[go: up one dir, main page]

EP2707008A1 - Utilisation d'arsenic dans la protection contre une thérapie contre le cancer - Google Patents

Utilisation d'arsenic dans la protection contre une thérapie contre le cancer

Info

Publication number
EP2707008A1
EP2707008A1 EP12781877.1A EP12781877A EP2707008A1 EP 2707008 A1 EP2707008 A1 EP 2707008A1 EP 12781877 A EP12781877 A EP 12781877A EP 2707008 A1 EP2707008 A1 EP 2707008A1
Authority
EP
European Patent Office
Prior art keywords
arsenic
compounds
day
treatment
human subject
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12781877.1A
Other languages
German (de)
English (en)
Other versions
EP2707008A4 (fr
Inventor
Zhi-Min Yuan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Texas System
University of Texas at Austin
Original Assignee
University of Texas System
University of Texas at Austin
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US13/110,737 external-priority patent/US8834938B2/en
Application filed by University of Texas System, University of Texas at Austin filed Critical University of Texas System
Publication of EP2707008A1 publication Critical patent/EP2707008A1/fr
Publication of EP2707008A4 publication Critical patent/EP2707008A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/36—Arsenic; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • TITLE USE OF ARSENIC FOR CANCER THERAPY PROTECTION
  • the present invention relates generally to the treatment of cancer.
  • the invention more particularly is directed to the amelioration of side effects caused by chemo and radiation cancer therapies.
  • Cancers are a leading cause of death in animals and humans.
  • a combination of chemotherapy and radiation therapy along with surgery has become a standard approach for treatment of cancer patients in the curative as well as in the palliative setting.
  • the present invention relates to a method of inhibiting, preventing, or reducing damage to non-cancerous cells in a human subject during radiation treatment of cancer cells in the human subject including administering to the human subject, in need of a radiation treatment for the treatment of cancer, one or more compounds of arsenic in a protective amount of from about 1 ⁇ g/kg/day to about 125 ⁇ g/kg/day. In some embodiments, a protective amount of one or more compounds of arsenic is from about 31 ⁇ g/kg/day to about 125 ⁇ g/kg/day.
  • Radiation is administered to the human subject subsequent to administration of one or more compounds of arsenic.
  • arsenic trioxide is administered to the human subject prior to administering the radiation treatment to the human subject.
  • one or more compounds of arsenic are administered to the human subject at least one day prior to administration of the radiation treatment to the human subject. In some embodiments, one or more compounds of arsenic are administered to the human subject daily for at least three days prior to administration of radiation to the human subject.
  • the present invention relates to a method of inhibiting, preventing, or reducing damage to non-cancerous cells in a human subject during chemotherapeutic treatment of cancer cells in the human subject including administering to the human subject, in need of a chemotherapeutic treatment, one or more compounds of arsenic in a protective amount of from about 1 ⁇ g/kg/day to about 125 ⁇ g/kg/day.
  • a protective amount of one or more compounds of arsenic is from about 31 ⁇ g/kg/day to about 125 ⁇ g/kg/day.
  • One or more chemotherapeutic agents are administered to the human subject subsequent to administration of one or more compounds of arsenic.
  • arsenic trioxide is administered to the human subject prior to administering the radiation treatment to the human subject.
  • one or more compounds of arsenic are administered to the human subject at least one day prior to administration of the one or more chemotherapeutic agents to the human subject.
  • one or more compounds of arsenic are administered to the human subject daily for at least three days prior to administration of one or more chemotherapeutic agents to the human subject.
  • the present invention relates to a method of inhibiting, preventing, or reducing side effects in a human subject during chemotherapeutic or radiation treatment of cancer cells in the human subject includes administering to the human subject, in need of a chemotherapeutic or radiation treatment for the treatment of cancer, one or more compounds of arsenic.
  • One or more chemotherapeutic agents or radiation is administered to the human subject subsequent to administration of one or more compounds of arsenic.
  • the one or more compounds of arsenic are administered in an amount sufficient to inhibit, prevent, or reduce side effects caused by the chemotherapeutic or radiation treatment in the human subject when the
  • chemotherapeutic agent is administered to the human subject.
  • the one or more compounds of arsenic are administered in a protective amount of from about 1 ⁇ g/kg/day to about 125 ⁇ g/kg/day.
  • Side effects that may be inhibited, prevented, or reduced include side effects associated with the gastrointestinal system; side effects associated with low red blood cell count; side effects associated with low white blood cell count; side effects associated with low blood platelet count; side effects associated with depletion of bone marrow cells; side effects associated with cardiotoxicity; and side effects associated with loss of hair.
  • FIG. 1 depicts the effect of arsenic pretreatment on male mice injected with human lung carcinoma cells under various treatment conditions
  • FIG. 2 depicts the effect of arsenic pretreatment on female mice injected with human lung carcinoma cells under various treatment conditions
  • FIG. 3 depicts the effect of arsenic pretreatment on female mice injected with human breast carcinoma cells under various treatment conditions
  • FIG. 4 depicts the effect of arsenic pretreatment on mice injected with human colon carcinoma cells under various treatment conditions
  • FIG. 5 depicts the effect of arsenic pretreatment on WT mice vs. p53 R172P knock in mice under x-ray irradiation
  • FIG. 6 depicts the effect of arsenic on the white blood cell count and small intestine damage after radiation treatment.
  • administering when used in the context of providing a composition to a subject generally refers to providing to the subject one or more pharmaceutical, “over-the-counter” (OTC) or nutraceutical compositions in combination with an appropriate delivery vehicle by any means such that the administered compound achieves one or more of the intended biological effects for which the compound was
  • a composition may be administered parenteral, subcutaneous, intravenous, intracoronary, rectal, intramuscular, intra-peritoneal, transdermal, or buccal routes of delivery. Alternatively, or concurrently, administration may be by the oral route.
  • the dosage administered will be dependent upon the age, health, weight, and/or disease state of the recipient, kind of concurrent treatment, if any, frequency of treatment, and/or the nature of the effect desired.
  • the dosage of pharmacologically active compound that is administered will be dependent upon multiple factors, such as the age, health, weight, and/or disease state of the recipient, concurrent treatments, if any, the frequency of treatment, and/or the nature and magnitude of the biological effect that is desired.
  • cancer as used herein is defined as a tissue of uncontrolled growth or proliferation of cells, such as a tumor.
  • the tumor leads to local invasion and metastasis.
  • chemotherapeutic agent as used herein is defined as a drug, toxin, compound, composition or biological entity which is used as treatment for cancer.
  • cytotoxic agent as used herein is defined as a drug, toxin, compound, composition or biological entity which is used to kill a cell.
  • the cell is a cancer cell.
  • DNA-damaging agent as used herein is a drug, toxin, compound, composition or biological entity which damages nucleic acid.
  • the damage may be of any kind to the nucleic acid, for example, to break one or both strands of a DNA double helix molecule or to cause mutation of one or more nucleotides.
  • drug as used herein is defined as a medicament or medicine which is used for the therapeutic treatment of a medical condition or disease. The drug may be used in combination with another drug or type of therapy and in an embodiment is effective for the treatment of cancer.
  • pharmaceutically or pharmacologically acceptable refers to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • phrases such as "pharmaceutical composition,” “pharmaceutical formulation,” “pharmaceutical preparation,” or the like generally refer to formulations that are adapted to deliver a prescribed dosage of one or more pharmacologically active compounds to a cell, a group of cells, an organ or tissue, an animal or a human. Methods of incorporating pharmacologically active compounds into pharmaceutical preparations are widely known in the art. The determination of an appropriate prescribed dosage of a pharmacologically active compound to include in a pharmaceutical composition in order to achieve a desired biological outcome is within the skill level of an ordinary practitioner of the art.
  • a pharmaceutical composition may be provided as sustained-release or timed-release formulations.
  • Such formulations may release a bolus of a compound from the formulation at a desired time, or may ensure a relatively constant amount of the compound present in the dosage is released over a given period of time.
  • Terms such as “sustained release,” “controlled release,” or “timed release” and the like are widely used in the pharmaceutical arts and are readily understood by a practitioner of ordinary skill in the art.
  • Pharmaceutical preparations may be prepared as solids, semi-solids, gels, hydrogels, liquids, solutions, suspensions, emulsions, aerosols, powders, or combinations thereof.
  • a pharmaceutical preparation may be one or more carriers, preservatives, flavorings, excipients, coatings, stabilizers, binders, solvents and/or auxiliaries that are, typically, pharmacologically inert. It will be readily appreciated by an ordinary practitioner of the art that, included within the meaning of the term are pharmaceutically acceptable salts of compounds. It will further be appreciated by an ordinary practitioner of the art that the term also encompasses those pharmaceutical compositions that contain an admixture of two or more pharmacologically active compounds, such compounds being administered, for example, as a combination therapy.
  • the terms "subject” generally refers to a mammal, and in particular to a human.
  • the subject who receives the arsenic-containing compound is one who is scheduled for chemotherapy or radiotherapy.
  • the subject can be a human patient or an animal who has been diagnosed with a cancer for which chemotherapy or radiation therapy is considered to be an advantageous treatment.
