EP0624096A4 - Taxol utilise comme sensibilisateur aux rayonnements. - Google Patents

Taxol utilise comme sensibilisateur aux rayonnements.

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Publication number
EP0624096A4
EP0624096A4 EP92915821A EP92915821A EP0624096A4 EP 0624096 A4 EP0624096 A4 EP 0624096A4 EP 92915821 A EP92915821 A EP 92915821A EP 92915821 A EP92915821 A EP 92915821A EP 0624096 A4 EP0624096 A4 EP 0624096A4
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EP
European Patent Office
Prior art keywords
cells
effective
dose
ionizing radiation
taxol
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Withdrawn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
EP92915821A
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German (de)
English (en)
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EP0624096A1 (fr
Inventor
Peter B Schiff
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Columbia University in the City of New York
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Columbia University in the City of New York
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Application filed by Columbia University in the City of New York filed Critical Columbia University in the City of New York
Publication of EP0624096A1 publication Critical patent/EP0624096A1/fr
Publication of EP0624096A4 publication Critical patent/EP0624096A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1282—Devices used in vivo and carrying the radioactive therapeutic or diagnostic agent, therapeutic or in vivo diagnostic kits, stents
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy

Definitions

  • Taxol is the prototype of a new class of antineoplastic agents that targets microtubules. It is a natural product isolated from the bark of the western yew, Taxus brevifolia. Its structure, a novel diterpene compound, and antitumor activity in rodents were reported in 1971 (16) . The drug's unigue mechanism of action has generated considerable interest, both for its use to probe the function of the cytoskeleton in basic science, and as a chemotherapeutic agent in oncology. Taxol is known to be a potent cytotoxic agent against a range of human malignancies using cell culture and xenographic model systems (9) .
  • taxol is an active agent in salvage treatment for epithelial ovarian malignancies (2, 5, 15) and has activity against breast cancer (3) as well as melanoma (7, 18).
  • taxol Unlike agents that bind to tubulin, the subunit of microtubules, and inhibit microtubule formation (vinca alkaloids, podophyllotoxin, and colchicine) , taxol induces in vitro formation of exceptionally stable microtubules (10) . Tissue and culture studies have shown the ability of taxol to block and/or prolong cells in the G2 or M phase of the cell cycle (11) .
  • the microtubule cytoskeletons of taxol-treated cells are exceedingly stable to depolymerization, as are isolated drug-treated microtubules.
  • electron microscopy reveals an abnormal microtubular cytoskeleton in drug-treated cells.
  • Taxol has undergone several Phase I trials at many institutions (9) .
  • Plasma concentrations of 1 nM to 5 ⁇ M taxol at safe therapeutic doses are comparable to those required for the antiproliferative and microtubule- stabilizing effects of the drug in vitro.
  • Mitotic arrest has been observed in the esophagus, stomach, small intestine, colon, liver, skin, bone marrow, and testes of patients biopsied within 11 days after receiving taxol (4) .
  • Dose-limiting toxicity includes leukopenia, thrombocytopenia, alopecia, nausea and vomiting, diarrhea, stomatitis, peripheral neuropathy, rashes, elevated serum triglyceride levels, and severe hypersensitivity (most 'likely related to the cremophor vehicle) (1, 5, 6, 17, 18). Partial responses have been reported in patients with non- small cell lung cancer, melanoma, and ovarian cancer.
  • One Phase II study has reported significant activity against standard drug protocol refractory ovarian cancer (8) . It is well known from radiobiological principles that G2/M is the most radiosensitive phase of the cell cycle (13) .
  • taxol, related compounds or pharmaceutically acceptable salts thereof to enhance the cytotoxic effect of ionizing radiation has not previously been described.
  • This invention provides a method of increasing the sensitivity of cells to the cytotoxic effects of ionizing radiation which comprises first incubating the cells with a spindle poison in a suitable carrier at a concentration effective to inhibit the cells from progressing through the G2 or M phases of the cell cycle for an amount of time effective to inhibit division of the cells and then administering an effective cytotoxic dose of ionizing radiation to the cells.
  • This invention also provides a method of treating a cancer patient which comprises first administering to the patient a spindle poison in a suitable carrier in an amount effective to inhibit tumor cells in the patient from progressing through the G2 or M phases of the cell cycle for an amount of time effective to inhibit division of the tumor cells and then administering an effective cytotoxic dose of ionizing radiation to the patient.
