specific for affected cells.
  • the liposomes will be targeted to and taken up selectively by the cells.
  • compositions can, if desired, be presented in a pack or dispenser device which can contain one or more unit dosage forms containing the active ingredient.
  • the pack can, e.g., comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device can be accompanied by instruction for administration.
  • Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Suitable conditions indicated on the label can include treatment of a disease such as described herein.
  • compositions are commonly added in typical drug formulations.
  • galactomannan has been used as a carrier for oral delivery of agents, which are in a non-liquid form. See U.S. Pat. Nos. 4,447,337; 5,128,143; and 6,063,402, the entire teaching of which is incorporated herein by reference.
  • compositions and methods of the present invention can be assayed by a variety of protocols.
  • the effects of reducing toxicity of a given chemotherapeutic treatment can be determined by methods routine to those skilled in the art including, but not limited to, both paper and pencil, and computer tests.
  • One of skill in the art can also directly measure mucositis progression or prevention in animal models.
  • cellular signaling molecules for example, but not limited to, nf-kB; TNF- ⁇ ; and IL-1 ⁇
  • upregulated and correlated with the onset and development of mucositis may be measured in an appropriate in vitro assay of human mucosa cells to which the compositions or methods described herein have been applied, as compared to a control experiment.
  • a measure of accumulation of cellular signaling molecules whose presence or increase may be correlated to the development of mucositis in vivo is an increase in levels circulating in the blood of a subject or in the in vitro medium, such levels may be measured by Enzyme-linked-lmmunoabsorbent- Assays (ELISAs), using a pair of antibodies, one for capture and the other for detection.
  • ELISAs Enzyme-linked-lmmunoabsorbent- Assays
  • the galactomannan oligomer of the present invention is a polysaccharide. In one aspect it has an average molecular weight of about 48,000 D. Shown below is the acceptable chemical nomenclature and structural formula for the galactomann of the present invention. Also shown is the stereochemical configuration.
  • IO0109J A backbone composed of linear (1 ,4)- ⁇ -D-Mannopyranosyl units, to which single . ⁇ -D-Galactopyranosyl is attached by (1.,6) linkage as illustrated below:
  • FIG. 2 shows the structure of the galactomannan polysaccharide of the present invention as determined by Nuclear Magnetic Resonance (NMR).
  • NMR Nuclear Magnetic Resonance
  • FIG. 3 shows the Fourier Transform 1 H-NMR spectrum of the guar gum galactomannan of the present invention.
  • the signal for the galactose anomehc protons appears at approximately 4.9 ppm (doublet).
  • the signal for the mannose anomehc protons appears at approximately 4.6 ppm (broad signal).
  • These signals are completely completely separated from those of the free monosaccharides; the galactose a proton at 5.1 ppm and (3 at 4.5 ppm, the mannose ⁇ at 4.8 ppm and ⁇ at 5.0 ppm).
  • the ratio of mannose to galactose units can be easily calculated for this working standard at 1.7.
  • FIG. 4 shows the 13C-NMR spectrum of the galactomannan of the present invention, showing detailed positions of the chemical shifts and their intensities. This study confirms the above chemical structure for the galactomannan.
  • FIG. 4 illustrate the following:
  • Mannose residues are attached to each other "head-to-tail", forming a backbone chain.
  • Man/Gal 1.4
  • FIG. 5 shows the quantitation and molecular weight of the galactomannan of the present invention by HPLC/RI-MALLS (high performance liquid chromatography/refractive index-multi-angle laser light scattering).
  • the principle of the GPC-MALLS method is based on the fact that light is more strongly scattered by large molecules than by small molecules.
  • the MALLS detector measures the degree of light scattering of a laser beam with detectors placed at fifteen different angles.
  • the output of the light scattering detector is proportional to the multiplication of the concentration and the molecular weight of macromolecules. Therefore, the shape of the light scattering peak is asymmetric. Further, it does not coincide with the Rl peak, because the Rl detector signal is proportional to the concentration only (see FIG. 5).
  • the molecular weight of the polymer eluting from the column can be calculated from the quotient of MALLS and Rl signals.
  • a graph of the molecular weight versus the elution volume is obtained and (average) molecular weights and molecular weight distributions can be calculated.
  • the present investigators have adapted the GPC/IR-MALLS technique to quantitate the drug substance and characterize the molecular weight average and distribution throughout the R&D and scale up phases for the invention.