  • to treat is defined as the practice of applying a treatment for a medical condition or disease.
  • the treatment need not provide a complete cure and is considered effective if at least one symptom is improved upon or eradicated. Furthermore, the treatment need not provide a permanent improvement of the disease state or medical condition, although this is preferable.
  • pharmacologically active composition generally refers to a judgment made by an appropriate healthcare provider that an individual or animal requires or will benefit from a specified treatment or medical intervention. Such judgments may be made based on a variety of factors that are in the realm of expertise of healthcare providers, but include knowledge that the individual or animal is ill, will be ill, or is at risk of becoming ill, as the result of a condition that may be ameliorated or treated with the specified medical intervention.
  • Side effects associated with chemotherapy or radiation therapy include, but are not limited to: abdominal pain, acid indigestion, acid reflux, alopecia (hair loss), anemia, poor appetite, early satiety, arthralgias (joint pain), asthenia, ataxia, azotemia, hepatotoxicity, bronchitis, constipation, cystitis, deep vein thrombosis (DVT), dyspepsia, dyspnea, edema, esophagitis, granulocytopenia, gynecomastia, hematoma, hemorrhagic cystitis, leukopenia, mucositis, myalgias, myocarditis, nephrotoxicity, neutropenia, pancytopenia, pericarditis, pharyngitis, stomatitis, thrombocytopenia, xerostomia, dry skin, flushing, hyperpigmentation, nail changes, photosensitivity
  • side effects include side effects due to neutropenia (a low white blood cell count).
  • a low white blood cell count can lead to an increase in infections in the body.
  • side effects include side effects due to anemia (a low red blood cell count).
  • a low red blood cell count can lead to side effects such as headaches and fatigue.
  • side effects include side effects due to thrombocytopenia (a low blood platelet count).
  • a low blood platelet count can lead to side effects such as increased bruising, petechiae, and bleeding (e.g., nose, gums, rectal, etc.).
  • side effects include gastrointestinal side effects (e.g., nausea, abdominal pain, abdominal cramping, flatulence (gas), acid indigestion, acid reflux, poor appetite, early satiety, etc.).
  • side effects include alopecia (hair loss) and skin reactions (e.g., dry skin, flushing, hyperpigmentation, nail changes, photosensitivity, radiation recall, and rashes).
  • terapéuticaally effective amount and “effective amount” are synonymous unless otherwise indicated, and mean an amount of a compound of the present invention that is sufficient to improve the condition, disease, or disorder being treated. Determination of a therapeutically effective amount, as well as other factors related to effective administration of a compound of the present invention to a patient in need of treatment, including dosage forms, routes of administration, and frequency of dosing, may depend upon the particulars of the condition that is encountered, including the patient and condition being treated, the severity of the condition in a particular patient, the particular compound being employed, the particular route of administration being employed, the frequency of dosing, and the particular formulation being employed. Determination of a therapeutically effective treatment regimen for a patient is within the level of ordinary skill in the medical or veterinarian arts.
  • an effective amount may be the amount that is recommended by the U.S. Food and Drug Administration, or an equivalent foreign agency.
  • the amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the mammalian host treated and the particular mode of administration.
  • tumor cell as used herein is defined as a cell of a malignant mass, such as a tumor or cancer. The cell may be located within the tumor, on the surface of the tumor, or it may be associated with the tumor.
  • reducing when used in the context of modulating a pathological or disease state, generally refers to the prevention and/or reduction of at least a portion of the negative consequences of the disease state.
  • a biochemical event or pathway When used in the context of a biochemical event or pathway, the term generally refers to a net reduction in the magnitude or activity of said pathway.
  • a range includes each individual member.
  • a group having 1-3 units refers to groups having 1, 2, or 3 units.
  • a group having 1-5 units refers to groups having 1, 2, 3, 4, or 5 units, and so forth.
  • Arsenic is useful for reducing side effects associated with chemotherapy or radiation therapy treatment of cancers such as breast, ovarian, colorectal, gastric, lung, kidney, bladder, prostate, uterine, thyroid, pancreatic, cervical, esophageal, mesothelioma, head and neck, hepatocellular, melanoma, brain, vulval, testicular, sarcoma, intestine, skin, leukemia, and lymphoma cancer.
  • a variety of animal models for such cancers are known, which can be used to explore the effectiveness of arsenic, as well as administration and dosing protocols.
  • the subject receives a protective amount of arsenic followed by a chemotherapeutic agent that is not an arsenic-containing compound.
  • a method in which the side effects of chemotherapy or radiation therapy in cancer patients are inhibited by administering one or more compounds of arsenic to a patient, in conjunction with the administration of a chemotherapeutic agent and/or radiation to the patient.
  • the one or more compounds of arsenic are administered in an amount that is effective to reduce the side effects, but that is in an amount that is much less than an amount that will induce additional tumor formation.
  • one or more compounds of arsenic are administered prior to the administration of chemotherapy or radiation therapy to the patient.
  • one or more compounds of arsenic are administered substantially simultaneously, or after, the administration of chemotherapy or radiation therapy to the patient.
  • One or more compounds of arsenic may be administered before; during and after chemotherapy or radiation therapy.
  • the reduction in the severity of post-chemotherapy and post- radiation therapy side effects increases the quality of life experienced by patients receiving chemotherapy or radiotherapy.
  • the cancer patient is observed to have better appetite, better sleep, higher level of energy, less pain, less gastrointestinal problems, less hair loss, reduced incidence of infection, and desired weight gain, in comparison to patients that have not undergone a pretreatment with arsenic.
  • Arsenic can be administered at any point in time near the administration of the treatment (e.g., chemotherapy or radiotherapy) to yield a desired protective effect.
  • arsenic is administered to a subject prior to administration of the treatment, for example, from 1 to 2 days prior, from 1 to 3 days prior, from 1 to 4 days prior, from 1 to 5 days prior or from 1 to 10 days prior to the administration of the treatment.
  • the arsenic is administered to a subject 1 day prior, 2 days prior, 3 days prior, 4 days prior, or 5 days prior to the administration of the treatment.
  • arsenic is administered 3 days prior to the administration of the treatment. During this period, administration may occur once a day, twice a day, three times a day, four times a day, six times a day, or substantially continuously (e.g., by intravenous administration).
  • an effective amount of the arsenic compositions ranges from about 5 ⁇ g per kilogram body weight per day to about 3,500 ⁇ g per kilogram body weight per day. In some embodiments, the effective amount ranges from about 10 ⁇ g per kilogram body weight per day to about 1 ,000 ⁇ g per kilogram body weight per day.
  • the effective amount ranges from about 5 to about 1,500 ⁇ g/kg/day, about 5 to about 1,000 ⁇ g/kg/day, about 5 to about 850 ⁇ g/kg/day, about 5 to about 500 ⁇ g/kg/day, about 5 to about 350 ⁇ g/kg/day, about 10 to about 500 ⁇ g/kg/day, about 15 to about 850 ⁇ g/kg/day, or about 15 to about 350 ⁇ g/kg/day.
  • the effective amount ranges from about 1 to about 30 ⁇ g/kg/day, about 5 to about 30 ⁇ g/kg/day, about 5 to about 25 ⁇ g/kg/day, about 5 to about 20 ⁇ g/kg/day, about 10 to about 20 ⁇ g/kg/day, or about 15 to about 20 ⁇ g/kg/day.
  • the dosage is about 15 ⁇ g/kg/day, about 20 ⁇ g/kg/day, about 25 ⁇ g/kg/day, about 30 ⁇ g/kg/day, about 35 ⁇ g/kg/day, about 40 ⁇ g/kg/day, about 50 ⁇ g/kg/day, about 100 ⁇ g/kg/day, about 150 ⁇ g/kg/day, about 250 ⁇ g/kg/day, or about 500 ⁇ g/kg/day.
  • the effective amount of the arsenic compositions sufficient for achieving a protective effect in humans, range from about 5 to about 200 ⁇ g/kg/day, about 10 to about 150 ⁇ g/kg/day, about 15 to about 150 ⁇ g/kg/day, about 30 to about 150 ⁇ g/kg/day, about 30 to about 125 ⁇ g/kg/day, about 30 to about 100 ⁇ g/kg/day, about 30 to about 85 ⁇ g/kg/day, about 15 to about 50 ⁇ g /kg/day; about 1 to about 125 ⁇ g/kg/day, about 1.5 to about 125 ⁇ g/kg/day, about 3 to about 125 ⁇ g/kg/day, about 1.5 to about 62.5 ⁇ g/kg/day, about 1 to about 40 ⁇ g/kg/day, or about 2 to about 85 ⁇ g/kg/day.
  • an appropriate total amount of one or more compounds of arsenic is in the range of about 31 to about 125 ⁇ g/kg/day, about 31 to about 85 ⁇ g/kg/day, about 35 to about 80 ⁇ g/kg/day, or about 40 to about 70 ⁇ g/kg/day.
  • Examples of compounds of arsenic that may be used include, but are not limited to: arsenic (III) oxide (arsenic trioxide,As203), arsenic (V) oxide (AS2O5), arsenic (III) selenide (As 2 Se3), arsenic (II) sulfide (AS2S2), arsenic (III) sulfide (AS2S3), arsenic (V) sulfide (AS2O5), arsenic (III) telluride (As 2 Te 3 ), sodium arsenate (Na 2 HAs0 4 ), sodium arsenite (NaAs0 2 ), potassium arsenate (KH 2 ASO 4 ), sodium arsenyl tartrate (NaC 4 H 4 As0 6 ), tetraarsenic tetrasulfide (As 4 S 4 ) and other derivatives of arsenic.
  • arsenic (III) oxide ar
  • arsenic trioxide may be used to inhibit, reduce, or prevent damage to non-cancerous cells in a human subject during radiation treatment or chemotherapeutic treatment of cancer cells in the human subject.
  • Arsenic trioxide may be administered in an amount ranging from about 1 ⁇ g/kg/day to about 125 ⁇ g/kg/day. In some embodiments, arsenic trioxide may be administered in an amount ranging from about 31 ⁇ g/kg/day to about 125 ⁇ g/kg/day. In some embodiments, arsenic trioxide may be administered in an amount ranging from about 31 ⁇ g/kg/day to about 85 ⁇ g/kg/day.
  • the arsenic trioxide can inhibit, reduce, or prevent damage to non-cancerous cells by at least 5%, at least 10%, at least 15%), at least 20%>, at least 25%, at least 30%>, at least 40%>, at least 50%> or more, compared to a control subject or population of control subjects that were not administered arsenic trioxide.
  • sodium arsenite may be used to inhibit, reduce, or prevent damage to non-cancerous cells in a human subject during radiation treatment or chemotherapeutic treatment of cancer cells in the human subject.
