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WO2004056371A1 - Utilisation d'aglycone protopanaxatriol dans la therapie du cancer - Google Patents

Utilisation d'aglycone protopanaxatriol dans la therapie du cancer Download PDF

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WO2004056371A1
WO2004056371A1 PCT/CA2003/001954 CA0301954W WO2004056371A1 WO 2004056371 A1 WO2004056371 A1 WO 2004056371A1 CA 0301954 W CA0301954 W CA 0301954W WO 2004056371 A1 WO2004056371 A1 WO 2004056371A1
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cancer
appt
mdr
treatment
carcinoma
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Dong Huang
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Panagin Pharmaceuticals Inc
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Panagin Pharmaceuticals Inc
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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention pertains to the field of cancer therapy and in particular to the use of aglycon protopanaxatriol (aPPT) in the treatment of cancer.
  • aPPT aglycon protopanaxatriol
  • MDR multi-drug resistance
  • combination chemotherapy which uses the differing mechanisms of action and cytotoxic potentials of multiple drugs.
  • combination chemotherapy has been successful in many cases, the need still exists for new anti-cancer drugs, it may still fail in cases involving drug resistant tumors having multiple resistance phenotypes.
  • An object of the present invention is to provide a use of aglycon protopanaxatriol
  • composition comprising a therapeutically effective amount of substantially purified aglycon protopanaxatriol (aPPT) and a physiologically acceptable carrier for the treatment of a multi-drug resistant (MDR) cancer in a mammal.
  • MDR multi-drug resistant
  • composition consisting essentially of a therapeutically effective amount of substantially purified aglycon protopanaxatriol (aPPT) and a physiologically acceptable carrier for the treatment of a multi-drug resistant (MDR) cancer in a mammal.
  • aPPT substantially purified aglycon protopanaxatriol
  • MDR multi-drug resistant
  • the MDR cancer is a primary or recurrent cancer selected from the group of: pancreatic cancer, lung cancer, stomach cancer, esophagus cancer, colon and rectum cancer, brain cancer, ovary cancer, liver cancer, kidney cancer, larynx cancer, bone cancer, multiple myeloma, melanoma, breast cancer, prostate cancer, bladder cancer, cancer in body of uterus, oral cavity cancer, thyroid cancer, cervix cancer, testis cancer, non-Hodgkin's lymphoma, leukemia, Hodgkin's disease, skin cancer, and soft tissue cancer.
  • aPPT substantially purified aglycon protopanaxatriol
  • aglycon protopanaxatriol aglycon protopanaxatriol
  • aglycon protopanaxatriol aPPT
  • MDR multi-drug resistant
  • a method of treating a multi-drug resistant cancer in a mammal comprising administering to said mammal an effective amount of substantially purified aglycon protopanaxatriol (aPPT).
  • aPPT substantially purified aglycon protopanaxatriol
  • aPPT substantially purified aglycon protopanaxatriol
  • Figure 1 provides a graphical representation of cell viability of multi-drug resistant cancer cells treated with various concentrations of aPPT
  • Figure 2 provides a graphical representation of (A) cell viability of multi-drug resistant cancer cells treated with various concentrations of aPPT and (B) cell viability of multi-drug resistant cancer cells treated with various concentrations of Taxol;
  • Figure 3 demonstrates the effect of aPPT in the mesothelioma cell line MS-1;
  • Figure 4 demonstrates the effects of aPPT on the drug resistant pancreatic cancer cell line BXPC in vitro
  • Figure 5 demonstrates the effects of aPPT on the drug resistant pancreatic cancer cell line BXPC in vivo
  • Figure 6 demonstrates the tumor inhibitory effect of aPPT on multi-drug resistant B16 melanoma cells
  • Figure 7 demonstrates the effects of aPPT on the drug resistant breast cancer cell line MCF7r in vivo
  • Figure 8 demonstrates that aPPT enhances BCNU inhibition of growth of U87 human glioma cells
  • Figure 9 demonstrates (A) the effect of aPPT on MDR cancer cell MCF7r, (B) the effect of aPPT and paclitaxel on MCF7 non-drug resistant cancer cells and (C) the effect of aPPT on MCF7r multi-drug resistant cancer cells; and Figure 10 demonstrates the effect of aglycon protopanaxatriol on multi-drug resistant cancer cells (A) shows cells pre-aPPT treatment and (B) shows cells 15 min. post- aPPT treatment.
  • Multi-drug resistant (MDR) refers to an innate or acquired ability of the cancer, tumor or neoplastic cells to develop resistance to treatment.
  • primary MDR is untreated cancer that is considered unresponsive to chemotherapy and secondary MDR develops resistance during the course of treatment.
  • multi-drug resistant cancer will refer to drug resistance that may be caused by several mechanisms including, but not limited to, decreased drug accumulation (e.g., active excretion of the chemotherapeutic by a protein pump (such as P-glycoprotein)), accelerated metabolism of the drug and other alterations of drug metabolism, and an increase in the ability of the cell to repair drug-induced damage.
  • a "refractory” cancer or tumor refers to a cancer or tumor that has not responded to treatment. Such cancers or tumors are often also MDR.