  • This invention further provides a method of increasing the sensitivity of cells to the cytotoxic effects of bleomycin which comprises first incubating the cells with a spindle poison in a suitable carrier at a concentration effective to inhibit the progression of the cells through the G2 or M phases of the cell cycle for an amount of time effective to inhibit cell division and then exposing the cells to an effective cytotoxic concentration of bleomycin.
  • This invention still further provides a kit useful for treating a cancer patient which comprises a spindle poison in an amount sufficient to establish a concentration of the poison in the body of the patient effective to inhibit the progression of tumor cells through the G2 and M phases of the cell cycle and an effective cytotoxic dose of a radioisotope in aqueous solution, an antibody-conjugated radioisotope or bleomycin.
  • Figure 1 Cell surviving fraction versus drug concentration following a 24 hr treatment of human astrocytoma cells with taxol. Control plating efficiencies ranged from 52 to 61%. Standard error bars are shown when greater than the size of the symbols.
  • Figure 2 Nomars i-interference contrast photomicrographs of human astrocytoma cells following a 24 hr treatment with various concentrations of taxol: (a) 0 nM; (b) 1 nM, (c) 10 nM; and (d) 100 nM.
  • the effect of the drug on cellular morphology is apparent as is nuclear multi-micronucleation at the higher concentrations. Cells progressively accumulate at the G2/M phase of the cell cycle.
  • FIG. 3 Radiation survival curves with different concentrations of taxol. Clonogenicity for G18 cells is expressed as a function of taxol concentration and radiation dose.
  • A. Survival is expressed on an absolute scale, relative to unirradiated controls without taxol. The effect of taxol alone on cell survival can be seen as the change in survival at 0 Gy. The interaction of taxol and radiation on cells is demonstrated by the change in the shape of the curves at higher taxol concentrations.
  • B Survival curves are presented with survival at a particular radiation dose expressed relative to unirradiated controls with the same concentration of taxol. This emphasizes the change in the shape of the survival curves.
  • FIG. 4 Cytotoxicity and enhancement of radiation sensitization as a function of time of exposure to 10 nM taxol.
  • Cells were exposed to 10 nM taxol for the indicated time periods and clonogenicity assessed with and without 6 Gy irradiation.
  • A. Plating efficiency, or effect of taxol alone on cell survival. For DMSO-treated controls, the plating efficiency is roughly stable, perhaps increasing slightly as a function of time, whereas for the taxol-treated cells, there is clearly a decrease in plating efficiency as a function of time.
  • B Survival of cells treated with 10 nM taxol and 6 Gy of radiation. Survival of irradiated cells is expressed relative to unirradiated cells treated with taxol for the same period of time.
  • the change in cell survival seen as a function of time of taxol exposure is a measure of the increased interaction between these two treatments.
  • a relative decrease in cell survival, and therefore an increase in the level of interaction between taxol and radiation is seen for cells treated for 16 and 24 hours.
  • This invention provides a method of increasing the sensitivity of cells to the cytotoxic effects of ionizing radiation which comprises first incubating the cells with a spindle poison in a suitable carrier at a concentration effective to inhibit the cells from progressing through the G2 or M phases of the cell cycle for an amount of time effective to inhibit division of the cells and then administering an effective cytotoxic dose of ionizing radiation to the cells.
  • Suitable cells for use in accordance with the practice of this invention may be tumor cells.
  • the tumor cells may be brain tumor cells, e.g., astrocytoma, glioblastoma multifor e or medulloblastoma cells.
  • the tumor cells may also be ovarian tumor cells, e.g., epithelial, sex-chord stromal, lipid, germ or gonadoblastoma cells.
  • the tumor cells may further be lung tumor cells, e.g., adenocarcinoma, large cell, small cell or squamous cell tumor cells.
  • the tumor cells may still further be breast tumor cells, e.g., invasive duct carcinoma, medullary carcinoma or muscinous carcinoma cells.
  • the tumor cells may also be melanoma cells.
  • spindle poison means any agent capable of interfering with the functioning of the microtubules in a cell with the result that cell division is inhibited and the cell is blocked in the G2 or M phases of the cell cycle.
  • Spindle poisons may be agents which interfere with microtubule formation and thereby inhibit cell division, e.g., vinblastin and vincristin.
  • Spindle poisons may also be agents which stabilize microtubules and prevent their disassembly during cell division. Examples of such icrotubule-stabilizing agents suitable for use in the practice of this invention include taxol-related compounds.
  • taxol-related compound encompasses compounds possessing a microtubule-stabilizing activity similar to taxol.
  • the taxol-related compound is taxol.
  • Taxol may be a natural product from the bark of the yew Taxus Sp. L.
  • One species of this genus useful as a source of taxol in the practice of this invention is the yew Taxus brevifolia.