  • Sodium arsenite may be administered in an amount ranging from about 1 ⁇ g/kg/day to about 125 ⁇ g/kg/day. In some embodiments, sodium arsenite may be administered in an amount ranging from about 31 ⁇ g/kg/day to about 125 ⁇ g/kg/day. In some embodiments, sodium arsenite may be administered in an amount ranging from about 31 ⁇ g/kg/day to about 85 ⁇ g/kg/day.
  • sodium arsenite may be administered in an amount ranging from about 31 ⁇ g/kg/day to about 65 ⁇ g/kg/day.
  • the sodium arsenite can inhibit, reduce, or prevent damage to non-cancerous cells by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%> or more, compared to a control subject or population of control subjects that were not administered sodium arsenite.
  • arsenic trioxide is used to inhibit, reduce, or prevent side effects cause by chemotherapeutic agents and/or radiation therapy. After administration of arsenic trioxide, radiation therapy or one or more chemotherapeutic agents may be administered to the human subject. In some embodiments, arsenic trioxide is given to the human subject at least one day prior to the administration of radiation or one or more chemotherapeutic agents to the human subject. In some embodiments, arsenic trioxide is given to the human subject for at least three days prior to the administration of radiation or chemotherapeutic agents to the human subject.
  • the arsenic trioxide can inhibit, reduce, or prevent one or more side effects by at least 5%, at least 10%, at least 15%, at least 20%>, at least 25%, at least 30%>, at least 40%), at least 50%> or more, compared to a control subject or population of control subjects that were not administered arsenic trioxide.
  • methods for treating a disease state in a subject by administering a treatment that has an associated toxicity in conjunction with the administration of one or more protective dose(s) of arsenic prior to the time of administration of the treatment.
  • the administration of a protective amount of an arsenic-containing compound is accompanied by an improvement in one or more side effects associated with chemotherapy or radiotherapy.
  • chemotherapy and radiation therapy used in the treatment of cancer and certain immunological disorders can cause pancytopenias or combinations of anemia, neutropenia and thrombocytopenia.
  • the increase or replacement of hematopoietic cells is often crucial to the success of such treatments.
  • An effect of the administration of arsenic to the subject is reduction of the toxicity (e.g., hematopoietic toxicity) of the treatment, thus permitting high-dose and dose dense protocols to be utilized in a particular subject's therapeutic regimen.
  • An overall benefit of practicing this embodiment is that the administration of arsenic to the subject reduces or decreases the toxicity of the treatment, such as the hematopoietic toxicity. Consequently, the maximum therapeutically acceptable dosage of the various treatment modalities may be altered. In some cases, the maximum therapeutically acceptable dosage of the treatment can be increased relative to the maximum therapeutically acceptable dose for a subject not administered arsenic prior to treatment.
  • the administration of a protective amount of arsenic is accompanied by an improvement in a bone marrow condition following the chemotherapy or radiotherapy exposure.
  • a bone marrow condition for a subject has improved if one or more of the following occurs: the density of bone marrow cells in the subject after cancer cell therapy (e.g., radiation therapy and/or chemotherapy) is greater than if no pretreatment of the subject with arsenic was made prior to cancer cell therapy; the density of progenitor cells or stem cells in bone marrow in the subject after cancer cell therapy is greater than if no pretreatment of the subject with arsenic was made prior to cancer cell therapy; the mass of bone marrow tissue in the subject after cancer cell therapy (e.g., radiation therapy and/or chemotherapy) is greater than if no pretreatment of the subject with arsenic was made prior to cancer cell therapy; or the rate of bone marrow cell proliferation n the subject after cancer cell therapy (e.g., radiation therapy and/or chemotherapy) is greater than if no pretreatment of the subject with ar
  • the determination of effectiveness can be made at any time following therapy with a chemotherapy or radiation agent.
  • the determination of effectiveness can be made at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more days after the agent (e.g., chemotherapeutic agent or radiation) is delivered to the subject.
  • a bone marrow sample can be obtained from any portion of bone marrow in the subject's body for this analysis.
  • data can be collected from one or more control individuals, preferably from several individuals, who receive the same or similar chemotherapy or radiation therapy, but who do not receive arsenic.
  • the control population is being treated for the same condition, e.g., for the same type of cancer.
  • An amount is a protective amount if any benefit whatsoever is produced compared to the control population. For example, if the treated individual or group has a bone marrow condition parameter, (e.g., proliferation rate of a given progenitor cell type) whose value, or mean value, is closer to the normal value (e.g., higher than) the value or mean value from a control individual or control group, then the bone marrow condition of the treated individual or group is improved.
  • a protective effective amount can be an amount that improves bone marrow condition by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50% or more.
  • therapeutically acceptable dose may be determined by monitoring the complete blood count ("CBC") of the subject. Damage to bone marrow of a subject may be manifested by low red blood cell counts, low white blood cell counts, low platelet counts, or combinations thereof. Generally, normal red blood cell counts range from about 4.5 million to about 6 million per microliter of blood. Red blood cell counts below about 4 million per microliter of blood may indicate that the chemotherapeutic dose and/or the radiation dose is above the maximum therapeutically acceptable dose. Generally, normal white blood cell counts range from about 4,000 to about 11,000 per microliter of blood. White blood cell counts below about 3,500 per microliter of blood may indicate that the chemotherapeutic dose and/or the radiation dose is above the maximum therapeutically acceptable dose.
  • CBC complete blood count
  • normal platelet counts range from about 150,000 to about 400,000 cells per microliter of blood. Platelet cell counts below about 50,000 per microliter of blood may indicate that the chemotherapeutic dose and/or the radiation dose is above the maximum therapeutically acceptable dose. Methods for determining the maximum therapeutically acceptable does are described in Gurey, "How to calculate the dose of chemotherapy", British Journal of Cancer (2002), 86, 1297-1302, which is incorporated herein by reference.
  • the maximum therapeutically acceptable amount may thus be determined by monitoring the CBC of the subject. It has been found that the amount of chemotherapeutic agents that may be used before causing one or more cell counts to drop below generally acceptable levels may be increased by the administration of one or compounds of arsenic the subject prior to the administration of the one or more chemotherapeutic agents.
  • chemotherapeutic agent administered to the subject will increase effectiveness of the treatment (e.g., increasing the rate at which the cancer cells are destroyed and/or reducing the incidence of recurrence).
  • the radiation dosage that may be used during radiotherapy before causing one or more cell counts to drop below generally acceptable levels may be increased by the administration of one or compounds of arsenic the subject prior to the administration of radiation to the subject.
  • increasing the amount of radiation administered to the subject will increase effectiveness of the treatment (e.g., increasing the rate at which the cancer cells are destroyed and/or reducing the incidence of recurrence).
  • a side effect of chemotherapy and radiation therapy may be injury to the intestinal mucosa.
  • This may also be a dose-limiting side effect of radiotherapy and chemotherapy, since the damage to the intestinal mucosa may affect the ability of the body to absorb nutrients.
  • the maximum therapeutically acceptable dose of a cancer cell therapy may be a dose that has an acceptable amount of damage to the intestinal mucosa.
  • the weight of the subject may be monitored to determine the state of the intestinal mucosa. For example, significant weight loss (e.g., a weight loss during treatment of more than 3 pounds from the starting weight of the subject), may indicate unacceptable damage to the intestinal mucosa.
  • the amount of chemotherapeutic agents that may be used before causing unacceptable damage to the intestinal mucosa may be increased by the administration of one or compounds of arsenic the subject prior to the administration of the one or more chemotherapeutic agents. It has also been found that the radiation dosage that may be used during radiotherapy before causing unacceptable damage to the intestinal mucosa may be increased by the administration of one or compounds of arsenic the subject prior to the administration of radiation to the subject.
  • Radiotherapeutic agents and factors include radiation and waves that induce DNA damage for example, gamma-irradiation, X-rays, UV-irradiation, microwaves, electronic emissions, radioisotopes, and the like. Therapy may be achieved by irradiating the localized tumor site with the above described forms of radiations. It is most likely that all of these factors effect a broad range of damage on: DNA; on the precursors of DNA; on the replication and repair ability of DNA, and on the assembly and maintenance of chromosomes.
  • Dosage ranges for X-rays range from daily doses of 50 to 200 roentgens for prolonged periods of time (3 to 4 weeks), to single doses of 2000 to 6000 roentgens.
  • Dosage ranges for radioisotopes vary widely, and depend on the half-life of the isotope, the strength and type of radiation emitted, and the uptake by the neoplastic cells.
  • Chemotherapeutic agents include agents that directly cross-link DNA, agents that intercalate into DNA, and agents that lead to chromosomal and mitotic aberrations by affecting nucleic acid synthesis.
  • chemotherapeutic agents include, but are not limited to: doxorubicin, daunorubicin, mitomycin, actinomycin D, bleomycin, cisplatin, etoposide, tumor necrosis factor, taxol, vincristine, vinblastine, carmustine, melphalan, cyclophosphamide, chlorambucil, busulfan, fluorouracil ("5FU”) and lomustine.
  • any of these agents may be used alone, or in combination with other agents, after pre -treatment of the patient with one or more compounds of arsenic.
  • the pretreatment of the patient with one or more compounds of arsenic reduces the intensity and occurrence of many of the side effects of the above-listed
