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WO1995008994A1 - Combinaison de taxol et de tiazofurine dirigee contre les neoplasmes - Google Patents

Combinaison de taxol et de tiazofurine dirigee contre les neoplasmes Download PDF

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Publication number
WO1995008994A1
WO1995008994A1 PCT/US1994/009949 US9409949W WO9508994A1 WO 1995008994 A1 WO1995008994 A1 WO 1995008994A1 US 9409949 W US9409949 W US 9409949W WO 9508994 A1 WO9508994 A1 WO 9508994A1
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Prior art keywords
approximately
tiazofurin
days
administered
composition
Prior art date
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PCT/US1994/009949
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English (en)
Inventor
George Weber
Katherine Y. Look
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Indiana University Foundation
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Indiana University Foundation
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Filing date
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Application filed by Indiana University Foundation filed Critical Indiana University Foundation
Priority to AU77199/94A priority Critical patent/AU7719994A/en
Publication of WO1995008994A1 publication Critical patent/WO1995008994A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof

Definitions

  • the field of the present invention is the treatment of neoplastic cells utilizing chemotherapeutic agents.
  • Neoplastic cells tend to grow and divide faster than ordinary cells, and several anti-cancer drugs have been developed which interfere with cell division.
  • Two such drugs, taxol (NSC 125975) and tiazofurin (NSC 286193) interfere with the formation of microtubules, structural elements employed in the formation of the mitotic spindle.
  • Microtubules are produced through polymerization of alpha- tubulin and beta-tubulin, under the influence of GTP (guanosine triphosphate) and microtubulin-associated proteins.
  • Taxol and tiazofurin interfere with mitotic spindle formation at two distinct sites. Taxol exerts its anti-cancer action by binding to the microtubule and promoting precocious microtubule assembly. It does not inhibit the binding or the hydrolysis of GTP.
  • Taxol exerts its anti-cancer action by binding to the microtubule and promoting precocious microtubule assembly. It does not inhibit the binding or the hydrolysis of GTP.
  • Tiazofurin exerts its anti-cancer action through conversion to an active metabolite, TAD (thiazole-4- carboxamide adenine dinucleotide) , which then inhibits IMPDH (inosine 5'phosphate dehydrogenase) , the rate limiting enzyme of de novo GTP synthesis.
  • TAD thiazole-4- carboxamide adenine dinucleotide
  • IMPDH inosine 5'phosphate dehydrogenase
  • Weber G. "Biochemical strategy of cancer cells and the design of chemotherapy, " H.A. Clowes Memorial Lecture, in Cancer Res 43:3466-3492, 1983; Weber, G., "IMP Dehydrogenase and GTP as Targets in Human Leukemia Treatment” Purine and Pyrimidine Metabolism in Man VII, pp.
  • tiazofurin can be enhanced by the synergistic effect of allopurinol, (1, 5-Dihydro-4H- pyrazolo [3,4-d]pyrimidin-4-one) .
  • Allopurinol decreases xanthine oxidase activity, which increases plasma hypoxanthine concentration, which in turn competitively inhibits the activity of GPRT and further inhibits the synthesis of GTP.
  • Weber, G. , 1991 supra; Weber, G., et al, "Enzyme-pattern-targeted chemotherapy with tiazofurin and allopurinol in human leukemia” , Adv. in Enzyme Regul. , 27:405-433, 1988 .
  • the present invention is directed to treating neoplastic disease, solid tumors, and leukemia, using a combination of taxol and tiazofurin. Accordingly, it is an object of the present invention to provide a combination drug treatment for neoplastic disease. Other and further objects and advantages will appear hereinafter.
  • taxol refers to 5320-epoxy-l,2ot,4,7/3,
  • tiazofurin refers to 2- / ⁇ -D-ribofuranosylthiazole-4-carboxamide, and pharmaceutically acceptable salts thereof (NSC 286193) .
  • Taxol is commercially available, and is administered at the rate of between approximately 110 mg/m 2 to approximately 250 mg/m 2 in a three hour infusion, once every 31 days.
  • the starting dose of taxol is preferably 175 mg/m 2 .
  • Tiazofurin may be prepared as described in U.S. Patent No. 4,680,285 or U.S. Patent No. 4,451,648, which are incorporated herein by reference. Tiazofurin also may be obtained from the National Cancer Institute as a sterile drug for injection in clear vials. Each vial contains 1 gram prepared as a white lyophilized powder with sodium hydroxide to adjust the pH. A tiazofurin solution is reconstituted by adding 4.6 ml of sterile water for injection USP the contents of each vial. One ml of the resulting solution will then contain 200 mg of tiazofurin with a pH of 6-8.
  • Tiazofurin is preferably administered by one-hour infusion as described in Jayaram, H. et al . , "Clinical Pharmacoanalytic Study of Tiazofurin Administered as a One Hour Infusion", Int. J. Cancer, 51 (2) :182-188, 1992), incorporated herein by reference.
  • tiazofurin is dissolved or suspended in a physiologically compatible solution, in a concentration of at least 0.1% by weight. More preferably, tiazofurin would be present in a concentration of about 10% to about 90% by weight.
  • baseline IMPDH activity is determined.
  • the ascites is removed by paracentesis, and at least 50,000,000 cells are assayed for IMPDH activity. Only those patients whose baseline IMPDH is elevated, suggesting that the drug may have utility in view of its mechanism of action, receive tiazofurin.
  • tiazofurin is reconstituted and diluted as described above and is administered by infusion pump over one hour at a dose of 4,400 mg/m 2 per day for the first two days. If the IMPDH activity after two days is higher than 10% of baseline, the tiazofurin treatment is discontinued.
  • the patient is maintained on tiazofurin at a dose of 2,200 mg/m 2 per day, given as a one hour infusion for a total of 8 days. Between each cycle there is a 21 day rest, such that an entire treatment cycle is 31 days.