  • Advanced cancer refers to overt cancer in a subject, wherein such overt cancer is usually not localized, and is not amenable to cure by local modalities of treatment, such as surgery or radiotherapy.
  • Primary cancer refers to the original tumor or primary tumor and is usually named for the part of the body in which it begins.
  • Metalstatic cancer refers to a cancer which has spread from an initial site (“primary cancer") to another site(s) (“secondary cancer”). Virtually all cancers can develop metastases. The term, thus, is not limited to any one particular type of cancer.
  • Recurrent cancer refers to a reappearance of a cancer that was thought to be cured or inactive (in remission). A cancer may recur after several weeks, several months, a few years, or many years. Recurrent cancer usually starts from cancer cells that were not removed or destroyed by the original therapy, e.g. chemotherapy.
  • aggressive cancer refers to a rapidly growing cancer.
  • aggressive cancer will refer to an advanced cancer that has relapsed within approximately the earlier two-thirds of the spectrum of relapse times for a given cancer, whereas for other types of cancer, such as small cell lung carcinoma (SCLC) nearly all cases present rapidly growing cancers which are considered to be aggressive.
  • SCLC small cell lung carcinoma
  • Relapse refers to the relapse of a patient with advanced disease.
  • Relapse time refers to the time from the initial appearance of a primary cancer to the appearance of advanced disease requiring chemotherapy.
  • adjuvant therapy refers to a treatment that is added to increase the effectiveness of a primary treatment.
  • adjuvant therapy usually refers to chemotherapy or radiation therapy after surgery (primary treatment) to increase the likelihood of killing all cancer cells.
  • neoadjuvant therapy refers to a treatment given before the- primary treatment.
  • examples of neoadjuvant therapy include chemotherapy, radiation therapy, and hormone therapy.
  • the present invention provides for the use of aglycon protopanaxatriol (aPPT) in the treatment of multi-drug resistant (MDR) cancer in mammalian subjects, including humans.
  • aPPT aglycon protopanaxatriol
  • MDR multi-drug resistant
  • many chemotherapeutics capable of inhibiting the growth of drug sensitive cells are ineffective in inhibiting the growth of MDR cancer cells.
  • the ability of a compound to inhibit the growth of drug sensitive cells is not predictive of its ability to attenuate the growth of MDR cancer cells.
  • the present invention relates to the unexpected cytotoxic effect of aPPT as a single agent, as well as in combination with other chemotherapeutics, on a range of MDR cancer cells, which have developed drug resistance through different mechanisms.
  • aPPT may act on MDR cancer cells by attenuating or decreasing the growth and/or viability of MDR neoplastic cells, or it may act as a chemosensitizing agent. aPPT may, therefore, be used alone or in combination with one or more standard chemofherapeutic agent(s) in the treatment of a range of MDR cancers.
  • mechanisms of multi-drug resistance in tumor cells can be generally divided into P-gp dependent and P-gp independent. Different mechanisms determine specific groups of chemotherapy drugs that tumor cells are resistant to and, therefore, different treatments need to be selected in order to try to re-sensitise the cells.
  • aPPD is demonstrated herein to be able to re-sensitise cancer cells that have developed multi-drug resistance through both P-gp dependent and P-gp independent mechanisms.
  • the aPPT for use in the treatment of MDR cancers is substantially purified.
  • substantially purified refers to a preparation in which the aPPT forms the major component, i.e. aPPT constitutes more than about 50% of the preparation.
  • a substantially purified aPPT preparation refers to a preparation in which the aPPT constitutes more than about 60% of the preparation, i another embodiment, the term refers to a preparation in which the aPPT constitutes more than about 70% of the preparation. In a further embodiment, the term refers to a preparation in which the aPPT constitutes more than about 75% of the preparation. In other embodiments, a substantially purified aPPT preparation refers to a preparation in which the aPPT constitutes more than about 80%, more than about 85%, more than about 90% and more than about 95% of the preparation.
  • aPPT can adopt a number of stereoisomeric forms.
  • the natural form of most ginsenosides is 20S, however, during the process of extracting the ginsenosides from plant material, 20R compounds may be formed.
  • the use of various stereoisomers of aPPT is contemplated.
  • One embodiment of the invention therefore, employs aPPT having the following chemical structure:
  • aPPT can be obtained from extracts prepared from plants of the genus Panax using standard techniques. The isolation and purification of aPPT from natural sources has been described in the art, for example, see U.S. Patent No. 4,157,894. Examples of plants from which aPPT may be obtained include, but are not limited to, Panax aureus; Panax bipinnatifidus (also known as: Panax major and Panax pseudoginseng var. bipinnatifidus); Panax ginseng C. A. Meyer (also known as: Panax schinseng); Panax japonicus (also known as: Panax pseudoginseng subsp.
  • Panax notoginseng also known as: Aralia quinquefolia var. notoginseng and Panax pseudoginseng var. notoginseng
  • Panax pseudoginseng also known as: Aralia pseudoginseng and Panax pseudoginseng var. pseudoginseng
  • Panax wangianus also known as: Panax pseudoginseng var. wangianus
  • Panax quinquefolius including P. quinquefolius L
  • Panax stipuleanatus Panax trifolius
  • aPPT can be obtained from Panax plant extracts using standard extraction, fractionation and/or purification techniques.