  • chemotherapeutic agents without significantly inhibiting the efficacy of such agents.
  • Agents that directly cross-link nucleic acids, specifically DNA are envisaged and are shown herein, to eventuate DNA damage leading to a synergistic antineoplastic combination.
  • Agents such as cisplatin, and other DNA alkylating agents may be used.
  • Agents that damage DNA also include compounds that interfere with DNA replication, mitosis, and chromosomal segregation.
  • these compounds include doxorubicin (also known as adriamycin), etoposide (also known as VP- 16), verapamil, podophyllotoxin, and the like. Widely used in clinical setting for the treatment of neoplasms, these compounds are administered through bolus injections intravenously at doses ranging from 25-75 mg/m 2 at 21 day intervals for adriamycin, to 35-100 mg/m 2 for etoposide intravenously or orally.
  • Doxorubicin hydrochloride 5,12-Naphthacenedione, (8s-cis )-10-((3-amino-2,3,6- trideoxy-a-L-lyxo-hexopyranosyl)oxy)-7,8,9, 10-tetrahy dro-6,8, 11 -trihydroxy-8- (hydroxyacetyl)-l-methoxy-hydrochloride (hydroxydaunorubicin hydrochloride, Adriamycin) is used in a wide antineoplastic spectrum. It binds to DNA and inhibits nucleic acid synthesis, inhibits mitosis and promotes chromosomal aberrations.
  • Administered alone it is the drug of first choice for the treatment of thyroid adenoma and primary hepatocellular carcinoma. It is a component of 31 first-choice combinations for the treatment of ovarian, endometrial and breast tumors, bronchogenic oat-cell carcinoma, non-small cell lung carcinoma, gastric adenocarcinoma, retinoblastoma, neuroblastoma, mycosis fungoides, pancreatic carcinoma, prostatic carcinoma, bladder carcinoma, myeloma, diffuse histiocytic lymphoma, Wilms' tumor, Hodgkin's disease, adrenal tumors, osteogenic sarcoma soft tissue sarcoma, Ewing's sarcoma, rhabdomyosarcoma and acute lymphocytic leukemia. It is an alternative drug for the treatment of islet cell, cervical, testicular and adrenocortical cancers. It is also an immunosuppressant.
  • Doxorubicin is absorbed poorly and is typically administered intravenously.
  • the pharmacokinetics are multicompartmental. Distribution phases have half- lives of 12 minutes and 3.3 hr. The elimination half-life is about 30 hr. Forty to 50% is secreted into the bile. Most of the remainder is metabolized in the liver, partly to an active metabolite (doxorubicinol), but a few percent is excreted into the urine. In the presence of liver impairment, the dose is typically inhibited.
  • Appropriate doses are, intravenous, adult, 60 to 75 mg/m 2 at 21 -day intervals or 25 to 30 mg/m 2 on each of 2 or 3 successive days repeated at 3- or 4-wk intervals or 20 mg/m 2 once a week.
  • the lowest dose should be used in elderly patients, when there is prior bone-marrow depression caused by prior chemotherapy or neoplastic marrow invasion, or when the drug is combined with other myelopoietic suppressant drugs.
  • the dose should be reduced by 50% if the serum bilirubin lies between 1.2 and 3 mg/dL and by 75% if above 3 mg/dL.
  • the lifetime total dose should not exceed 550 mg/m 2 in patients with normal heart function and 400 mg/m 2 in persons having received mediastinal irradiation. Alternatively, 30 mg/m 2 on each of 3 consecutive days, repeated every 4 wk.
  • Exemplary doses may be 10 mg/m 2 , 20 mg/m 2 , 30 mg/m 2 , 50 mg/m 2 , 100 mg/m 2 , 150 mg/m 2 , 175 mg/m 2 , 200 mg/m 2 , 225 mg/m 2 , 250 mg/m 2 , 275 mg/m 2 , 300 mg/m 2 , 350 mg/m 2 , 400 mg/m 2 , 425 mg/m 2 , 450 mg/m 2 , 475 mg/m 2 , 500 mg/m 2 .
  • all of these dosages are exemplary, and any dosage in-between these points is also expected to be of use in the invention.
  • Suitable doses are (base equivalent), intravenous adult, younger than 60 yr. 45 mg/m 2 /day (30 mg/m 2 for patients older than 60 yr.) for 1, 2 or 3 days every 3 or 4 wk or 0.8 mg/kg/day for 3 to 6 days every 3 or 4 wk; no more than 550 mg/m 2 should be given in a lifetime, except only 450 mg/m 2 if there has been chest irradiation; children, 25 mg/m 2 once a week unless the age is less than 2 yr. or the body surface less than 0.5 m, in which case the weight-based adult schedule is used. It is available in injectable dosage forms (base equivalent) 20 mg (as the base equivalent to 21.4 mg of the hydrochloride).
  • Exemplary doses may be 10 mg/m 2 , 20 mg/m 2 , 30 mg/m 2 , 50 mg/m 2 , 100 mg/m 2 , 150 mg/m 2 , 175 mg/m 2 , 200 mg/m 2 , 225 mg/m 2 , 250 mg/m 2 , 275 mg/m 2 , 300 mg/m 2 , 350 mg/m 2 , 400 mg/m 2 , 425 mg/m 2 , 450 mg/m 2 , 475 mg/m 2 , 500 mg/m 2 .
  • these dosages are exemplary, and any dosage in-between these points is also expected to be of use in the invention.
  • Mitomycin also known as mutamycin and/or mitomycin-C
  • mutamycin and/or mitomycin-C is an antibiotic isolated from the broth of Streptomyces caespitosus which has been shown to have antitumor activity.
  • the compound is heat stable, has a high melting point, and is freely soluble in organic solvents.
  • Mitomycin selectively inhibits the synthesis of deoxyribonucleic acid (DNA).
  • the guanine and cytosine content correlates with the degree of mitomycin-induced cross-linking.
  • cellular RNA and protein synthesis are also suppressed.
  • Time required to reduce the serum concentration by 50% after a 30 mg bolus injection is 17 minutes. After injection of 30 mg., 20 mg., or 10 mg. I.V., the maximal serum concentrations were 2.4 mg./mL, 1.7 mg./rnL, and 0.52 mg./mL, respectively. Clearance is effected primarily by metabolism in the liver, but metabolism occurs in other tissues as well. The rate of clearance is inversely proportional to the maximal serum concentration because, it is thought, of saturation of the degradative pathways.
  • Actinomycin D (Dactinomycin) (50-76-0); C62H86N12O16 (1255.43) is an antineoplastic drug that inhibits DNA-dependent RNA polymerase. It is a component of first-choice combinations for treatment of choriocarcinoma, embryonal rhabdomyosarcoma, testicular tumor and Wilms' tumor. Tumors which fail to respond to systemic treatment sometimes respond to local perfusion. Dactinomycin potentiates radiotherapy. It is a secondary (efferent)
  • Actinomycin D is used in combination with primary surgery, radiotherapy, and other drugs, particularly vincristine and cyclophosphamide. Antineoplastic activity has also been noted in Ewing's tumor, Kaposi's sarcoma, and soft-tissue sarcomas. Actinomycin D can be effective in women with advanced cases of choriocarcinoma. It also produces consistent responses in combination with chlorambucil and methotrexate in patients with metastatic testicular carcinomas. A response may sometimes be observed in patients with Hodgkin's disease and non-Hodgkin's lymphomas. Actinomycin D has also been used to inhibit immunological responses, particularly the rejection of renal transplants.
  • Half of the dose is excreted intact into the bile and 10% into the urine; the half- life is about 36 hr.
  • the drug does not pass the blood-brain barrier.
  • Actinomycin D is supplied as a lyophilized powder (0/5 mg in each vial).
  • the usual daily dose is 10 to 15 mg/kg; this is given intravenously for 5 days; if no manifestations of toxicity are encountered, additional courses may be given at intervals of 3 to 4 weeks.
  • Daily injections of 100 to 400 mg have been given to children for 10 to 14 days; in other regimens, 3 to 6 mg/kg, for a total of 125 mg/kg, and weekly maintenance doses of 7.5 mg/kg have been used.
  • Exemplary doses may be 100 mg/m 2 , 150 mg/m 2 , 175 mg/m 2 , 200 mg/m 2 , 225 mg/m 2 , 250 mg/m 2 , 275 mg/m 2 , 300 mg/m 2 , 350 mg/m 2 , 400 mg/m 2 , 425 mg/m 2 , 450 mg/m 2 , 475 mg/m 2 , 500 mg/m 2 .
  • All of these dosages are exemplary, and any dosage in-between these points is also expected to be of use in the invention.
  • Bleomycin is a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus. It is freely soluble in water.
  • mice high concentrations of bleomycin are found in the skin, lungs, kidneys, peritoneum, and lymphatics. Tumor cells of the skin and lungs have been found to have high concentrations of bleomycin in contrast to the low concentrations found in hematopoietic tissue.
  • the low concentrations of bleomycin found in bone marrow may be related to high levels of bleomycin degradative enzymes found in that tissue.
  • the serum or plasma terminal elimination half-life of bleomycin is approximately 115 minutes.
  • the plasma or serum terminal elimination half-life increases exponentially as the creatinine clearance decreases.
  • 60% to 70% of an administered dose is recovered in the urine as active bleomycin.
  • Bleomycin should be considered a palliative treatment. It has been shown to be useful in the management of the following neoplasms either as a single agent or in proven combinations with other approved chemotherapeutic agents in squamous cell carcinoma such as head and neck (including mouth, tongue, tonsil, nasopharynx, oropharynx, sinus, palate, lip, buccal mucosa, gingiva, epiglottis, larynx), skin, penis, cervix, and vulva. It has also been used in the treatment of lymphomas and testicular carcinoma.
  • lymphoma patients should be treated with two units or less for the first two doses. If no acute reaction occurs, then the regular dosage schedule may be followed.
  • Bleomycin may be given by the intramuscular, intravenous, or subcutaneous routes.
  • Cisplatin has been widely used to treat cancers such as metastatic testicular or ovarian carcinoma, advanced bladder cancer, head or neck cancer, cervical cancer, lung cancer or other tumors. Cisplatin can be used alone or in combination with other agents, with efficacious doses used in clinical applications of 15-20 mg/m 2 for 5 days every three weeks for a total of three courses.
  • Exemplary doses may be 0.50 mg/m 2 , 1.0 mg/m 2 , 1.50 mg/m 2 , 1.75 mg/m 2 , 2.0 mg/m 2 , 3.0 mg/m 2 , 4.0 mg/m 2 , 5.0 mg/m 2 , 10 mg//m 2
  • all of these dosages are exemplary, and any dosage in-between these points is also expected to be of use in the invention.
  • Cisplatin is not absorbed orally and must therefore be delivered via injection
  • cisplatin is used in combination with emodin or emodin-like compounds in the treatment of non-small cell lung carcinoma. It is clear, however, that the combination of cisplatin and emodin and or emodin-like compounds could be used for the treatment of any other neu-mediated cancer.
  • Etoposide is also know as VP 16 and is used primarily for treatment of testicular tumors, in combination with bleomycin and cisplatin, and in combination with cisplatin for small-cell carcinoma of the lung. It is also active against non-Hodgkin's lymphomas, acute
  • nonlymphocytic leukemia carcinoma of the breast, and Kaposi's sarcoma associated with acquired immunodeficiency syndrome (AIDS).
  • AIDS acquired immunodeficiency syndrome
  • Etoposide is available as a solution (20 mg/ml) for intravenous administration and as 50- mg, liquid-filled capsules for oral use.
  • the intravenous dose in combination therapy