  • taxol as used herein encompasses not only taxol from this source, but taxol produced by any method, including chemical synthesis or tissue culture production.
  • Suitable carriers for a spindle poison may be any of a number of aqueous solutions well known to those skilled in the art. Presently preferred are aqueous solutions of dimethyl sulfoxide.
  • an "effective inhibiting concentration" of the spindle poison is any concentration of the spindle poison effective to inhibit the progression of the cells through the cell cycle and cause cells to accumulate in the G2 or M phases.
  • the effective inhibiting concentration of the spindle poison is a concentration from about 1 nM to about 50 ⁇ M.
  • an "effective inhibiting amount of time” is any amount of time for which incubation of the cells with the spindle poison at an effective inhibiting concentration will be effective to inhibit the progression of cells through the G2 or M phases of the cell cycle.
  • the effective inhibiting amount of time is an amount from about 6 hours to about 24 hours, desirably an amount from about 8 hours to about 20 hours. More desirably, the effective inhibiting amount of time is an amount about 18 hours.
  • administering comprises exposing the cells to a beam of ionizing radiation.
  • an effective cytotoxic dose of ionizing radiation is any dose of ionizing radiation effective to kill cells.
  • the effective cytotoxic dose of ionizing radiation is a dose from about 1 Gy to about 10 Gy, desirably a dose from about 2 Gy to about 8 Gy.
  • Methods of producing a beam of ionizing radiation suitable for the exposure of cells in accordance with the practice of this invention are well known to those skilled in the art.
  • the beam of radiation is produced by an irradiator.
  • irradiator as used herein is intended to mean a device comprising a lead shield surrounding a radioisotope which emits ionizing radiation and a mechanism for exposing cells placed adjacent to the irradiator to the ionizing radiation. Methods of using an irradiator to expose cells to ionizing radiation are well known to those skilled in the art. In the practice of this invention, the irradiator may comprise the radioisotope Cesium-137 or the radioisotope Iridium-192.
  • an effective cytotoxic dose of ionizing radiation comprises contacting the cells with an aqueous solution containing a radioisotope.
  • an "effective cytotoxic dose" of ionizing radiation is any dose of ionizing radiation effective to kill cells.
  • the effective cytotoxic dose of ionizing radiation is a dose from about 1 Gy to about 10 Gy, desirably a dose from about 2 Gy to about 8 Gy.
  • Suitable radioisotopes for use in accordance with the practice of this invention may be any of a number of radioisotopes well known to those skill in the art. In the presently preferred embodiment of this invention, the radioisotope is Phosphorous-32.
  • This invention also provides a method of treating a cancer patient which comprises first administering to the patient a spindle poison in a suitable carrier in an amount effective to inhibit tumor cells in the patient from progressing through the G2 or M phases of the cell cycle for an amount of time effective to inhibit division of the tumor cells and then administering an effective cytotoxic dose of ionizing radiation to the patient.
  • Administration of a spindle poison to a patient may be by any of the means well known to those skilled in the art suitable for contacting cells in the body of a patient with a spindle poison, e.g., by intravenous injection.
  • the patient is a human patient.
  • spindle poison encompasses any agent capable of interfering with the functioning of the microtubules in a cell with the result that cell division is inhibited and the cell is blocked in the G2 or M phases of the cell cycle.
  • the spindle poison may be an agent which stabilizes microtubules, e.g., a taxol-related compound.
  • the taxol-related compound is taxol.
  • Taxol may be a natural product of the yew Taxus Sp. L.
  • the term “taxol” as used herein encompasses taxol produced by any method, including chemical synthesis or tissue culture production.
  • Suitable carriers for administering a spindle poison to a patient may be any of a number of aqueous infusion solutions well known to those skilled in the art. Presently preferred is an aqueous infusion solution comprising 5% dextrose injection USP, i.e., D5 .
  • the amount of the spindle poison effective to inhibit the progression of cells through the G2 or M phases of the cell cycle is an amount of the spindle poison sufficient to establish a concentration of the agent in the blood of the patient effective to inhibit the cells from progressing through the G2 or M phases of the cell cycle.
  • an effective inhibiting concentration" of a spindle poison is any amount of the poison effective to inhibit the progression of cells through the G2 or M phases of the cell cycle.
  • the effective inhibiting concentration of the spindle poison is a concentration from about 1 nM to about 50 ⁇ M.
  • the effective concentration of the spindle poison in the blood of the animal may be maintained by readministering the poison to the patient at an interval of time after the preceding administration. Methods of determining the appropriate length of the interval between administrations of the spindle poison are well known to those skilled in the art. Presently preferred is an interval of about one week between administrations.