  • taxol On days that both taxol and tiazofurin are given, tiazofurin is preferably administered in the morning, and taxol is preferably administered in the evening. During the course of combined taxol and tiazofurin treatment as described herein, the patient's hematology is carefully monitored. In the event of excessive toxicity, administration of one or both of taxol and tiazofurin is reduced or discontinued. In the event of severe anemia (hemoglobin concentration of less than 8 gm/lOOml) , taxol should be reduced to a dosage of about 110 mg/m 2 . In the event severe leukopenia (less than 1000 absolute granulocyte count) tiazofurin should be reduced to a dosage of about 1800 mg/m 2 .
  • severe anemia hemoglobin concentration of less than 8 gm/lOOml
  • tiazofurin In the event of severe leukopenia (less than 1000 absolute granulocyte count) tiazofur
  • the approximately eight day maintenance dose of tiazofurin depends on how well tiazofurin is tolerated by an individual patient. If tiazofurin appears to be well tolerated, the maintenance dosage is increased to 3,300 mg/m 2 from 2,200 mg/m 2 . If tiazofurin appears to be poorly tolerated, the maintenance dosage is decreased to 1,800 mg/m 2 from 2,200 mg/m 2 .
  • Allopurinol is preferably, but not necessarily used in conjunction with tiazofurin treatment. Allopurinol is commercially available in 100 mg tablets. During the tiazofurin treatment, the patient may receive 100 mg by month every four hours in order to attain plasma hypoxanthine levels of 40-80 micromoles. Should the allopurinol starting dose fail to achieve a hypoxanthine concentration of abut 40 ⁇ m, the allopurinol dose can be increased to a maximum of 100 mg by month every three hours.
  • the amount of oral and intravenous fluids are limited to less than 3 liters per day to maintain plasma hypoxanthine levels, but at least 2 liters per day to minimize the risk of hypoxanthine renal stones.
  • the synergistic activity of taxol and tiazofurin in attacking microtubular synthetic processes of the mitotic spindle has been tested in human ovarian, pancreatic and lung carcinoma cells, and in rat hepatoma 3924A cells. As described below, taxol and tiazofurin proved synergistic in all four cell lines tested (p > 0.05) .
  • taxol and tiazofurin should also have synergistic effect in the clinical treatment of human solid tumors, including tumors of the ovary, pancreas, lung and liver. Such improved effectiveness should permit dose reductions which result in lower toxicity, decreased emergence of resistant clones, and more rational modulation of chemotherapy schedules.
  • the cell lines studied were human ovarian carcinoma OVCAR-5, human pancreatic carcinoma PANC-1, human non- small cell adenosquamous carcinoma H-235 cells and rat hepatoma 3924A cells. All cells were maintained in RPMI- 1640 medium, supplemented with 10% FBS (GIBCO, Grand Island, NY) , penicillin (100 U/ml) and streptomycin (100 ⁇ g/ml) . Cells were incubated in 5% C0 2 with 95% humidified air at 37°C. For subcultures, cells were dispersed with 0.25% trypsin containing 1 Mm EDTA at 37°C for 10 min, then centrifuged, suspended in fresh medium and seeded in culture flasks.
  • Exponentially growing cells were seeded in 24-well plates in triplicate at a density of 2 x 10 4 cells/ml/well and drugs were added alone or simultaneously 6 hr later. After 3 days (OVCAR-5, 3924A cells) or 4 days (PANC-1, H-125 cells)- of drug exposure, cells were harvested and counted in a Coulter counter.
  • Taxol (lOmM) was prepared in DMSO (dimethyl sulfoxide) and diluted in PBS (phosphate balanced solution) for a 25 ⁇ M stock solution and from this solution aliquots were dissolved in RPMI-1640 medium. The highest concentration of taxol (0.025 ⁇ M) contained 0.0019% DMSO which had no effect on the cells. Tiazofurin was dissolved in PBS. Stock solutions were stored at -20°C.
  • ⁇ SE of cells in triplicate samples were tabulated and percent inhibition was calculated and compared with control.
  • the Chou-Talalay method (Chou and Talalay, 1984) was used to determine the nature of the interaction of the two drugs.
  • Fa denotes the fraction affected
  • CI denotes the combination index.
  • CI of less than 1 indicates synergism
  • values greater than 1 denote antagonism
  • values equal to 1 reveal summation (additivity) (Chou and Talalay, 1984) .
  • Table II summarizes the effect of taxol and tiazofurin in human ovarian carcinoma cells.
  • Taxol (2 to 25 nM) stopped cell growth in 4 to 25% of the OVCAR-5 cells.
  • the two drugs were synergistic in the concentrations tested as shown by the C.I. of 0.40 to .90.
  • the most effective combination included 25 nM taxol with 15 ⁇ M tiazofurin, (1:600 ratio) , which inhibited 84% of cell growth
  • Table III summarizes the synergistic activity of taxol and tiazofurin in pancreatic cancer cells.
  • Taxol (0.4 to 10 nM) stopped proliferation in 2 to 68% of the PANC-1 cells. Tiazofurin in concentrations of 0.1 through 10 ⁇ M inhibited 4 to 83% of cell proliferation. In the various combinations tested, synergism was observed against PANC-1 cells. In the best combination, 10 nM taxol and 10 ⁇ M tiazofurin yielded 96% inhibition of cell proliferation. A 10-fold increase (1 to 10 ⁇ M) in tiazofurin concentration yielded little anti-proliferative advantage. Hence, with respect to PANC-1 cells, the combination of 10 nM taxol and 1 ⁇ M tiazofurin, (1:100 ratio), was the most effective combination tested.
  • Table IV summarizes the synergistic activity of taxol and tiazofurin in human lung cancer cells.
  • Taxol 0.4 to 10 nM
  • Tiazofurin 0.1 to 10 ⁇ M
  • the two drugs were synergistic in the concentrations tested with best results obtained with 10 nM taxol and 10 ⁇ M tiazofurin (1:1000 ratio), yielding 89% inhibition of cell proliferation.
  • a 5-fold increase in taxol concentration to 10 nM in the presence of 10 ⁇ M tiazofurin improved results, with 89% inhibition of cell proliferation.
  • taxol and tiazofurin inhibited 7 to 18% of cells and tiazofurin (1 to 10 ⁇ M) inhibited 15 to 62% of cells.
  • taxol and tiazofurin were synergistic (not shown) .
  • the best combination appeared to be 25 nM taxol and 10 ⁇ M tiazofurin (1:400 ratio) which provided 81% inhibition of cell proliferation.