  • the intravenous dose is can be as much as 100 mg/m 2 or as little as 2 mg/m 2 , routinely 35 mg/m 2 , daily for 4 days, to 50 mg/m 2 , daily for 5 days have also been used.
  • the dose should be doubled.
  • the doses for small cell lung carcinoma may be as high as 200-250 mg/m 2 .
  • the intravenous dose for testicular cancer (in combination therapy) is 50 to 100 mg/m 2 daily for 5 days, or 100 mg/m 2 on alternate days, for three doses. Cycles of therapy are usually repeated every 3 to 4 weeks.
  • the drug should be administered slowly during a 30- to 60-minute infusion in order to avoid hypotension and bronchospasm, which are probably due to the solvents used in the formulation.
  • Tumor Necrosis Factor is a glycoprotein that kills some kinds of cancer cells, activates cytokine production, activates macrophages and endothelial cells, promotes the production of collagen and collagenases, is an inflammatory mediator and also a mediator of septic shock, and promotes catabolism, fever and sleep. Some infectious agents cause tumor regression through the stimulation of TNF production. TNF can be quite toxic when used alone in effective doses, so that the optimal regimens probably will use it in lower doses in combination with other drugs. Its immunosuppressive actions are potentiated by ⁇ -interferon, so that the combination potentially is dangerous. A hybrid of TNF and interferon-a also has been found to possess anti-cancer activity.
  • Taxol is an experimental antimitotic agent, isolated from the bark of the ash tree, Taxus brevifolia. It binds to tubulin (at a site distinct from that used by the vinca alkaloids) and promotes the assembly of microtubules. Taxol is currently being evaluated clinically; it has activity against malignant melanoma and carcinoma of the ovary. Maximal doses are 30 mg/m 2 per day for 5 days or 210 to 250 mg/m 2 given once every 3 weeks. Of course, all of these dosages are exemplary, and any dosage in-between these points is also expected to be of use in the invention.
  • Figure 6 is the illustration showing the conjugation of peptide with liposome carrying anti-cancer agent taxol through polyethylene glycol adapters.
  • Vinblastine and vincristine bind to plasma proteins. They are extensively concentrated in platelets and to a lesser extent in leukocytes and erythrocytes.
  • Vincristine has a multiphasic pattern of clearance from the plasma; the terminal half-life is about 24 hours.
  • the drug is metabolized in the liver, but no biologically active derivatives have been identified.
  • Doses should be reduced in patients with hepatic dysfunction. At least a 50% reduction in dosage is indicated if the concentration of bilirubin in plasma is greater than 3 mg/dl (about 50 mM).
  • Vincristine sulfate is available as a solution (1 mg/ml) for intravenous injection.
  • Vincristine used together with corticosteroids is presently the treatment of choice to induce remissions in childhood leukemia; the optimal dosages for these drugs appear to be vincristine, intravenously, 2 mg/m 2 of body-surface area, weekly, and prednisolone, orally, 40 mg/m 2 , daily.
  • Adult patients with Hodgkin's disease or non-Hodgkin's lymphomas usually receive vincristine as a part of a complex protocol.
  • the recommended dose of vincristine is 1.4 mg/m 2 .
  • High doses of vincristine seem to be tolerated better by children with leukemia than by adults, who may experience sever neurological toxicity.
  • Precautions should also be used to avoid extravasation during intravenous administration of vincristine.
  • Vincristine (and vinblastine) can be infused into the arterial blood supply of tumors in doses several times larger than those that can be administered intravenously with comparable toxicity.
  • Vincristine has been effective in Hodgkin's disease and other lymphomas. Although it appears to be somewhat less beneficial than vinblastine when used alone in Hodgkin's disease, when used with mechlorethamine, prednisolone, and procarbazine (the so-called MOPP regimen), it is the preferred treatment for the advanced stages (III and IV) of this disease. In non-Hodgkin's lymphomas, vincristine is an important agent, particularly when used with cyclophosphamide, bleomycin, doxorubicin, and prednisolone. Vincristine is more useful than vinblastine in lymphocytic leukemia. Beneficial response have been reported in patients with a variety of other neoplasms, particularly Wilms' tumor, neuroblastoma, brain tumors,
  • rhabdomyosarcoma and carcinomas of the breast, bladder, and the male and female reproductive systems.
  • Doses of vincristine for use will be determined by the clinician according to the individual patients need. 0.01 to 0.03 mg/kg or 0.4 to 1.4 mg/m 2 can be administered or 1.5 to 2 mg/m 2 can also be administered. Alternatively 0.02 mg/m 2 , 0.05 mg/m 2 , 0.06 mg/m 2 , 0.07 mg/m 2 , 0.08 mg/m 2 , 0.1 mg/m 2 , 0.12 mg/m 2 , 0.14 mg/m 2 , 0.15 mg/m 2 , 0.2 mg/m2 , 0.25 mg/m 2 can be given as a constant intravenous infusion. Of course, all of these dosages are exemplary, and any dosage in-between these points is also expected to be of use in the invention.
  • Vinblastine and vincristine bind to plasma proteins. They are extensively concentrated in platelets and to a lesser extent in leukocytes and erythrocytes. After intravenous injection, vinblastine has a multiphasic pattern of clearance from the plasma; after distribution, drug disappears from plasma with half-lives of approximately 1 and 20 hours.
  • Vinblastine is metabolized in the liver to biologically activate derivative
  • desacetylvinblastine Approximately 15% of an administered dose is detected intact in the urine, and about 10% is recovered in the feces after biliary excretion. Doses should be reduced in patients with hepatic dysfunction. At least a 50% reduction in dosage is indicated if the concentration of bilirubin in plasma is greater than 3 mg/dl (about 50 mM).
  • Vinblastine sulfate is available in preparations for injection.
  • the drug is given intravenously; special precautions must be taken against subcutaneous extravasation, since this may cause painful irritation and ulceration.
  • the drug should not be injected into an extremity with impaired circulation.
  • myelosuppression reaches its maximum in 7 to 10 days. If a moderate level of leukopenia (approximately 3000 cells/mm 3 ) is not attained, the weekly dose may be increased gradually by increments of 0.05 mg/kg of body weight.
  • vinblastine is used in doses of 0.3 mg/kg every 3 weeks irrespective of blood cell counts or toxicity.
  • vinblastine The most important clinical use of vinblastine is with bleomycin and cisplatin in the curative therapy of metastatic testicular tumors. Beneficial responses have been reported in various lymphomas, particularly Hodgkin's disease, where significant improvement may be noted in 50 to 90% of cases.
  • the effectiveness of vinblastine in a high proportion of lymphomas is not diminished when the disease is refractory to alkylating agents. It is also active in Kaposi's sarcoma, neuroblastoma, and Letterer-Siwe disease (histiocytosis X), as well as in carcinoma of the breast and choriocarcinoma in women.
  • Doses of vinblastine for use will be determined by the clinician according to the individual patients need. 0.1 to 0.3 mg/kg can be administered or 1.5 to 2 mg/m 2 can also be
  • all of these dosages are exemplary, and any dosage in-between these points is also expected to be of use in the invention.
  • Carmustine (sterile carmustine) is one of the nitrosoureas used in the treatment of certain neoplastic diseases. It is l,3bis (2-chloroethyl)-l -nitrosourea. It is lyophilized pale yellow flakes or congealed mass with a molecular weight of 214.06. It is highly soluble in alcohol and lipids, and poorly soluble in water. Carmustine is administered by intravenous infusion after reconstitution as recommended. Sterile carmustine is commonly available in 100 mg single dose vials of lyophilized material.
  • carmustine alkylates DNA and R A it is not cross resistant with other alkylators. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins.
  • Carmustine is indicated as palliative therapy as a single agent or in established combination therapy with other approved chemotherapeutic agents in brain tumors such as glioblastoma, brainstem glioma, medullobladyoma, astrocytoma, ependymoma, and metastatic brain tumors. Also it has been used in combination with prednisolone to treat multiple myeloma. Carmustine has proved useful, in the treatment of Hodgkin's Disease and in non-Hodgkin's lymphomas, as secondary therapy in combination with other approved drugs in patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy.
  • the recommended dose of carmustine as a single agent in previously untreated patients is 150 to 200 mg/m 2 intravenously every 6 weeks. This may be given as a single dose or divided into daily injections such as 75 to 100 mg/m 2 on 2 successive days.
  • the doses should be adjusted accordingly. Doses subsequent to the initial dose should be adjusted according to the hematologic response of the patient to the preceding dose.
  • Melphalan also known as alkeran, L-phenylalanine mustard, phenylalanine mustard, L- PAM, or L-sarcolysin, is a phenylalanine derivative of nitrogen mustard.
  • Melphalan is a bifunctional alkylating agent which is active against selective human neoplastic diseases. It is known chemically as 4-(bis(2-chloroethyl)amino)-L-phenylalanine.
  • Melphalan is the active L-isomer of the compound and was first synthesized in 1953 by
  • the D-isomer known as medphalan
  • the racemic (DL-) form is known as merphalan or sarcolysin.
  • Melphalan is insoluble in water and has a pKai of .about.2.1.
  • Melphalan is available in tablet form for oral administration and has been used to treat multiple myeloma.
  • Melphalan has been used in the treatment of epithelial ovarian carcinoma.
  • One commonly employed regimen for the treatment of ovarian carcinoma has been to administer melphalan at a dose of 0.2 mg/kg daily for five days as a single course. Courses are repeated every four to five weeks depending upon hematologic tolerance.
  • the dose of melphalan used could be as low as 0.05 mg/kg/day or as high as 3 mg/kg/day or any dose in between these doses or above these doses. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for
  • administration will, in any event, determine the appropriate dose for the individual subject.
  • Cyclophosphamide is 2H-l,3,2-Oxazaphosphorin-2-amine, N,N-bis(2- chloroethyl)tetrahydro-, 2-oxide, monohydrate; termed Cytoxan available from Mead Johnson; and Neosar available from Adria. Cyclophosphamide is prepared by condensing 3 -amino- 1- propanol with N,N-bis(2-chlorethyl)phosphoramidic dichloride ((ClCH 2 CH 2 ).sub.2 N— POCl 2 ) in dioxane solution under the catalytic influence of triethylamine. The condensation is double, involving both the hydroxyl and the amino groups, thus effecting the cyclization.
  • the substance Unlike other ⁇ -chloroethylamino alkylators, it does not cyclize readily to the active ethyleneimonium form until activated by hepatic enzymes. Thus, the substance is stable in the gastrointestinal tract, tolerated well and effective by the oral and parental routes and does not cause local vesication, necrosis, phlebitis or even pain.