  • an amount of time effective to inhibit the progression of cells through the G2 or M phases of the cell cycle is any amount of time for which incubation of the cells with a spindle poison will be effective to inhibit the progression of cells through the cell cycle and cause the cells to accumulate in the G2 or M phases.
  • the "effective inhibiting amount" of time is an amount greater than about 24 hours.
  • the effective cytotoxic dose of ionizing radiation is administered by exposing the patient to a beam of radiation produced by a linear accelerator.
  • an "effective cytotoxic dose" of ionizing radiation is any dose of ionizing radiation effective to kill cells.
  • the effective cytotoxic dose of ionizing radiation absorbed by a patient from exposure to a beam of radiation in accordance with the practice of this invention is a dose from about 4,000 cGy to about 8,000 cGy.
  • the effective cytotoxic dose of ionizing radiation is a dose from about 6,500 cGy to about 7,500 cGy.
  • the effective cytotoxic dose of ionizing radiation may be administered to the patient in a schedule of increments.
  • Methods of establishing a schedule of increments for administering ionizing radiation to a patient are well known to those skilled in the art.
  • An example of such a schedule contemplated by this invention comprises a dose of ionizing radiation of about 200 cGy per day for five days per week for a period from about six weeks to about eight weeks.
  • an effective cytotoxic dose of ionizing radiation is administered by implanting a radioisotope in tumors in the body of the patient for an amount of time sufficient to expose the tumor to the effective cytotoxic dose.
  • an "effective cytotoxic dose" of ionizing radiation is any dose of ionizing radiation effective to kill cells.
  • the effective cytotoxic dose of ionizing radiation is a dose from about 8,000 cGy to about 20,000 cGy. Desirably, the effective cytotoxic dose is a dose about 16,000 cGy.
  • Suitable radioisotopes for implanting in tumors in the body of a patient in accordance with the practice of this invention may be any of those well known to those skilled in the art. Presently preferred are Iodine-125 or Iridium-192.
  • the practice of this invention also contemplates exposing the patient to a beam of ionizing radiation. Methods of generating a beam of ionizing radiation suitable for application to a patient are well known to those skilled in the art. In the presently preferred embodiment of this invention, the radiation beam is generated by a linear accelerator.
  • a linear accelerator One skilled in the art would be readily able to determine without undue experimentation whether the beam of radiation is to be applied to the patient before or after the radioisotope is implanted.
  • the effective cytotoxic dose of ionizing radiation to which the patient is exposed in accordance with the practice of this invention comprises a dose of ionizing radiation from about 4,000 cGy to about 6,000 cGy administered by the beam of radiation and a dose of ionizing radiation from about 2,000 cGy to about 4,000 cGy administered by the radioisotope implant.
  • the effective cytotoxic dose of ionizing radiation is administered to the patient by radiosurgery.
  • radiosurgery as used herein is intended to mean a procedure for applying a dose of ionizing radiation to a narrowly defined area of tissue in the body of the patient while avoiding exposing surrounding tissue. Radiosurgery allows for the accurate determination of target size and location, treatment planning and accurate delivery of radiation.
  • a radiosurgery system includes a stereotactic frame, an appropriate radiation source and computer hardware and software.
  • the appropriate radiation source may be a "gamma-knife", e.g., a gamma knife containing Cobalt-60, or a linear accelerator.
  • the dose of ionizing radiation a patient is exposed to by radiosurgery is a dose from about 1,200 cGy to about 2,800 cGy.
  • This invention further provides a method of increasing the sensitivity of cells to the cytotoxic effects of bleomycin which comprises first incubating the cells with a spindle poison in a suitable carrier at a concentration effective to inhibit the progression of the cells through the G2 or M phases of the cell cycle for an amount of time effective to inhibit cell division and then exposing the cells to an effective cytotoxic concentration of bleomycin.
  • an "effective cytotoxic concentration of bleomycin” is any concentration of bleomycin effective to kill cells.
  • This invention still further provides a kit useful for treating a cancer patient which comprises a spindle poison in an amount sufficient to establish a concentration of the poison in the body of the patient effective to inhibit the progression of tumor cells through the G2 and M phases of the cell cycle and an effective cytotoxic dose of a radioisotope in aqueous solution, an antibody-conjugated radioisotope or bleomycin.
  • the kit of this invention may include instructions for administering the spindle poison and the aqueous solution of the radioisotope, the antibody- conjugated radioisotope or bleomycin in accordance with the practice of this invention.