  • the use of the MALLS analysis removes many factors interfering with MW estimation by the "Classical GPC".
  • GPC separations are based on differences in hydrodynamic volume instead of differences in molecular weight. Differences in molecular conformation, e.g. branching in dextrans, can strongly influence the hydrodynamic volume.
  • GPC elution of positively or negatively charged polymers can be non-ideal because of repulsion or attraction by the stationary phase.
  • the GPC-MALLS results are not affected by these chromatographical drawbacks, and absolute molecular weights are obtained.
  • FIG. 6 Shown in FIG. 6 is a flow chart of an example for a purification and manufacturing process for a galactomannan of the present invention.
  • High grade Guar gum is dissolved in warm water at 1 % at 45.degree. C. for 2 hr.
  • the pH is reduced to 2.2 with 1 M HCI and solution is heated to 95.degree. C. for 2 hours.
  • pH is adjust to 5.8 with 1 M NaOH.
  • the solution is then cool to 2O.degree. C. and filter with glass filter.
  • CuSO4/Na-K tartrate is added and the precipitate is collected on 200 mesh filter, wash with water solution and than washed in 5% HC1 in 960% EtOH. Then washed with 75% EtOH and twice with 96% EtOH.
  • Galactomannan from a readily available source (e.g., Guar gum), was selected for process optimization and manufacturing.
  • the soluble galactomannan oligomer was tested in-vivo (in animals) for both efficacy and overall reduction of toxicity.
  • the manufacturing process described above produces a product in the form of a highly soluble oligomer of Galactomannan (GM) from certified premium Guar Gum powder (from seeds of Cyamopsis tetragonoloba).
  • GM Galactomannan
  • the process is designed to generate a highly pure soluble and homogeneous oligomer with an average molecular weight in the range of about 48,000 daltons, and mannose to galactose ratio in the range of about 1 :7.
  • the process incorporates four major phases; controlled depolymerization to produce the desired galactomannan oligomer and three purification steps, removal of insoluble impurities, removal of water soluble impurities, removal of organic soluble impurities, and finally freeze drying to generate a pure and stable form of galactomannan powder.
  • Galactomannan can be packaged and delivered as a sterile concentrated solution in a single use vial, while bulk galactomannan can be produced and stored as powder.
  • the process described herein is for both bulk drug and final drug product.
  • the galactomannan drug product can be combined and administered together with a pharmaceutical like 5-fluorouracil to form the active ingredients of a pharmaceutical preparation.
  • the drug product contains normal saline for infusion (about 0.9 M sodium chloride in water) and has a pH of about 6.5.
  • the galactomannan of the present invention is a galactomannan derivative comprising exposed galactose moieties attached to a mannose backbone.
  • the compound is thought to interact with galactose-binding lectins or galectins that are generally located on cell surfaces.
  • Lectins are carbohydrate-binding proteins, typically located on the cell surface, which mediate various types of cellular interactions. It is generally accepted that lectins mediate many biological recognition events in plants and in animal tissues, and in tumor cell lines. Lectins play a role in cell-cell adhesion, and in the organization of the extracellular matrix.
  • lectins can act as receptors involved in selective intercellular adhesion and cell migration, recognition of circulating glycoproteins, and modulation of cell-cell and cell-matrix interactions.
  • Galectins are members of a family of ⁇ -galactoside-binding lectins with related amino acid sequences. Galectins and lectins have been the target of many experimental agents (monoclonal antibodies, simple sugars, and some polysaccharides, such as pectins) which allegedly interact with them on the cancer cell surface. The use of some of these agents has been shown to result in inhibition of tumor cell colony development.
  • the galactomannan of the invention can be distinctly identified and characterized, unlike many known polysaccharides. Its exposed galactose residues can readily interact with biological targets, such as lectins and galectins, thereby modulating signal transduction, cell-cell interactions or other functions. It thus can block the actions of galectins (or other receptors), thereby competing with their specific (or non-specific) ligands.
  • the galactomannan of the invention enhances the antineoplastic effects of 5-FU in animal models of colorectal cancer, although the precise mechanism has yet to be defined.
  • 5-fluorouracil has been the standard first-line agent used either alone, or in combination with, other agents in the treatment of metastatic colorectal cancer.