  • Suitable doses for adults include, orally, 1 to 5 mg/kg/day (usually in combination), depending upon gastrointestinal tolerance; or 1 to 2 mg/kg/day; intravenously, initially 40 to 50 mg/kg in divided doses over a period of 2 to 5 days or 10 to 15 mg/kg every 7 to 10 days or 3 to 5 mg/kg twice a week or 1.5 to 3 mg/kg/day .
  • a dose 250 mg/kg/day may be administered as an antineoplastic. Because of gastrointestinal adverse effects, the intravenous route is preferred for loading. During maintenance, a leukocyte count of 3000 to 4000/mm 3 usually is desired. The drug also sometimes is administered intramuscularly, by infiltration or into body cavities.
  • Chlorambucil also known as leukeran is a bifunctional alkylating agent of the nitrogen mustard type that has been found active against selected human neoplastic diseases.
  • Chlorambucil is known chemically as 4-(bis(2-chlorethyl)amino)benzenebutanoic acid.
  • Chlorambucil is available in tablet form for oral administration. It is rapidly and completely absorbed from the gastrointestinal tract. After single oral doses of 0.6-1.2 mg/kg, peak plasma chlorambucil levels are reached within one hour and the terminal half-life of the parent drug is estimated at 1.5 hours. 0.1 to 0.2 mg/kg/day or 3 to 6 mg/m 2 /day or alternatively 0.4 mg/kg may be used for antineoplastic treatment. Treatment regimes are well know to those of skill in the art and can be found in the "Physicians Desk Reference" and in "Remington's Pharmaceutical Sciences" referenced herein.
  • Chlorambucil is indicated in the treatment of chronic lymphatic (lymphocytic) leukemia, malignant lymphomas including lymphosarcoma, giant follicular lymphoma and Hodgkin's disease. It is not curative in any of these disorders but may produce clinically useful palliation.
  • Busulfan (also known as myleran) is a bifunctional alkylating agent. Busulfan is known chemically as 1 ,4-butanediol dimethanesulfonate.
  • Busulfan is not a structural analog of the nitrogen mustards. Busulfan is available in tablet form for oral administration. Each scored tablet contains 2 mg busulfan and the inactive ingredients magnesium stearate and sodium chloride. Busulfan is indicated for the palliative treatment of chronic myelogenous (myeloid, myelocytic, granulocytic) leukemia. Although not curative, busulfan reduces the total granulocyte mass, relieves symptoms of the disease, and improves the clinical state of the patient. Approximately 90% of adults with previously untreated chronic myelogenous leukemia will obtain hematologic remission with regression or stabilization of organomegaly following the use of busulfan. It has been shown to be superior to splenic irradiation with respect to survival times and maintenance of hemoglobin levels, and to be equivalent to irradiation at controlling splenomegaly.
  • 5FU Fluorouracil
  • Fluoroplex is a drug that is a pyrimidine analog which is used in the treatment of cancer. Some of its principal uses are in colorectal cancer, and pancreatic cancer. It is also sometimes used in the treatment of inflammatory breast cancer.
  • Lomustine is one of the nitrosoureas used in the treatment of certain neoplastic diseases. It is l-(2-chloro-ethyl)-3-cyclohexyl-l nitrosourea. It is a yellow powder with the empirical formula of C 9 H 16 CIN 3 O 2 and a molecular weight of 233.71. Lomustine is soluble in 10% ethanol (0.05 mg per mL) and in absolute alcohol (70 mg per mL). Lomustine is relatively insoluble in water ( ⁇ 0.05 mg per mL). It is relatively unionized at a physiological pH. Inactive ingredients in lomustine capsules are: magnesium stearate and mannitol.
  • lomustine alkylates DNA and R A it is not cross resistant with other alkylators. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins.
  • Lomustine may be given orally. Following oral administration of radioactive lomustine at doses ranging from 30 mg/m 2 to 100 mg/m 2 , about half of the radioactivity given was excreted in the form of degradation products within 24 hours.
  • the serum half- life of the metabolites ranges from 16 hours to 2 days. Tissue levels are comparable to plasma levels at 15 minutes after intravenous administration.
  • Lomustine has been shown to be useful as a single agent in addition to other treatment modalities, or in established combination therapy with other approved chemotherapeutic agents in both primary and metastatic brain tumors, in patients who have already received appropriate surgical and/or radiotherapeutic procedures. It has also proved effective in secondary therapy against Hodgkin's Disease in combination with other approved drugs in patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy.
  • the recommended dose of lomustine in adults and children as a single agent in previously untreated patients is 130 mg/m 2 as a single oral dose every 6 weeks. In individuals with compromised bone marrow function, the dose should be reduced to 100 mg/m 2 every 6 weeks. When lomustine is used in combination with other myelosuppressive drugs, the doses should be adjusted accordingly. It is understood that other doses may be used for example, 20 mg/m 2 , 30 mg/m2 , 40 mg/m2 , 50 mg/m2 , 60 mg/m2 , 70 mg/m2 , 80 mg/m2 , 90 mg/m2 , 100 mg/m 2 , 120 mg/m 2 or any doses between these figures as determined by the clinician to be necessary for the individual being treated.
  • Surgical treatment for removal of the cancerous growth is another standard procedure for the treatment of tumors and cancers. This attempts to remove the entire cancerous growth.
  • surgery is generally combined with chemotherapy and/or radiotherapy to ensure the destruction of any remaining neoplastic or malignant cells. Thus, surgery may be used in addition to using radiation therapy and chemotherapy to treat tumors.
  • chemotherapies to kill cancer cells which also potently activates p53.
  • Abundant evidence indicates that DNA damaging anticancer therapy-induced acute toxicity is mainly mediated by p53, which, upon activation, induces massive apoptotic cell death in sensitive tissues, including intestinal epithelium, spleen, bone marrow, thymus, tongue, testis and hair follicles, leading to severe pathological consequences.
  • p53 -deficient mice are refractory to toxicity induced by radiation and chemotherapy.
  • p53 -mediated pathological response to chemotherapy and radiation therapy would suggest that suppression of p53 may serve as a potential approach for amelioration of the adverse side effects, allowing patients to tolerate much more aggressive (and so potentially more successful) treatment regimes.
  • p53 is one of the most important tumor suppressors, so the potential cancer risk resulting from its inhibition needs to be addressed.
  • the p53 tumor suppressor is a transcription factor that controls the expression of a number of genes whose products mediate cell cycle arrest, DNA repair, senescence, or apoptosis.
  • the critical role of p53 in prevention of carcinogenesis is supported by its universal inactivation in cancer cells either through mutations affecting the p53 locus directly or through aberration of its normal regulation. Because the DNA damage response pathway and the oncogenic stress pathway converge on p53, it has been thought that both pathways are integral to the tumor suppressor function of p53. Recent genetic studies, however, have provided compelling evidence indicating that the oncogenic stress pathway, rather than the DNA damage pathway, is essential for p53 -mediated tumor suppression.
  • the knockin mice were incompetent for DNA damage-induced apoptosis yet fully protected from cancer development. These studies together indicate that temporary suppression of p53 activity can significantly reduce DNA damage-induced cytotoxicity without compromising the tumor suppression function, providing a rationale to explore temporary p53 inhibition as an approach of cancer therapy protection.
  • Arsenic is a naturally occurring metalloid that induces oxidative stress by activating NADPH oxidase activity through a Ras-GTPase-dependent mechanism, which creates an intracellular burst of reactive oxygen. Exposure of human, experimental animals and cultured cells to arsenic is associated with a variety of diverse effects. While arsenic is an established human carcinogen, there has been much controversy about the shape of the arsenic response curve, particularly at low doses. This controversy is further complicated by the fact that the mechanism of arsenic carcinogenesis remains unclear because of a lack of consistent success in inducing cancer in animal models through arsenic exposure.
  • Arsenic was even applied to the skin by women to improve their complexion.
  • a concentration-related hierarchy of responses to arsenic has been well documented.
  • arsenite treatment at concentrations at or below 5 ⁇ for 24 hr resulted in induced proliferation that is accompanied with enhanced nuclear factor- ⁇ (NF - ⁇ ) and activator protein- 1 (AP-1) activity, transcription factors that are known to promote cell proliferation and cell survival.
  • NF - ⁇ nuclear factor- ⁇
  • AP-1 activator protein- 1
  • lung carcinoma cell line A549 was used to generate a mouse xenograft model for assessing the effect of arsenic.
  • Athymic nude mice (Balb c nu/nu, 4-6 weeks old) were purchased from Harlan laboratories. Mice were housed under pathogen-free conditions and maintained on a 12 h light/ 12 h dark cycle, with food and water supplied ad libitum.
  • Human lung carcinoma cells A549 (cells as a 50% suspension in matrigel) as 3 million cells per mice in a final volume of ⁇ were injected subcutaneously in the right flank of Balb c nude mice.
  • mice were randomized into the following groups; control; arsenite only; 5FU only; arsenite and 5FU; X-ray irradiation only; arsenite and X-ray irradiation.
  • mice treated with either 5FU or irradiation significantly lost their body weight. This is likely caused by toxicity of the treatments as tumor growth in those animals was almost completely suppressed (see FIGS. 1 and 2).
  • significantly, such therapy-induced body weight loss was effectively prevented by arsenic pretreatment, as demonstrated by a minimum decrease in body weight of the mice fed with arsenic-containing water.
  • Arsenic-mediated p53 inhibition is temporary and reversible
  • mice We next used mice to examine arsenic-mediated modulation of p53 activity in vivo.
  • peripheral blood lymphocytes to monitor the p53 response to irradiation. Mice were fed with water containing arsenic for 3 days. Whole blood was collected from the animals 1, 3, 5, 7, 9, or 11 days after arsenic removal. Lymphocytes were isolated by using the Ficoll method. The cells were cultured for 24 h, then irradiated at a dose of 2 Gy and harvested 3 hours post-treatment. Western analysis was performed. Consistent with the results from cell-based studies, p53 activation by radiation recovered, albeit with a slightly slower kinetics, after arsenic was removed.