  • Such techniques include, for example, solid-liquid extraction, liquid-liquid extraction, solid-phase extraction (SPE), membrane filtration, ultrafiltration, dialysis, electrophoresis, solvent concentration, centrifugation, ultracentrifugation, liquid or gas phase chromatography (including size exclusion, affinity, and the like) with or without high pressure, thin-layer chromatography, lyophilisation, evaporation, precipitation with various "carriers" (including PVPP, carbon, antibodies, and the like), or various combinations of these techniques.
  • SPE solid-liquid extraction
  • SPE solid-phase extraction
  • membrane filtration ultrafiltration
  • dialysis dialysis
  • electrophoresis solvent concentration
  • centrifugation ultracentrifugation
  • liquid or gas phase chromatography including size exclusion, affinity, and the like
  • aPPT is also available commercially (Pegasus Pharmaceuticals, Inc., Richmond, British Columbia, Canada) or can be chemically or biologically synthesized using techniques well known to persons of skill in the art (see, for example, Shibata, S. (2001) J. Korean Med. Sci., 16 Suppl.: S28-37, and references therein).
  • Preparations of aPPT can be assayed to determine their ability to attenuate the growth of MDR neoplastic cells, or sensitize such cells to a chemotherapeutic, using standard techniques well known to workers skilled in the art. Exemplary testing methods are outlined herein and are not intended to limit the scope of the present invention.
  • Suitable MDR cell lines for testing the ability of the preparations to attenuate MDR cancer cell growth include, for example, LNCaP prostate cancer cells, MS-1 mesothelioma cancer cells, BXPC pancreatic cancer cells, U87 glioma cells and MCF-7r breast cancer cells.
  • the cytotoxic activities of aPPT can be measured using a standard method for adherent cell lines such as the microculture tetrazolium assay that utilises 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Details of this assay have been published (Alley, M C et al, Cancer Research 48:589-601, 1988).
  • MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
  • the plates are analyzed and the number of viable cells in each well containing cells treated with aPPT is calculated from the absorbance at 570 nm compared to untreated controls, or controls treated with a standard chemotherapeutic.
  • the concentration of aPPT that gives a T/C of 50% growth inhibition is designated as the IC 50 value.
  • An alternative method of evaluating anti-cancer activity of aPPT involves determining the effect of various concentrations on the viability of cancer cells. Exponentially growing cancer cells are treated with various concentrations of aPPT. The cells are further incubated for 24 h and stained with a molecule that allows a distinction between viable and non-viable cells, for example crystal violet. The absorbency of the stained cells at 590nm is then measured. The percent viability of treated cells is then compared to that of control cells. Average absorbency of the control wells (A c ) without any treatment is calculated, average absorbency of each treatment group (A T ;) is determined, and then the average cell viability of each treatment group (V) is derived using the following formula:
  • a decrease in viability in the treated cells in comparison to the control cells is indicative of anti-cancer activity.
  • the aPPT preparations can also be tested by determining their ability to inhibit anchorage-independent growth of tumor cells.
  • Anchorage-independent growth is known in the art to be a good indicator of tumorigenicity.
  • anchorage- independent growth is assessed by plating cells from an appropriate cancer cell-line onto soft agar and determining the number of colonies formed after an appropriate incubation period. Growth of cells treated with aPPT can then be compared with that of cells treated with an appropriate control compound and with that of untreated cells.
  • the ability of the aPPT preparations to sensitise MDR cancer cells to the effects of one or more standard chemotherapeutic can also be assessed using the above- described assays by contacting the cells with both the aPPT preparation and the chemotherapeutic(s).
  • the cells maybe contacted with the aPPT preparation prior to, at the same time as, or subsequent to contact with the chemotherapeutic(s).
  • the effect on the cells is then compared to control cells that were contacted with the chemotherapeutic(s) alone.
  • toxicity of the preparations can also be initially assessed in vitro using standard techniques.
  • human primary fibroblasts can be treated in vitro with the compositions and then tested at different time points following treatment for their viability using a standard viability assay, such as the trypan-blue exclusion assay.
  • Cells can also be assayed for their ability to synthesize DNA, for example, using a thymidine incorporation assay, and for changes in cell cycle dynamics, for example, using a standard cell sorting assay in conjunction with a fluorocytometer cell sorter (FACS).
  • FACS fluorocytometer cell sorter
  • compositions to inhibit tumor growth or proliferation in vivo can be determined in an appropriate animal model using standard techniques known in the art (see, for example, Enna, et al, Current Protocols in Pharmacology, J. Wiley & Sons, Inc., New York, NY).
  • xenograft models in which a human tumor has been implanted into an animal.
  • xenograft models of human cancer include, but are not limited to, human solid tumor xenografts in mice, implanted by sub-cutaneous injection and used in tumor growth assays; human solid tumor isografts in mice, implanted by fat pad injection and used in tumor growth assays; experimental models of lymphoma and leukaemia in mice, used in survival assays, and experimental models of lung metastasis in mice.
  • aPPT can be tested in vivo on solid tumors using mice that are subcutaneously grafted bilaterally with 30 to 60 mg of a tumor fragment on day 0.