  • Preliminary animal studies with a variety of soluble galactomannan oligomers have shown promising response to the combination therapy of 5-FU and galactomannan with mannose to galactose ratio of 1 :7.
  • Example 3 Greater Decrease in Tumor Growth when Anti-Tumor Drug 5-FU Administered in the Presence of Galactomannan
  • the results of this study are summarized in FIG. 7. However, when the galactomannan of the invention at 120 mg/kg/day (360 mg/m2) combined with the above dose of 5-FU was administered, the tumor growth was further decreased for both mean tumor size and growth rate.
  • the time required to quadruple tumor weight increased from 23.5 days for 5-FU alone to 56.0 days for the galactomannan of the invention/5-FU combination versus 12.5 days for the control (untreated) animals.
  • the results of this study are summarized in FIG. 8. The both studies were conducted as follows.
  • the galactomannan from Cyamopsis tetragonoloba was administered intravenously (i.v.) once every four days for a total of three injections (q4d.times.3) at a doses of 120 mg/kg/dose (360 mg/m2/dose), or was co-administered as one injection with 5-FU on the same q4d.times.3 treatment schedule at doses of 120 mg/kg/dose of GM and 75 mg/kg/dose (225 mg/m2/dose) of 5-FU.
  • 5-FU alone was administered i.v. on the same q4d.times.3 treatment schedule at doses of 75 mg/kg/dose (225 mg/m2/dose).
  • 5-FU was formulated in saline fresh on each day of treatment at a concentration of 3.75 mg/mL, at pH 9.2.
  • GM powder was dissolved in the 5-FU solution to yield the GM concentration of 6 mg/mL and 5-FU concentration of 3.75 mg/mL. Both individual compounds and their mixture were administered according to exact body weight with injection volume being 0.2 mL/10 g body weight.
  • IOO100J There were a total of four groups of 10 animals each, s.c. -implanted with
  • COLO 205 human colon tumor xenografts The groups were treated on day 13 after tumor implantation on q4d.times.3 schedule as follows: 1 ) saline (NaCI, 0.9%), 2) 5-FU (75 mg/kg/dose), 3) GM (120 mg/kg/dose), 4) 5-FU (75 mg/kg/dose)+GM (120 mg/kg/dose).
  • a dosage of 75 mg/kg/dose of 5-FU (i.e., 225 mg/kg total dose over 8 days) was in excess of the maximum tolerated dosage and produced treatment-related deaths for three of ten mice within two weeks.
  • the treatment caused a delay in a median to quadrupling of tumor volume from 12.5 to 23.7 days. Again, there was no tumor regression after 56 days of the study; however, two relatively small tumors were observed that grew from 75 mm3 each at initiation of treatment to 126 mm3 and 567 mm3 by the end of the study. Median tumor volume increased from 101 mm3 at treatment initiation to 2254 mm3 after 56 days of the study. Mean survival time shifted from 14.2 days (control, untreated animals) to 23.7 days.
  • IOO190J GM at a dosage of 120 mg/kg/dose administered alone on a q4d.times.3 schedule, was well tolerated. No deaths or body weight loss was observed.
  • the median to quadrupling of tumor volume equaled 15.5 days, that is slightly longer than the value for untreated animals (12:5 days). There was no tumor regression after 56 days of study, however, two relatively small tumors (compared to median tumor volume) were observed that grew from 100 mm3 and 126 mm3, at initiation of treatment, to 270 mm3 and 729 m3, respectively, by the end of the study.
  • Median tumor volume increased from 100 mm3 at treatment initiation to 1813 mm3 after 56 days of the study, that is noticeably less compared to 2058 mm3 for untreated animals, and 2254 mm3 for 5-FU (75 mg/kg/dose)-treated animals.
  • Mean survival time was prolonged from 14.2 days (control, untreated animals) to 19.2 days.
  • a second study using COLO 205 tumors in mice evaluated the compatibility of the investigator's galactomannan/5-FU with Leucovohn (given orally, 25 mg/kg/dose) and dose escalation of galactomanna from 6 to 600 mg/kg/day (or 18 to 1800 mg/m2).
  • the combination of 5-FU+galactomannan (at 48 mg/kg and 120 mg/kg, respectively) had the best anti-tumor response for both mean tumor size and time required to quadruple tumor weight, being superior to the 5-FU alone or 5-FU+Leucovorin combination.