  • the astrocytoma cell line (G18) was established in culture from a surgical specimen obtained from the Neurological Institute of New York, Columbia-Presbyterian Medical Center (12) .
  • Cells were grown in Modified Eagles Medium (MEM) with Hanks Balanced Salts (HBS, obtained from Gibco) and 10% Fetal Calf Serum (Hyclone) with 12.5 ml SerXtend (Hana Biological) per 500 ml of serum.
  • MEM L-glutamine essential amino acids, non-essential amino acids, vitamins, and gentamicin.
  • the medium was supplemented with penicillin/streptomycin.
  • Cells were routinely grown in flasks with loosely capped tops, in incubators with 5% C0 2 and subcultured 1-2 times per week at a ratio of 1:20 (12).
  • Taxol (NSC 125973) was obtained from the NCI drug program. A stock solution of 10 *2 M was prepared in dimethyl sulfoxide (DMSO) , kept at -40°C and thawed for use. The quantity of drug and DMSO added per dish was between 0.1%-1.0% of the total volume of medium.
  • DMSO dimethyl sulfoxide
  • Cells were acutely irradiated with-a 137 Cs irradiator (Atomic Energy of Canada Model GC40) operating at a dose rate of 1.12 Gy/min. Irradiation times ranged from 1.8 to 7.1 minutes. Cells were plated in 100 mm dishes with 10 ml of medium and allowed to attach for approximately 20 hr. The number of cells per dish was chosen such that 100-200 colonies would survive after a specified treatment. Taxol or DMSO was then added and the cells allowed to incubate for another 20-24 hr with drug present. Following the incubation period, cells were acutely irradiated, medium removed by aspiration, and 10 ml of medium was added back.
  • a 137 Cs irradiator Atomic Energy of Canada Model GC40 operating at a dose rate of 1.12 Gy/min. Irradiation times ranged from 1.8 to 7.1 minutes.
  • Cells were plated in 100 mm dishes with 10 ml of medium and allowed to attach for approximately 20
  • Samples with unirradiated controls were also prepared in the same way. Dishes were then incubated for 10 days. Three plates were prepared for each concentration and dose of irradiation. Cells were fixed in 75% methanol/25% acetic acid and stained with crystal violet. Colonies were considered to be a collection of 50 or more cells and were counted on a per dish basis. Survival was determined from the number of cells per dish, normalized by unirradiated controls treated with the same concentration of taxol or DMSO.
  • Cells were irradiated with 6 Gy of 137 gamma rays at 0, 8, and 24 hr after addition of 10 nM taxol.
  • cells were additionally prepared for flow cytometry as follows: the medium was aspirated, cells washed with HBS, then trypsinized and washed in normal medium. Cells were rewashed and then resuspended in cold methanol and refrigerated. Cells were resuspended in 50 ⁇ g/ml propidiu iodide prior to flow cytometry using a Coulter dual laser EPICS 752. Flow studies measured the number of cells versus DNA content and allowed for the determination of the fraction of cells in each phase of the cell cycle. Cells were also studied (a) after exposure to a range of concentrations and (b) as a function of length of exposure to 10 nM taxol. Results and Discussions
  • cytotoxic effect on the human astrocytoma cell line G18 of a range of concentrations of taxol are shown in Figure 1. At 1 nM, and for a 24-hour exposure, there is no significant difference from the control, while after a 100 nM treatment, about 0.1% of cells retain clonogenic potential relative to controls.
  • this microtubule stabilizing agent has a dose dependent effect on cellular behavior, consistent initially with a breakdown of cytoskeletal function and hence cellular shape and mobility, and then accumulation of cells in late G2/M.
  • the inability of cells to erect functioning spindles then results in either the reformation of nuclear membranes around groups of chromosomes (multi-micronucleation) , or else, the nuclear membrane breaks down only partially and then reforms in clusters.
  • the results would then be expected to be a time- and concentration-dependent increase in the proportion of cells with a G2 DNA content and accumulation in the G2/M phases of the cell cycle. This was confirmed in the astrocytoma cell line by flow cytometric analysis of cellular DNA contents.
  • the fraction of cells at different stages of the cell cycle following treatment with 10 nM taxol is shown in Table 1.
  • % Percentage of cells in different stages of the cell cycle.
  • taxol alone is dose-dependently cytotoxic, with less than 0.1% clonogenic capacity at 100 nM, about 5% at 10 nM and about 90% at 1 nM. Constant treatment with taxol (i.e., for the 10 day cell incubation period) again resulted in about 90% clonogenicity at 1 nM but less than 0.01% clonogenicity at 10 nM, indicating a time- and concentration-dependent cytotoxicity.
  • Taxol would be classified as a radiosensitizer when employed at this concentration (15) .
  • the sensitizer enhancement ratio (SER) at 10% survival for 10 nM taxol was approximately 1.8 and for 1 nM taxol the SER was approximately 1.2.
  • Taxol a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann. Intern. Med. 111:273; 1989. 9. Rowinsky, E. K. et al. Taxol: a novel investigational antimicrotubule agent. JNCI £2.:1247; 1990.