  • an appropriate number of cancer cells can be implanted subcutaneously.
  • the animals bearing tumors are mixed before being subjected to the various treatments and controls.
  • tumors are allowed to develop to the desired size, animals having insufficiently developed tumors being eliminated.
  • the selected animals are distributed at random to undergo the treatments and controls. Animals not bearing tumors may also be subjected to the same treatments as the tumor-bearing animals in order to be able to dissociate the toxic effect from the specific effect on the tumor.
  • Chemotherapy generally begins from 3 to 22 days after grafting, depending on the type of tumor, and the animals are observed every day.
  • the aPPT can be administered to the animals, for example, interperitoneally or by bolus infusion.
  • the different animal groups are weighed about 3 or 4 times a week until the maximum weight loss is attained, after which the groups are weighed at least once a week until the end of the trial.
  • the tumors are measured after a pre-determined time period, or they can be monitored continuously by measuring about 2 or 3 times a week until the tumor reaches a predetermined size and / or weight, or until the animal dies if this occurs before the tumor reaches the pre-determined size / weight.
  • the animals are then sacrificed and the tissue histology, size and / or proliferation of the tumor assessed.
  • the animals are grafted with a particular number of leukaemic cells, and the anti-tumor activity is determined by the increase in the survival time of the treated mice relative to the controls.
  • tumor cells are typically treated with aPPT ex vivo and then injected into a suitable test animal. The spread of the tumor cells from the site of injection is then monitored over a suitable period of time.
  • the ability of the preparations to sensitise MDR tumors to the effects of one or more standard chemotherapeutic can also be assessed in the above models.
  • the aPPT preparation can be administered prior to, in combination with, or subsequent to the chemotherapeutic(s) and the effects compared to control animals that received the chemotherapeutic(s) alone.
  • In vivo toxic effects of the aPPT preparations can be evaluated by measuring their effect on animal body weight during treatment and by performing haematological profiles and liver enzyme analysis after the animal has been sacrificed.
  • the present invention provides for methods of treating a MDR cancer in a mammal comprising administering to the mammal an effective amount of aPPT, either alone or in combination with one or more chemotherapeutic.
  • aPPT chemotherapeutic
  • forms of cancer with a high malignancy potential, or present with metastasis at diagnosis, typify the MDR category.
  • a variety of tumors with a frequency of primary MDR have been reported (Yin L., et al; 19(6) :420-2, 1997), for example: lung (55%), stomach (33%), esophagus (37%), colorectal (31%), and thyroid (40%).
  • Examples of other forms of cancer that develop secondary MDR after treatment include: breast, prostate, Hodgkins & Non-Hodgkins lymphoma, bladder, leukemia, endometrial, oropharyngeal, cervical, testis, skin, and soft tissue cancer; this does not exclude the occurrence of a primary MDR in these groups.
  • pancreatic cancer is one example of a tumor impervious to conventional chemotherapy, i.e.
  • MDR cancer h contrast
  • breast cancer often achieves high remission rates in response to chemotherapy, but relapses are exclusively secondary MDR (Liu X., et al; Zhonghua YiXue Za Zhi 77(7):488-90, 1997).
  • aPPT is used to treat primary cancers that are usually resistant to conventional chemotherapeutics, including without limitation: pancreatic cancer, lung cancer, stomach cancer, esophageal cancer, colon and rectal cancer, brain cancer (including gliomas), ovary cancer, liver cancer, kidney cancer, larynx cancer, bone cancer, multiple myeloma, mesothelioma and melanoma.
  • aPPT is used to treat MDR cancers developed in subjects who have undergone prior chemotherapy, including without limitation, the above cancers as well as: breast cancer, prostate cancer, bladder cancer, cancer in body of uterus, oral cavity cancer, thyroid cancer, cervix cancer, testis cancer, non-Hodgkin's lymphoma, leukemia, Hodgkin's disease, skin cancer, and soft tissue cancer.
  • aPPT is used to treat advanced and metastatic cancers, which are usually drug resistant, including the above cancers when in an advanced and/or metastatic stage.
  • the aPPT may also be used to treat aggressive, refractory and recurrent cancers.
  • aggressive cancers are typically also metastatic.
  • Additional cancers encompassed by the present invention include, for example, primary and metastatic multi-drug resistant leukaemias, carcinomas, adenocarcinomas, melanomas and sarcomas.
  • Solid tumors Carcinomas, adenocarcinomas and sarcomas are also frequently referred to as "solid tumors," examples of commonly occurring solid tumors include, but are not limited to, cancer of the brain, breast, cervix, colon, head and neck, kidney, liver, lung, ovary, pancreas, prostate, stomach and uterus, non-small cell lung cancer and colorectal cancer.
  • leukaemia refers broadly to progressive, malignant diseases of the blood- forming organs. Leukaemia is typically characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow but can also refer to malignant diseases of other blood cells such as erythroleukaemia, which affects immature red blood cells. Leukaemia is generally clinically classified on the basis of (1) the duration and character of the disease - acute or chronic; (2) the type of cell involved - myeloid (myelogenous), lymphoid (lymphogenous) or monocytic, and (3) the increase or non-increase in the number of abnormal cells in the blood - leukaemic or aleukaemic (subleukaemic).