  • tetragonoloba was administered intravenously (i.v.) once every four days for a total of four injections (q4d.times.4) at a dosage of 120 mg/kg/dose (360 mg/m2/dose) or was co-administered as one injection with 5-FU on the same q4d.times.4 treatment schedule at a dosage of 6, 30, 120, and 600 mg/kg/dose (18, 90, 360, and 1800 mg/m2/dose, respectively) of GM and 48 mg/kg/dose (144 mg/m2/dose) dose of 5-FU.
  • 5-FU alone was administered i.v. on the same q4d.times.4 treatment schedule at dosages of 48 mg/kg/dose.
  • 5-FU was formulated in saline fresh on each day of treatment at a concentration of 4.8 mg/mL, at pH 9.2.
  • GM powder was dissolved in the 5-FU solution to yield the GM concentration of 0.6, 3.0, 12, and 60 mg/mL and 5-FU concentration of 4.8 mg/mL.
  • Leucovorin powder (clinical formulation, Leucovorin calcium for injection) was reconstituted with water for injection to yield a concentration of 10 mg/mL. On each day of treatment the stock solution was diluted with water for injection to yield a concentration of 2.5 mg/mL.
  • 5-FU and GM and their mixture with each other and leucovorin were administered by exact body weight with injection or p.o. volume being 0.1 mL/10 g body weight.
  • mice Two more combination-treatment groups were also included in the study.
  • One group of mice was treated with 5-FU (48 mg/kg/dose, i.v., q4d.times.4), followed by oral gavage (p.o.) with leucovorin, administered two hours after 5-FU at a dosage of 25 mg/kg/dose.
  • Another two groups of mice were treated with 5-FU in a combination with the galactomannan (48 mg/kg/dose and 120 mg/kg/dose, respectively, i.v., q4d.times.4), followed by p.o. leucovorin treatment, administered at a dosage of 25 mg/kg/dose two hours after 5-FU plus the galactomannan.
  • a dosage of 48 mg/kg/dose of 5-FU (that is, 192 mg/kg total dose over 12 days) was well tolerated and produced some growth delay in the median to quadrupling of tumor volume, increasing it from 7.2 to 8.7 days.
  • Two tumors in the group of 10 mice were significantly (three times or more) smaller, compared with the median tumor size, after 13 days of treatment, growing from 100 and 163 mm3 at initiation of treatment to 270 mm3 and 138 mm3, respectively, by the end of the study.
  • Median tumor volume increased from 172 mm3 at treatment initiation to 800 mm3 after 13 days of the study, less than the control value 1288 mm3.
  • GM at a dosage of 120 mg/kg/dose administered alone on a q4d.times.4 schedule did not delay growth (the median to quadrupling of tumor volume equaled 6.9 days, compared to that of 7.2 days in the control group). No tumor regression occurred after 13 days of study, and no relatively small tumors (compared to median tumor volume) were observed. Median tumor volume increased from 157 mm3 at treatment initiation to 1152 mm3, a value essentially equal to that of the untreated animals (1288 mm3).
  • 5-FU and the 120 mg/kg/dose galactomannan which resulted in a median tumor volume of 540 mnn3 at day 13, the day after the final day of treatment, compared with that of 800 mm3 for 5-FU treatment alone. Also, median days to quadrupling of tumor volume was almost twice as much for the 5-FU+GM 120 mg/kg/dose than for the 5-FU alone.
  • the GM was co-administered i.v. via tail vein injection once every four days for a total of four injections (q4d.times.4) at a doses of 30 and 120 mg/kg/dose as one injection with 5-FU (48 mg/kg/dose), followed by oral gavage (p.o.) of leucovohn, administered two hours after the injection, at a dose of 25 mg/kg/dose on the same q4d.times.4 schedule.
  • GM or 5-FU were administered also on the same q4d.times.4 treatment schedule at doses of 120 mg/kg/dose (GM) or 48 mg/kg/dose (5-FU), followed by 25 mg/kg of leucovohn, administered two hours later.
  • GM was formulated in 0.9% sterile saline fresh on each day of treatment at a concentration of 12 mg/mL.
  • Leucovorin powder (clinical formulation, Leucovohn calcium for injection) was reconstituted with 0.9% sterile saline to yield a concentration of 2.5 mg/mL.