  • mice (Balb c nu/nu, 4-6 weeks old) were purchased from Harlan laboratories. Mice were housed under pathogen-free conditions and maintained on a 12 h light/12 h dark cycle, with food and water supplied ad libitum.
  • Human breast carcinoma cells, MDA-MB-231 (cells as a 50% suspension in matrigel) as 3 million cells per mice in a final volume of 100ml were injected subcutaneously at right flank of Balb c nude mice. When the average tumor volume reached about 100 mm 3 , mice were randomized into following groups; control; 5FU only; arsenite and 5FU.
  • mice (Balb c nu/nu, 4-6 weeks old) were purchased from Harlan laboratories. Mice were housed under pathogen-free conditions and maintained on a 12 h light/ 12 h dark cycle, with food and water supplied ad libitum. Human colon carcinoma cells, SW-480 (cells as a 50% suspension in matrigel) as 3 million cells per mice in a final volume of 100ml were injected subcutaneously at right flank of Balb c nude mice. When the average tumor volume reached about 100 mm 3 , mice were randomized into following groups; control; arsenite, 5FU only; arsenite and 5FU.
  • mice treated with 5FU exhibited a significant decrease in body weight. This is likely caused by toxicity of the treatments as tumor in those animals was almost completely regressed.
  • the 5FU-induced body weight loss was almost completely prevented by arsenic pretreatment, as demonstrated by a minimum decrease in body weight of both male and female mice that were fed with arsenic-containing water.
  • mice were fed with water containing arsenic trioxide (as 1.Omg/L) for 3 days. Mice were then irradiated with 2Gy TBI daily for one week. Body weight was monitored throughout the period of the experiment. The numbers are means ⁇ SE from two independent experiments with total of 10 mice per group. Results from this experiment are presented in FIG. 5. In contrast with the wild type littermates, arsenic provided little protection against 5FU- induced toxicity in p53 mutant mice, supporting the model in which arsenic exerts the protective effect selective to healthy normal tissues via suppression of p53.
  • arsenic trioxide as 1.Omg/L
  • mice pretreated with sodium arsenite were subjected to radiation therapy (2Gy or 6Gy), or chemotherapy (cisplatin or 5-FU) and the damage to various cells were assessed.
  • Table 1 shows the status of kidney cells after chemotherapy or radiation therapy, with or without arsenate pretreatment.
  • Table 2 shows the status of bone marrow cells after chemotherapy or radiation therapy, without arsenate pretreatment.
  • Cisplatin 5mg/kg Yes Zero
  • Table 3 shows the status of spleen cells after chemotherapy or radiation therapy, with without arsenate pretreatment.
  • Table 4 shows the status of small intestine cells after chemotherapy or radiation therapy, with or without arsenate pretreatment.
  • Table 5 shows the status of various tissues after chemotherapy or radiation therapy, with or without arsenate pretreatment
  • the data collected from the studies on mice may be used to determine the appropriate dosing ranges for use in humans.
  • the dose range for humans, based on mice studies, may be determined using equation (1);
  • Arsenic Trioxide is available in sterile injectable solution.
  • the molecular formula in solid state is AS2O3. Its molecular weight is 197.8 grams. Though its mechanism of action is not completely understood, it is thought to inhibit growth and promote apoptosis in many different cancer cell lines. At a currently used 10 mg (consistent with the FDA approved dose of
  • arsenic trioxide The metabolism of arsenic trioxide involves reduction of pentavalent arsenic to trivalent arsenic by arsenate reductase and methylation of trivalent arsenic to monomethylarsonic acid and monomethylarsonic acid to dimethylarsinic acid by methyltransferases.
  • the main site of methylation reactions appears to be the liver.
  • Arsenic is stored in liver, kidney, heart, lung and nails. The usual mode of excretion is in urine.
  • arsenic trioxide hematologic toxicity evaluation For the arsenic trioxide hematologic toxicity evaluation, a comparison of alternating chemotherapy cycles without and with arsenic administration is used and measurements of the effect on hematological endpoints is studied using a repeated-measures design.
  • the dose of arsenic trioxide determined from the dose escalation will be used as a fixed dose for each patient for clinical toxicity evaluation. Endpoints include change in hematological parameters over time (white blood cell count, platelet count, and hematocrit) comparing alternating cycles of chemotherapy.
  • the toxicity evaluation will only be performed for patients whose in vitro p53 activation is blocked at the administered dose of arsenic trioxide.
  • arsenic trioxide will not be administrated for cycles 1, 3, and 5 of chemotherapy.
  • Arsenic trioxide will be administered for cycles 2, 4, and 6.
  • Each patient will receive the same dose of arsenic trioxide before the even numbered cycles of chemotherapy.
  • chemotherapies to kill cancer cells which also potently activates p53.
  • Abundant evidence indicates that DNA damaging anticancer therapy-induced acute toxicity is mainly mediated by p53, which, upon activation, induces massive apoptotic cell death in sensitive tissues, including intestinal epithelium, spleen, bone marrow, thymus, tongue, testis and hair follicles, leading to severe pathological consequences.
  • p53 -deficient mice are refractory to toxicity induced by radiation and chemotherapy.
  • p53 -mediated pathological response to chemo- and radiotherapy would suggest that suppression of p53 may serve as a potential approach for amelioration of the adverse side effects, allowing patients to tolerate much more aggressive (and so potentially more successful) treatment regimes.
  • p53 is one of the most important tumor suppressors, so the potential cancer risk resulting from its inhibition needs to be addressed.
  • the p53 tumor suppressor is a transcription factor that controls the expression of a number of genes whose products mediate cell cycle arrest, DNA repair, senescence, or apoptosis.
  • the critical role of p53 in prevention of carcinogenesis is supported by its universal inactivation in cancer cells either through mutations affecting the p53 locus directly or through aberration of its normal regulation. Because the DNA damage response pathway and the oncogenic stress pathway converge on p53, it has been thought that both pathways are integral to the tumor suppressor function of p53. Recent genetic studies, however, have provided compelling evidence indicating that the oncogenic stress pathway, rather than the DNA damage pathway, is essential for p53 -mediated tumor suppression.
  • the knockin mice were incompetent for DNA damage-induced apoptosis yet fully protected from cancer development. These studies together indicate that temporary suppression of p53 activity can significantly reduce DNA damage-induced cytotoxicity without compromising the tumor suppression function, providing a rationale to explore temporary p53 inhibition as an approach of cancer therapy protection.
  • Arsenic is a naturally occurring metalloid that induces oxidative stress by activating NADPH oxidase activity through a Ras-GTPase-dependent mechanism, which creates an intracellular burst of reactive oxygen. Exposure of human, experimental animals and cultured cells to arsenic is associated with a variety of diverse effects.
  • arsenic has also been touted as having beneficial effects on health at lower doses.
  • Fowler's Solution 1% potassium arsenite
  • Arsenic was even applied to the skin by women to improve their complexion.
  • a concentration-related hierarchy of responses to arsenic has been well documented.
  • arsenite treatment at concentrations at or below 5 ⁇ for 24 hr resulted in induced proliferation that is accompanied with enhanced nuclear factor- ⁇ (NF- ⁇ ) and activator protein- 1 (AP-1) activity, transcription factors that are known to promote cell proliferation and cell survival.
  • NF- ⁇ nuclear factor- ⁇
  • AP-1 activator protein- 1
  • the goal of this study was to assess the activity of arsenic trioxide in blocking p53 activation in human patients. Activation of p53 was measured by an in vitro assay of patients' lymphocytes.
  • this assay is a solid phase sandwich enzyme-linked immunosorbent assay (ELISA) that detects endogenous levels of Phospho-p53 (Serl5) protein.
  • ELISA enzyme-linked immunosorbent assay
  • a p53 Rabbit mAb was coated onto the microwells. After incubation with cell lysates, both nonphospho- and phospho-p53 proteins were captured by the coated antibody. Following extensive washing, a phospho-p53 (16G8) Mouse mAb was added to detect the captured phospho-p53 protein. HRP- linked antimouse antibody was then used to recognize the bound detection antibody. HRP substrate, TMB, was added to develop color. The magnitude of optical density for this developed color is proportional to the quantity of phospho-p53 protein.
  • the activation of p53 in the treated (irradiated) sample and the untreated sample was compared by examining difference in optical density between the two samples.
  • the difference in optical density between the treated and untreated samples was divided by the optical density of the untreated sample to give a percentage difference (ELISA percentage).
  • a preliminary cohort of 10 patients was studied.
  • the patients included in this analysis are defined as patients who complete at least one cycle of arsenic trioxide paired with a non- arsenic trioxide cycle.
  • One of ten patients (Subject #007) in the cohort showed a p53 activation inducible upon radiation with 2 Gy in culture at Cycle 1/Day 1, indicating that this patient's lymphocytes had inducible p53.
  • arsenic pretreatment Cycle 2/Day 1
  • the subject showed a reduced p53 activation inducible upon radiation with 2 Gy in culture.
  • the result for Subject #007 is shown in the Table 6 below.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Toxicology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un procédé d'inhibition, de prévention, ou de réduction des lésions entraînées sur les cellules non cancéreuses chez un sujet humain durant le traitement chimiothérapeutique ou radiothérapeutique de cellules cancéreuses chez ledit sujet humain. Ledit procédé comprend l'administration au dit sujet humain d'arsenic et/ou d'un ou de plusieurs composés de l'arsenic en une quantité thérapeutiquement efficace avant le traitement par rayonnement ou par un ou plusieurs agents chimiothérapeutiques.
EP12781877.1A 2011-05-12 2012-05-11 Utilisation d'arsenic dans la protection contre une thérapie contre le cancer Withdrawn EP2707008A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201113106516A 2011-05-12 2011-05-12
US13/110,737 US8834938B2 (en) 2011-05-18 2011-05-18 Use of arsenic for cancer therapy protection
PCT/US2012/037560 WO2012155061A1 (fr) 2011-05-12 2012-05-11 Utilisation d'arsenic dans la protection contre une thérapie contre le cancer