  • Leukaemia includes, for example, acute nonlymphocytic leukaemia, chronic lymphocytic leukaemia, acute granulocytic leukaemia, chronic granulocytic leukaemia, acute promyelocytic leukaemia, adult T- cell leukaemia, aleukaemic leukaemia, aleukocythemic leukaemia, basophylic leukaemia, blast cell leukaemia, bovine leukaemia, chronic myelocytic leukaemia, leukaemia cutis, embryonal leukaemia, eosinophilic leukaemia, Gross' leukaemia, hairy-cell leukaemia, hemoblastic leukaemia, hemocytoblastic leukaemia, histiocytic leukaemia, stem cell leukaemia, acute monocytic leukaemia, leukopenic leukaemia, lymphatic leukaemia, lymphoblastic leukaemia, lymphocytic leuk
  • sarcoma generally refers to a tumor which originates in connective tissue, such as muscle, bone, cartilage or fat, and is made up of a substance like embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance.
  • Sarcomas include soft tissue sarcomas, chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented haemorrhagic
  • melanoma refers to a tumor arising from the melanocytic system of the skin and other organs.
  • Melanomas include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, and superficial spreading melanoma.
  • carcinoma refers to a malignant growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases.
  • exemplary carcinomas include, for example, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colorectal carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcer
  • carcinomas that originate in cells that make organs which have glandular (secretory) properties or that originate in cells that line hollow viscera, such as the gastrointestinal tract or bronchial epithelia. Examples include, but are not limited to, adenocarcinomas of the breast, lung, pancreas and prostate.
  • cancers encompassed by the present invention include, for example, Hodgkin's Disease, Non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, small-cell lung tumors, primary brain tumors, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, gliomas, testicular cancer, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, mesothelioma and medulloblastoma.
  • aPPD is used in the treatment of primary, advanced, recurrent or metastatic MDR cancers selected from the group of: solid tumors, adenocarcinomas, melanomas, cancers of the mesothelium and brain cancers.
  • aPPD is used in the treatment of primary, advanced, recurrent or metastatic MDR cancers selected from the group of: ovarian cancer, renal cancer, colorectal cancer, uterine cancer, liver cancer, adenocarcinoma of the lung, lung cancer, breast cancer, pancreatic cancer, melanoma, mesothelioma and glioma.
  • aPPD is used in the treatment of primary, advanced, recurrent or metastatic MDR cancers selected from the group of: breast cancer, pancreatic cancer, melanoma, mesothelioma and glioma.
  • aPPT in adjuvant therapy after primary therapy as well as in neoadjuvant therapy, i.e. before the primary treatment.
  • aPPT can be used to treat subjects who have undergone prior chemotherapy or it may be used to treat chemotherapy naive subjects.
  • aPPT is used as part of an adjuvant therapy.
  • aPPT is used to treat subjects who have already undergone one or more courses of prior chemotherapy.
  • aPPT may be used as part of a combination chemotherapy regimen to treat a subject having a multi-drug resistant cancer.
  • aPPT according to the present invention can be used either alone or in combination with other pharmacologically active chemotherapeutic agents or other anti-cancer therapeutics to treat multi-drug resistant cancers.
  • aPPT may be active in its own right or it may at as a "sensitizing agent," which selectively inhibits the growth of cancer cells.
  • aPPT alone may not have a cytotoxic effect on the cancer cell, but provides a means of weakening the cancer cells, and thereby facilitates the benefit from conventional anti-cancer therapeutics.
  • an "anti-cancer therapeutic” is a compound, composition or treatment that prevents or delays the growth and or metastasis of cancer cells.
  • anti-cancer therapeutics include, but are not limited to, chemotherapeutic drug treatment, radiation, gene therapy, hormonal manipulation, immunotherapy and antisense oligonucleotide therapy.
  • Chemotherapeutic agents can be specific for the treatment of a particular type of cancer or they may be applicable to a range of cancers, for example doxorubicin, mitoxantrone, and irinotecan (CPT-11) are generally applicable chemotherapeutics.
  • chemotherapeutic agents suitable for the treatment of breast cancer include, but are not limited to, cyclophosphamide, ifosfamide, cisplatin, carboplatin, 5-fluorouracil (5-FU), taxanes such as paclitaxel and docetaxel and various anthracyclines, such as doxorubicin and epi-doxorubicin (also known as epirubicin).
  • Combination therapies using standard cancer chemotherapeutics may also be used in conjunction with aPPT and are also well known in the art, for example, the combination of epirubicin with paclitaxel or docetaxel, or the combination of doxorubicin or epirubicin with cyclophosphamide, which are used for breast cancer treatments.
  • Polychemotherapeutic regimens are also useful and may consist, for example, of doxorubicin/cyclophosphamide/5-fluorouracil or cyclophosphamide/epirubicin/5-fluorouracil.
  • Cyclophosphamide, mitoxantrone and estramustine are known to be suitable for the treatment of prostate cancer.
  • Cyclophosphamide, vincristine, doxorubicin and etoposide are used in the treatment of small cell lung cancer, as are combinations of etoposide with either cisplatin or carboplatin.