  • 5-FU was formulated in 0.9% sterile saline fresh on each day of treatment at a concentration of 4.80 mg/mL, at pH 9.2.
  • GM powder and 5-FU were dissolved in 0.9% fresh saline to yield the GM concentration of 3.0 mg/mL or 12 mg/mL, and 5-FU concentration of 4.80 mg/mL.
  • the groups were treated on day 7 after tumor implantation on q4d.times.4 schedule as follows: 1 ) Saline (NaCI, 0.9%), 2) GM (120 mg/kg/dose)+leucovohn (p.o., 25 mg/kg/dose), 3) 5-FU (48 mg/kg/dose)+leucovohn (p.o., 25 mg/kg/dose), 4) 5-FU (48 mg/kg/dose)+GM (30 mg/kg/dose)+leucovohn (p.o., 25 mg/kg/dose), and 5) 5-FU (48 mg/kg/dose)+GM (120 mg/kg/dose)+leucovohn (p.o., 25 mg/kg/dose).
  • control (untreated) tumors grew well in all mice, with a median of 13.3 days for quadrupling of tumor volume.
  • the treatment caused a delay of two days for the quadrupling of tumor volume (from 13.3 to 15.3 days).
  • 3H- galactomannan elimination from plasma, kidneys, lungs and tumor in the various groups was rapid, an average of approximately 50% of the one-hour radioactivity was detected at six hours except in tumor-bearing mice, where the radioactivity in tumor samples from mice treated with 6 or 60 mg/kg of 3H-galactomannan with or without 5-FU averaged approximately 72% remaining after six hours. Elimination of 3H-galactomannan from the liver was more gradual than in other tissues, and on average, more than 50% of the radioactivity detected at one hour after injection was still present at 24 hours. [001191 Male NCr-nu athymic nude mice (Charles Rivers Laboratories, Raleigh, N. C.) were acclimated and housed as described above.
  • the first set of animals were non-tumored mice.
  • the second set of 18 mice were tumored as follows. Thirty to forty mg fragments from an in vivo passage of COLO 205 human colon tumor were implanted subcutaneously (s.c.) in mice as described above, and allowed to grow. Tumors were allowed to reach 245-392 mg in weight before the start of treatment. A sufficient number of mice were implanted so that tumors in a weight range as narrow as possible were selected for the trial on the day of treatment initiation. Those animals selected with tumors in the proper size range were divided into the various treatment groups.
  • Tritiation of GM from G. t ⁇ acanthos was performed as follows. 12.8 mg of GM was dissolved in 2.0 mL of water and exposed to 25 Curies of tritium gas in the presence of Pd/BaSO4 catalyst (120 mg, totally insoluble in water). After one hour the gas supply was removed, the catalyst was filtered away, and the aqueous solution of GM was evaporated to dryness repeatedly (four-fold, adding water), until no labile tritium was found. Total yield of the labeled GM was 3.8 mCi, specific radioactivity was 300 .mu.Ci/mg.
  • mice All 36 mice, divided into 18 groups, were given a single intravenous injection of cold or tritiated GM (either 6 or 60 mg/kg) or of a combination of GM (60 mg/kg, cold or tritiated) and 5-FU (114 mg/kg) on the same day.
  • Non-labeled GM was formulated in saline, and tritiated GM was added to the solution so that each animal received 10 .mu.Ci of radioactivity.
  • 5-FU was dissolved in the solution containing GM (at a concentration of 6 mg/mL). All dosing solutions (100 .mu.L each) were counted in duplicate.
  • mice per group were bled at 1 , 6, and 24 hrs after injection, and plasma was prepared. Animals were then sacrificed; livers, kidneys, lungs, and tumors (from tumored animals) were collected, weighed and flash-frozen for further analysis.
  • livers were dissolved in 10 ml_ of Soluene 350 (Packard Instruments, Downers Grove, III.) and incubated first for 4 hrs at 5O.degree. C, and at room temperature, until tissues were solubilized. One millilter of the resulting solution was counted in a scintillation counter as a single sample. Based on tissue weight and the sample volume, the number of .mu.Ci of tritiated GM per gram of tissue was calculated.