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EP92915821A 1992-01-31 1992-01-31 Taxol utilise comme sensibilisateur aux rayonnements. Withdrawn EP0624096A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/US1992/000851 WO1993014787A1 (fr) 1992-01-31 1992-01-31 Taxol utilise comme sensibilisateur aux rayonnements
CA002128693A CA2128693A1 (fr) 1992-01-31 1992-01-31 Utilisation du taxol comme agent de radiosensibilisation

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EP0624096A1 EP0624096A1 (fr) 1994-11-17
EP0624096A4 true EP0624096A4 (fr) 1995-04-19

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EP92915821A Withdrawn EP0624096A4 (fr) 1992-01-31 1992-01-31 Taxol utilise comme sensibilisateur aux rayonnements.

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JP (1) JPH07506341A (fr)
AU (1) AU2333892A (fr)
CA (1) CA2128693A1 (fr)
WO (1) WO1993014787A1 (fr)

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AU728057B2 (en) * 1995-09-13 2001-01-04 Florida State University Radiosensitizing taxanes and their pharmaceutical preparations
GB9705903D0 (en) 1997-03-21 1997-05-07 Elliott Gillian D VP22 Proteins and uses thereof
JP2003513756A (ja) * 1999-11-12 2003-04-15 アンジオテック ファーマシューティカルズ，インコーポレイテッド 放射性治療と細胞周期インヒビターとの組合せの組成物
GB0104383D0 (en) 2001-02-22 2001-04-11 Psimedica Ltd Cancer Treatment

Citations (1)

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Publication number Priority date Publication date Assignee Title
WO1992019765A1 (fr) * 1991-05-08 1992-11-12 The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services Procede de conception de traitements du cancer, procedes et compositions pharmaceutiques de traitements du cancer

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FR2601675B1 (fr) * 1986-07-17 1988-09-23 Rhone Poulenc Sante Derives du taxol, leur preparation et les compositions pharmaceutiques qui les contiennent
US4876399A (en) * 1987-11-02 1989-10-24 Research Corporation Technologies, Inc. Taxols, their preparation and intermediates thereof
US5157049A (en) * 1988-03-07 1992-10-20 The United States Of America As Represented By The Department Of Health & Human Services Method of treating cancers sensitive to treatment with water soluble derivatives of taxol
US4960790A (en) * 1989-03-09 1990-10-02 University Of Kansas Derivatives of taxol, pharmaceutical compositions thereof and methods for the preparation thereof
US5059699A (en) * 1990-08-28 1991-10-22 Virginia Tech Intellectual Properties, Inc. Water soluble derivatives of taxol

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992019765A1 (fr) * 1991-05-08 1992-11-12 The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services Procede de conception de traitements du cancer, procedes et compositions pharmaceutiques de traitements du cancer

Non-Patent Citations (2)

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Title
RADHEY S. GUPTA: "GENETIC, BIOCHEMICAL, AND CROSS-RESISTANCE STUDIES WITH MUTANTS OF CHINESE HAMSTER OVARY CELLS RESISTANT TO THE ANTICANCER DRUGS, VM-26 AND VP16-213.", CANCER RES., vol. 43, no. 4, April 1983 (1983-04-01), pages 1568 - 1574 *
See also references of WO9314787A1 *

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EP0624096A1 (fr) 1994-11-17
WO1993014787A1 (fr) 1993-08-05
CA2128693A1 (fr) 1993-08-05
JPH07506341A (ja) 1995-07-13
AU2333892A (en) 1993-09-01

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