  • combinations of doxorubicin or epirubicin with cisplatin and 5- fluorouracil are useful.
  • CPT-11 alone or in combination with 5- fluorouracil-based drugs, or oxaliplatin in combination with 5-fluorouracil-based drugs can be used.
  • doxorubicin examples include the combination of cyclophosphamide, doxorubicin, vincristine and prednisone in the treatment of non-Hodgkin's lymphoma; the combination of doxorubicin, bleomycin, vinblastine and DTIC in the treatment of Hodgkin's disease and the combination of cisplatin or carboplatin with any one or a combination of gemcitabine, paclitaxel, docetaxel, vinorelbine or etoposide in the treatment of non-small cell lung cancer.
  • Carmustine (N,N'-bis(2-hydroxyethyl)-N-nit ⁇ osourea or BCNU) is useful in the treatment of brain tumors (such as gliomas), multiple myeloma, Hodgkin's disease, non-Hodgkin's lymphoma and other malignant neoplasms.
  • chemotherapeutic agents include, but are not limited to, mitomycin C, IL-2-II and IL-2-I, novantrone, DTIC, hydroxyurea, busulphan, chlorambucil, melphalan, Ifosphamide, danorubicin, Navelbine® (vinorelbine), teniposide, cytosine, arabinoside, neocarcinostatin, suramin and the like.
  • aPPT is used in a chemotherapy regimen that involves the use of a taxane chemotherapeutic (such as paclitaxel, docetaxel or taxol), an alkylating agent (such as BCNU, cyclophosphamide, melphalan, mitomycin C or chlomambucil) or an antimetabolite (such as gemcitabine, methotrexate, 5-FU or cytarabine).
  • a taxane chemotherapeutic such as paclitaxel, docetaxel or taxol
  • an alkylating agent such as BCNU, cyclophosphamide, melphalan, mitomycin C or chlomambucil
  • an antimetabolite such as gemcitabine, methotrexate, 5-FU or cytarabine
  • aPPT is used in a chemotherapy regimen that involves the use of paclitaxel, BCNU or gemcitabine.
  • the chemotherapy regimen can be polycheniotherapeutic and involve the use of other chemotherapeutic drugs in addition to those listed above.
  • the present invention further provides for compositions comprising aPPT and an appropriate physiologically acceptable carrier, diluent, excipient or vehicle.
  • the pharmaceutical compositions may also be formulated to contain aPPT and one or more other chemotherapeutic agents for simultaneous administration to a subject.
  • the pharmaceutical compositions of the present invention may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • compositions may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions and may contain one or more agents selected from the group of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with suitable non- toxic pharmaceutically acceptable excipients including, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch, or alginic acid; binding agents, such as starch, gelatine or acacia, and lubricating agents, such as magnesium stearate, stearic acid or talc.
  • suitable non- toxic pharmaceutically acceptable excipients including, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch, or alginic acid; binding agents, such as starch, gelatine or acacia, and lubricating agents, such as magnesium stearate, stearic acid or talc.
  • the tablets can be uncoated,
  • compositions for oral use may also be presented as hard gelatine capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • an oil medium such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active compound in admixture with suitable excipients including, for example, suspending agents, such as sodium carboxymethylcellulose, methyl cellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum fragacanth and gum acacia; dispersing or wetting agents such as a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethyene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, hepta-decaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol for example, polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate.
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl -hydroxy- benzoate, one or more colouring agents, one or more flavouring agents or one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl -hydroxy- benzoate
  • colouring agents for example ethyl, or n-propyl -hydroxy- benzoate
  • flavouring agents for example sucrose or saccharin.
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and/or flavouring agents may be added to provide palatable oral preparations. These compositions can be preserved by the addition of an anti- oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent, suspending agent and one or more preservatives are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present.
  • compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oil phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example, liquid paraffin, or it may be a mixtures of these oils.
  • Suitable emulsifying agents may be naturally-occurring gums, for example, gum acacia or gum fragacanth; naturally-occurring phosphatides, for example, soy bean, lecithin; or esters or partial esters derived from fatty acids and hexitol, anhydrides, for example, sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monoleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • sweetening agents for example, glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, and/or flavouring and colouring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to known art using suitable dispersing or wetting agents and suspending agents such as those mentioned above.
  • the sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • Acceptable vehicles and solvents that may be employed include, but are not limited to, water, Ringer's solution, lactated Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils which are conventionally employed as a solvent or suspending medium
  • a variety of bland fixed oils including, for example, synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions and methods of preparing pharmaceutical compositions are known in the art and are described, for example, in "Remington: The Science and Practice of Pharmacy,” Gennaro, A., Lippincott, Williams & Wilkins, Philidelphia, PA (2000) (formerly “Remingtons Pharmaceutical Sciences”).
  • the invention also provides for aPPT to be administered as a non-pharmaceutical composition in an appropriate physiologically acceptable medium such as a buffer, a solvent, a diluent, an inert carrier, an oil, a creme, or an edible material.