  • Kidneys were treated in the same manner, but dissolved in 2 ml_ of Soluene. After the tissue was solubilized at room temperature, 15 ml_ of Safety Solve scintillation fluid (Research Products International, Mount Prospect, III.) was added and samples were incubated overnight. Five ml_ of the resulting solution were diluted in 15 ml_ of Safety Solve and counted in a scintillation counter as a single sample. Lungs were treated in the same manner but dissolved in 1 ml_ of Soluene. Plasma samples (50 .mu.L each) were placed direct into Safety Solve and counted as a single sample.
  • tumors were dissolved in one or two milliliters of Soluene and incubated for three days at 500C to solubilize. Fifteen milliliters of Safety Solve were then added and samples were incubated overnight at room temperature. Two milliliters of water were then added and samples were counted in a scintillation counter as a single sample. [001261 Male NCr-nu athymic nude mice were divided into two principal sets, 18 animals in each. The first set of animals were non-tumored mice. The second set were tumored as follows.
  • mice were given a single intravenous injection of cold or tritiated GM (either 6 or 60 mg/kg) or of a combination of GM (60 mg/kg, cold or tritiated) and 5-FU (114 mg/kg) on the same day. Thtiation of GM (with the resulting specific activity of 300 .mu.Ci/mg) is described above.
  • Cold GM was formulated, in saline, and tritiated GM was added to the solution so that each animal received 10 .mu.Ci of radioactivity.
  • 5-FU was dissolved in the solution containing GM (at a concentration of 6 mg/mL).
  • mice per group were bled at 1 , 6, and 24 hrs after injection, and plasma was prepared. Animals were then sacrificed; livers, kidneys, lungs, and tumors (from tumored animals) were collected, weighed and flash-frozen for further analysis, as described above.
  • 5-FU and GM work in a synergism when delivered into the tumor.
  • 5-FU and GM work as antagonists (apparently, compete with each other for the same binding sites in the liver) when delivered into the liver.
  • Examples 7-9 Acute Toxicology Studies [001361 Acute toxicology studies of the galactomannan of the present invention were performed in mice, rats and dogs and subchronic toxicology studies were performed in rats and dogs. The following is a summary of the findings of these studies:
  • the galactomannan of the invention has minimal histological effects with only 1/30 rats injected with 48 mg/kg dose of the GMP galactomannan clinical solution having granulomatous inflammation. None of the 30 rats injected with the 96 mg/kg dose of the GMP galactomannan clinical solution were affected. It was concluded that galactomannan clinical solutions, up to a dose of 15 mg/kg (555 mg/m2; 9 mg/mL), is safe for human use and poses no undue risk to health.
  • Cytokines and chemokines have been shown, in in vitro studies, to promote cancer cells susceptibility to destruction by the immune response. (Cytokines and chemokines are well known to those skilled in the art and a list of such can be found in any modem biology/medicine text). In few cases it has been shown that cytokines directly inhibit tumor cell growth. Cytokines function as messengers of the immune system by regulating the intensity and duration of the immune response by exerting a variety of effects on lymphocytes and other immune cells. Cytokines also control cellular proliferation and differentiation. In the USA, the Food and Drug Administration (FDA) has already approved the use of two cytokines-IL-2 and ⁇ -interferon for treatment of cancer.
  • FDA Food and Drug Administration
  • IL-2 has biological activity against renal cell disease, melanoma, lymphoma, and leukemia. Interferon has been effective against these cancers as well as against Kaposi's sarcoma, chronic myelogenous leukemia, and hairy cell leukemia.
  • a Phase I dose-escalating safety clinical trial was initiated. Patients that were enrolled in the study were those who had different types of solid tumors, and who had failed standard, approved treatments. This study evaluated the tolerability of six rising doses of DAVANAT® alone ranging from 30 to 280 mg/m2 and then in combination with 5-FU (500 mg/m2) over 2 cycles of therapy with 30 minute dose duration. A total of 40 patients enrolled in the study. [00255] A Phase Il safety and efficacy clinical trial was initiated.
  • Patients that were enrolled in the study were those who had a histologically proven adenocarcinoma of the colon or rectum, and had documentation of locally advanced or metastatic colorectal cancer not amenable to curative surgery or radiotherapy, and had one or more measurable lesion(s) according to RESIST (Response Evaluation Criteria in Solid Tumors) criteria. Furthermore, eligible subjects were those who had unresectable, locally advanced or metastatic colorectal cancer that progressed during or after receiving treatment with at least two lines of therapy, which collectively must have included at a minimum all of the following agents: 5-FU or capecitibine, ihnotecan, and oxaliplatin. Simply put, this Phase Il experimental study using DAVANAT® ® was their last resort. All preceding treatments with approved therapies failed in their cases.