Publications (2)

Publication Number Publication Date
EP2707008A1 true EP2707008A1 (fr) 2014-03-19
EP2707008A4 EP2707008A4 (fr) 2014-11-26

Family

ID=47139696

Family Applications (1)

Application Number Title Priority Date Filing Date
EP12781877.1A Withdrawn EP2707008A4 (fr) 2011-05-12 2012-05-11 Utilisation d'arsenic dans la protection contre une thérapie contre le cancer

Country Status (5)

Country Link
EP (1) EP2707008A4 (fr)
JP (1) JP2014513698A (fr)
CN (1) CN103826645A (fr)
CA (1) CA2835631A1 (fr)
WO (1) WO2012155061A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104546757A (zh) * 2014-12-25 2015-04-29 海南卫康制药(潜山)有限公司 一种白消安组合物冻干片及其制备方法
CN114028425A (zh) * 2021-09-24 2022-02-11 上海交通大学医学院附属新华医院 硫化砷及其与放疗联合在治疗横纹肌肉瘤上的应用

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7405080B2 (en) * 2000-03-23 2008-07-29 Voellmy Richard W Compositions and methods relating to prevention of chemotherapy-induced alopecia
KR20030058019A (ko) * 2001-12-29 2003-07-07 한국원자력연구소 삼산화비소(Ａｓ₂Ｏ₃)를 유효 성분으로 포함하는 방사선치료증진제
US20090246291A1 (en) * 2008-03-27 2009-10-01 Angelika Burger Method and compositions for treatment of cancer
US8795738B2 (en) * 2009-11-12 2014-08-05 Board Of Regents Of The University Of Texas System Use of arsenic for cancer therapy protection

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Week 200380 Thomson Scientific, London, GB; AN 2003-861793 XP002730750, & KR 2003 0058019 A (KOREA ATOMIC ENERGY RES INST) 7 July 2003 (2003-07-07) *
FARAH I O ET AL: "Differential protection and transactivation of P53, P21, Bcl2, PCNA, cyclin G, and MDM2 genes in rat liver and the HepG2 cell line upon exposure to pifithrin", BIOMEDICAL SCIENCES INSTRUMENTATION, INSTRUMENT SOCIETY OF AMERICA, PITTSBURGH, US, vol. 43, 1 January 2007 (2007-01-01), pages 116-121, XP009180503, ISSN: 0067-8856 *
KUMAR P ET AL: "Arsenic trioxide enhances the therapeutic efficacy of radiation treatment of oral squamous carcinoma while protecting bone", MOLECULAR CANCER THERAPEUTICS 2008 US, vol. 7, no. 7, 2008, pages 2060-2069, XP55134570, ISSN: 1535-7163 *
See also references of WO2012155061A1 *
SHEN S-X ET AL: "USE OF ARSENIC TRIOXIDE (AS2O3) IN THE TREATMENT OF ACUTE PROMYELOCITIC LEUKEMIA (APL): II. CLINICAL EFFICACY AND PHARMACOKINETICS IN RELAPSED PATIENTS", BLOOD, AMERICAN SOCIETY OF HEMATOLOGY, US, vol. 89, no. 9, 1 May 1997 (1997-05-01), pages 3354-3360, XP000891715, ISSN: 0006-4971 *

Also Published As

Publication number Publication date
CA2835631A1 (fr) 2012-11-15
WO2012155061A1 (fr) 2012-11-15
EP2707008A4 (fr) 2014-11-26
JP2014513698A (ja) 2014-06-05
CN103826645A (zh) 2014-05-28

Similar Documents

Publication Publication Date Title
EP3169312B1 (fr) Traitement du cancer associant un rayonnement, des nanoparticules d'oxyde de cérium et un agent chimiothérapeutique
ES2661216T3 (es) Método combinado para tratar el cáncer o un estado precanceroso
US20100029683A1 (en) Methods for regulating cell mitosis by inhibiting serine/threonine phosphateses
ES2945712T3 (es) Método de tratamiento de cáncer de mama triple negativo
CA2397598A1 (fr) Combinaisons permettant de traiter des neoplasmes
KR20220151027A (ko) Ｍｄｍ２ 억제제의 간헐적 투여
Tian et al. Preclinical evaluation of promitil, a radiation-responsive liposomal formulation of mitomycin c prodrug, in chemoradiotherapy
US8795738B2 (en) Use of arsenic for cancer therapy protection
JP5642892B2 (ja) 多形膠芽腫の治療のためのマシテンタンを含有する組み合わせ剤
Tiwari et al. Akt1/NFκB signaling pathway activation by a small molecule DMA confers radioprotection to intestinal epithelium in xenograft model
JP2006528696A (ja) 抗癌剤の抗腫瘍活性を増強する方法
WO2012155061A1 (fr) Utilisation d'arsenic dans la protection contre une thérapie contre le cancer
US8834938B2 (en) Use of arsenic for cancer therapy protection
ES2624644T3 (es) Inhibidores de proteasoma para el tratamiento de cáncer
US20170202965A1 (en) Treatment of cancer with a combination of radiation, cerium oxide nanoparticles, and a chemotherapeutic agent
US20060263346A1 (en) Combined pharmaceutical preparations for the treatment of cancer, containing glutaminase and antineoplastic anthracyclines or platinum compounds
TW202408485A (zh) 用於減少癌症治療中不良副作用之組合物及方法
US20080038376A1 (en) Anti-cancer composition and method for using the same
ES3017257T3 (en) Abt-751 and ionizing radiation for use in treating a brain tumor
TWI898418B (zh) 用以治療大腸癌的藥學套組及其用途
US20240415869A1 (en) Compositions, systems, and methods for treating cancer using tumor treating fields (ttfields) and thioredoxin/glutathione inhibitors
Liao et al. Radioprotectors in the Management of Lung Cancer
HK40026959A (en) Treatment of cancer with a combination of radiation, cerium oxide nanoparticles, and a chemotherapeutic agent
Alhadyan Targeting thioredoxin reductase in pancreatic cancer
Werner-Wasik Clinical applications of radioprotectors

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20131205

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAX Request for extension of the european patent (deleted)
A4 Supplementary search report drawn up and despatched

Effective date: 20141024

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 33/36 20060101AFI20141017BHEP

Ipc: A61P 43/00 20060101ALI20141017BHEP

Ipc: A61P 39/00 20060101ALI20141017BHEP

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20150522