  • the non- pharmaceutical composition may be in the form of, for example, a nutraceutical composition, a food, a health food, a natural health product, a functional food, a nutritional supplement, a dietary supplement, an herbal supplement, an herb, an alternative medicine, and a naturopathic product.
  • the non-pharmaceutical composition comprises a therapeutically effective amount of aPPT in a physiologically acceptable medium.
  • the non-pharmaceutical compositions disclosed herein can be provided in various forms, for example, as a tablet, a capsule, or an ointment.
  • a therapeutically effective amount of aPPT is administered to a subject in order to treat a multi-drug resistant cancer.
  • aPPT or a pharmaceutical composition comprising aPPT may be administered in a manner consistent with conventional chemotherapeutic practice.
  • aPPT to be administered will be dependent upon the type of cancer to be treated and the size of the subject and can be readily determined by a skilled practitioner. It is to be understood, however, that the dosage and frequency of administration may be adapted to the circumstances in accordance with known practices in the art, for the treatment of different cancers.
  • Daily dosages of the compounds of the present invention will typically fall within the range of about 0.01 g to about 50g per 70 kg bodyweight per day. However, it will be understood that the actual amount of the compound(s) to be administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the age, weight, and response of the individual patient, and the severity of the patient's symptoms. The above dosage range is given by way of example only and is not intended to limit the scope of the invention in any way.
  • daily dosages of aPPT are within the range of about 0.02g to about 40g per 70 kg bodyweight per day. In another embodiment, daily dosages of aPPT are within the range of about 0.03g to about 30g per 70 kg bodyweight per day. In a further embodiment, daily dosages of aPPT are within the range of about 0.04g to about 20g per 70 kg bodyweight per day.
  • daily dosages of aPPT are within the range of about 0.05g to about 15g, about 0.05g to about lOg, about 0.05g to about 0.9g and about 0.05g to about 0.8g per 70 kg bodyweight per day.
  • the present invention further contemplates the administration to a subject of a therapeutically effective amount of aPPT in combination with one or more anti-cancer therapeutics for the treatment of a MDR cancer.
  • aPPT can be administered before, during or after treatment with the anti-cancer therapeutic.
  • the present invention additionally provides for therapeutic kits containing aPPT for use in the treatment of multi-drug resistant cancer.
  • Individual components of the kit would be packaged in separate containers and, associated with such containers, can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • the liquid solution can be an aqueous solution, for example a sterile aqueous solution.
  • the container means may itself be an inhalant, syringe, pipette, eye dropper, or other such like apparatus, from which the composition may be administered to a subject.
  • kits of the invention may also be provided in dried or lyophilised form and the kit can additionally contain a suitable solvent for reconstitution of the lyophilised components.
  • the kits of the invention also may comprise an instrument for assisting with the administration of the composition to a subject.
  • an instrument may be an inhalant, syringe, pipette, forceps, measured spoon, eye dropper or any such medically approved delivery vehicle.
  • the kit may further comprise one or more other chemotherapeutic agents for administration to a subject in conjunction with aPPT.
  • Cytotoxicity was measured using a standard microculture tetrazolium assay (MTT) (Alley, M C et al, Cancer Research 48:589-601, 1988). Exponentially growing cultures of tumor cells, including multi-drug resistant cell lines, were used to make microtiter plate cultures. Cells were seeded at 1.2 x 10 3 cells per well in 96-well plates, and grown overnight at 37°C. aPPT was then added. Cells were treated for 24 hours. To determine the number of viable cells in each well, MTT dye (3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide in saline) was added in accordance with the standard practice known in the art.
  • MTT dye 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide in saline
  • Multi-drug resistant human breast cancer (MCF7r) and mesothelioma (MS-1) cells were treated with aPPT at various concentrations.
  • the cell viabilities were examined with MTT at 24 hours.
  • Figure 1 shows the comparison of the effect of the various concentrations of aPPT on a human mesothelioma cell line (MS-1) and a multi-drug resistant human breast cancer cell line (MCF7R).
  • MS-1 human mesothelioma cell line
  • MCF7R multi-drug resistant human breast cancer cell line
  • Figure 2a illustrates the effect of aPPT on a multi-drug resistant human breast cancer cell line (MCF7r).
  • MCF7r multi-drug resistant
  • MCF7-7 drug sensitive
  • the cells were treated with 6, 12, 24, and 48 jUg/ml of aPPT for 24 hours prior to determining cell viability using the MTT method as described in Example 1.
  • aPPT showed equal potency on inhibiting both drug sensitive and drug resistant cancer cells.
  • FIG 2b illustrates the effect of Taxol on the same human breast cancer cell lines as was used in Figure 2a.
  • Human breast cancer cells both multi-drug resistant (MCF7r) and drug sensitive (MCF7) were treated with the chemotherapy drug Taxol at various concentrations.
  • the cells were treated with 0.1, 1, 10, 100, and 1000 nM of Taxol for 24 hours prior to determining cell viability using the MTT method. Taxol showed significant cytotoxicity on drug sensitive cells but was much less effective for the drug resistant cells.
  • the cytotoxic efficacy of aPPT on the multi-drug resistant cancer cells was comparable to its effect on the drug-sensitive control, hi contrast, however, the efficacy of Taxol was markedly inhibited in the drug resistant cancer cells.