  • a standard dose of 280 mg/m 2 DAVANAT® ® and 500 mg/m 2 5-FU was given in monthly cycles for at least two cycles, or until their disease progressed.
  • DAVANAT® ® and 5-FU were treated in the aforementioned Phase I (40 patients) and Phase Il trials.
  • Phase I Phase I
  • Phase II Phase II
  • 5FU 5-FU
  • 60 patients were treated in the aforementioned Phase I (40 patients) and Phase Il trials.
  • Phase Il trial which was a first line study for patients diagnosed with Cholangiocarcinoma
  • 20 patients were treated at three US sites.
  • Phase Il trial which was a first line study for patients diagnosed with Colorectal Cancer, 10 patients were treated at four sites.
  • 7 patients have been sponsored for treatment in compassionate use studies. All the Phase I, Phase II, and compassionate use studies were conducted according to standard regimens.
  • 280 mg/m 2 of DAVANAT® ® and 500 mg/m 2 of 5-FU were administered i.v. for a dose duration of 30 min, and the procedure was repeated four days in a row.
  • Adverse effects were all reported to the FDA, and included anemia, dehydration, gastrointestinal disorders (nausea, diarrhoea, vomiting, abdominal pain, constipations, abdominal distention, dyspepsia, flatulence), general disorders (fatigue, pyrexia, asthenia), infections and infestations (urinary tract infection, rhinitis), weight decrease, anorexia, back pain, arthralgia, nervous system disorders (headache, dizziness, neuropathy), respiratory, thoracic, and mediastinal disorders (dyspnoea, cough), skin and subcutaneous tissue disorders (rash, palmar-plantar erythrodysaesthesia syndrome), as well as others.
  • Serious adverse events included anemia, dehydration, hemorrhage, severe abdominal pain, constipation, nausea, and vomiting. Only two of the events, anemia and dehydration, were classified as "possibly related" to the treatment. Mucositis was not among them. In fact, only three subjects out of 40 (7.5%) had a mild form of mucositis: subject 02-009, grade 2, "severity - mild" .
  • chemotherapeutic agents will be used at its full effective dose, regardless of the relative closeness of that dose to the LD 50 of that chemotherapeutic agent.
  • the amount of 5-FU utilized will be in excess of 500 mg/m 2 .
  • the amount of 5-FU utilized will be in excess of 600 mg/m 2 . Results are expected to show that the use of a polysaccharide of the instant invention in conjunction with a high dose of a chemotherapeutic treatment will yield less incidence or severity of mucositis.
  • chemotherapeutic agents are used a fraction of its effective dose, .
  • the dose of 5-FU utilized per dose will be less than of 500 mg/m 2 .
  • the dose of 5-FU utilized per dose will be less than 200 mg/m 2 .
  • Results are expected to show that the use of a polysaccharide of the instant invention in conjunction with a metronomic dosing of a chemotherapeutic treatment will yield less incidence and/or severity of mucositis than might be expected from such chronic administration of chemotherapy.
  • Example 15 Prospective Use Of An In Vitro Assay To Determine Relative Mucositis Inhibition
  • experiments will be conducted so as to ascertain the ability to utilize an in vitro assay so as to demonstrate the ability of the polysaccharide of the instant invention to modulate incidence and/or severity of mucositis.
  • Results are expected to show that the use of a polysaccharide of the instant invention in conjunction with a metronomic dosing of a chemotherapeutic treatment will yield less incidence or severity of mucositis.
  • HPV16/E6E7-immortalized human vaginal (Vk2/E6E7), ectocervical (Ect1/E6E7), and endocervical (End1/E6E7) epithelial cell lines will be grown until confluence in 96-well tissue-culture plates and incubated with two-fold dilutions of chemotherapeutic agents or treated with various radiation therapy regimens, alone or in combination with administration of a polysaccharide of the instant invention and maintained in such medium for 30 min, 6 and 24 h.
  • the 24 h exposure experiments may be repeated with 3rd and 5th passage of primary human ectocervical epithelial cells (CrEC-Ec) obtained from Clonetics (BioWhitaker Inc., San Diego, CA).
  • the nonradioactive Cell Titer 96 MTT assay (Promega, Madison, Wl) may be performed to assess viability based on mitochondrial enzyme function.
  • Cytokine levels may be measured in cell culture supernatant by ELISA using commercially available human cytokine kits (R&D system, Minneapolis, MN). For these experiments, immortalized and primary epithelial cell cultures may be grown until confluence in 96 or 24 well plates and treated for 24 h in duplicates or triplicates with respectively 0.1 ml or 1 ml compound supplemented medium/well. MTT assay may be run on each plate after removal of culture supernatants to adjust cytokine concentrations by percentage of viable cells.
  • IL-1 ⁇ , IL-6 and TNF- ⁇ may be quantified using cross-reactive kits (human IL-1 ⁇ from Genzyme, Cambridge, MA; IL-6 from R&D Systems, Minneapolis, MN). Optical densities may be read using a Multilabel Microplate Counter Victor 2 (Perkin Elmer Life Sciences, Boston, MA) and WorkOut Version 1.5 Wallac Software (DAZDAQ Ltd., Brighton, UK). Cytokine concentrations may be calculated by quadratic regression analysis based on logarithmically transformed optical densities. Interference of compounds with cytokine ELISA may be ruled out by spiking various compound concentrations with cytokine standards provided by manufacturer.

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  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

L'invention porte sur des procédés et sur des compositions qui concernent l'administration d'un agent toxique à un sujet dans une formulation dans laquelle la toxicité est sensiblement réduite, conduisant ainsi à une incidence diminuée ou une gravité diminuée d'une mucosité induite par chimiothérapie, ainsi qu'à la capacité d'administrer une intensité de dose accrue d'agents chimiothérapeutiques pour traiter des tumeurs seuls ou en combinaison avec d'autres thérapies ou des thérapies complémentaires. Pris ensemble, ces procédés constituent une nouvelle arme thérapeutique contre les maladies réfractaires et fournissent aux professionnels médicaux des options améliorées pour administrer à la fois des régimes de traitement du cancer intensifs et métronomes (par exemple, à faible intensité, prolongée). La formulation comprend un composant polysaccharide et une dose efficace d'un agent chimiothérapeutique, l'administration du traitement conduisant à une réduction de la toxicité de l'agent chimiothérapeutique.
PCT/US2009/053115 2009-08-07 2009-08-07 Procédés pour réduire l'incidence d'une mucosité induite par chimiothérapie Ceased WO2011016811A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030039656A1 (en) * 2001-08-03 2003-02-27 Jeffrey Tarrand Modified reoviral therapy
US20030064957A1 (en) * 2001-03-27 2003-04-03 Anatole Klyosov Co-administration of a polysaccharide with a chemotherapeutic agent for the treatment of cancer
US20040038935A1 (en) * 2001-03-27 2004-02-26 Pro-Pharmaceuticals, Inc. Delivery of a therapeutic agent in a formulation for reduced toxicity
US20080085871A1 (en) * 2006-02-23 2008-04-10 Tam Joemy C Novel polysaccharide pro-drug 5-fluorouracil (5-FU) with enhanced target specificity for colorectal cancer and its preparation methods
US20080107622A1 (en) * 2006-05-16 2008-05-08 David Platt Galactose-pronged polysaccharides in a formulation for antifibrotic therapies

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030064957A1 (en) * 2001-03-27 2003-04-03 Anatole Klyosov Co-administration of a polysaccharide with a chemotherapeutic agent for the treatment of cancer
US20040038935A1 (en) * 2001-03-27 2004-02-26 Pro-Pharmaceuticals, Inc. Delivery of a therapeutic agent in a formulation for reduced toxicity
US20030039656A1 (en) * 2001-08-03 2003-02-27 Jeffrey Tarrand Modified reoviral therapy
US20080085871A1 (en) * 2006-02-23 2008-04-10 Tam Joemy C Novel polysaccharide pro-drug 5-fluorouracil (5-FU) with enhanced target specificity for colorectal cancer and its preparation methods
US20080107622A1 (en) * 2006-05-16 2008-05-08 David Platt Galactose-pronged polysaccharides in a formulation for antifibrotic therapies

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