  • MS-1 mesothelioma cancer cell line using the MTT assay outlined in Example 1.
  • MS-1 is highly drug resistant, but does not express P-gp or P-gp like membrane pumps.
  • aPPT was shown to be cytotoxic to the MS-1 cell line in vitro ( Figure 3).
  • EXAMPLE 4 aPPT Sensitizes Pancreatic Cancer Cells to Gemcitabine.
  • aPPT sensitizes BXPC cells to gemcitabine (Gemzar).
  • BXPC cells were not sensitive to gemcitabine alone, but were sensitive when treated with a combination of aPPT and gemcitabine.
  • EXAMPLE 5 Anti-tumor Efficacy of Gemcitabine (Gemzar) and aPPT In Vivo.
  • EXAMPLE 6 Effect of aPPT on Multi-Drug Resistant B16 Melanoma Cancer Cells
  • the tumor inhibitory effect of aPPT was determined in the highly drug resistant B16 melanoma cell line. Briefly, cells were treated with various concentrations of aPPT and the viability was measured 24 hours post treatment as described previously.
  • aPPT has a potent tumor inhibitory effect on the B16 melanoma cell line.
  • EXAMPLE 7 Effect Of aPPT Alone and In Combination with Paclitaxel on MDR MCF7r Cancer In Vivo.
  • aPPT and paclitaxel were examined in vivo using a human breast cancer SCID mouse model. Briefly, human breast cancer cells MCF7r cells were implanted subcutaneously in SCID mice and tumor size was measured every second day for 30 days post-implantation. Animals received either i) saline, ii) paclitaxel i.p. (5 mg/kg) once a week, iii) aPPT (lOmg/kg) orally every second day or iv) both paclitaxel and aPPT.
  • paclitaxel and aPPT combination treatment resulted in significant inhibition in tumor growth compared to the other three groups (p ⁇ 0.05 at all the data points day 23 forward).
  • the results indicate that aPPT exhibited anti- tumor efficacy in the drug resistant MCF7r SCID model. Further, aPPT enhanced the anti-cancer effect of paclitaxel in this model.
  • EXAMPLE 8 Effect Of aPPT Alone and In Combination with BCNU on Drug Resistant U87 Glioma Cells In Vivo.
  • aPPT alone or in combination with BCNU was examined in a human glioma cell SCID mouse model. Briefly, human malignant U87 glioma cells were implanted subcutaneously in SCID mice and tumor size were measured every second day for 33 days post-implantation. Animals received either i) saline, ii) N,N'-bis(2-hydroxyethyl)-N-nitrosourea (BCNU) 5 mg/kg i.p. once, iii) aPPT lOmg/kg orally every second day, or iv) both BCNU and aPPT.
  • BCNU N,N'-bis(2-hydroxyethyl)-N-nitrosourea
  • BCNU and aPPT combination treatment resulted in significant inhibition in tumor growth compared to the other three groups (p ⁇ 0.001 at all the data points day 17 forward).
  • the results indicate that aPPT exhibited anti-tumor efficacy in the glioma SCID model. Further, aPPT enhanced the anti-cancer effect of BCNU in this model.
  • EXAMPLE 9 The Cytotoxic and Chemosensitising Activity of aPPT.
  • the cytotoxic activity of aPPT alone was examined in the multi-drug resistant breast cancer cell line MCR7r cells in vitro using the MTT assay described in Example 1.
  • aPPT to enhance the efficacy of paclitaxel in the drug sensitive breast cancer cell line MCF7 and the multi-drug resistant breast cancer cell line MCR7r was examined in vitro. Briefly, MCF7 or MCF7r cells were treated with various concentrations of paclitaxel alone or in the presence of 6 ⁇ g/ml aPPT.
  • aPPT enhanced the chemotherapy efficacy of paclitaxel in cancer cells that are drug resistant due to by P-gp independent mechanisms. This enhanced effect was most prominent in drug resistant tumor cells (MCF7r).
  • Table 1 illustrates enhancement effect of aPPT on the IC 50 of paclitaxel on drug sensitive (MCF7) and drag resistant (MCF7r) cell lines.
  • the enhancement effect of aPPT was much more dramatic in drug resistant cell lines than in the drug sensitive cells, especially aPPT.
  • P-gp P-glycoprotein
  • Examples 9 and 10 indicate that aPPT is capable of enhancing the effect of chemotherapeutics on MDR cancer cell lines irrespective of the mechanism by which drug resistance evolved.

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Abstract

L'invention concerne des méthodes pour traiter des tumeurs présentant une résistance pléiotrope chez un mammifère, au moyen d'aglycone protopanaxatriol (aPPT) seul ou en combinaison avec un ou plusieurs agents chimiothérapeutiques. L'invention concerne également des compositions pharmaceutiques et non pharmaceutiques, contenant de l'aPPT, destinées au traitement de sujets mammifères présentant un cancer à résistance pléiotrope, ainsi que des kits pharmaceutiques contenant lesdites compositions.
PCT/CA2003/001954 2002-12-19 2003-12-19 Utilisation d'aglycone protopanaxatriol dans la therapie du cancer Ceased WO2004056371A1 (fr)

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