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  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
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Abstract

L'invention concerne un procédé de traitement des cellules néoplasiques utilisant une combinaison de taxol et de tiazofurine. De préférence, on administre un dosage de taxol d'environ 110 mg/m2 à environ 250 mg/m2 sur une période de vingt-quatre heures, puis on observe un repos de 31 jours, après quoi on administre un dosage de tiazofurine d'environ 1 800 à 4 400 mg/m2 sur une période d'environ dix jours, puis on observe à nouveau un repos de 21 jours, les cycles d'administration de taxol et de tiazofurine étant en phase l'un avec l'autre.
PCT/US1994/009949 1993-09-29 1994-09-02 Combinaison de taxol et de tiazofurine dirigee contre les neoplasmes Ceased WO1995008994A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU77199/94A AU7719994A (en) 1993-09-29 1994-09-02 Antineoplastic combination of taxol and tiazofurin

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US12884393A 1993-09-29 1993-09-29
US08/128,843 1993-09-29

Publications (1)

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WO1995008994A1 true WO1995008994A1 (fr) 1995-04-06

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AU (1) AU7719994A (fr)
CA (1) CA2129282A1 (fr)
WO (1) WO1995008994A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999054445A3 (fr) * 1998-04-22 1999-12-09 Inex Pharmaceuticals Corp Traitement associe utilisant des acides nucleiques et des medicaments classiques
US6632795B1 (en) 1997-03-13 2003-10-14 Basf Aktiengesellschaft Dolastatin-15 derivatives in combination with taxanes
US6841537B1 (en) 1998-04-22 2005-01-11 Protiva Biotherapeutics Inc. Combination therapy using nucleic acids and conventional drugs
US6841538B1 (en) 1998-04-22 2005-01-11 Inex Pharmaceuticals Corporation Combination therapy using nucleic acids and radio therapy

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ADVANCES IN ENZYME REGULATION, Vol. 27, issued 1988, WEBER et al., "Enzyme Pattern - Targeted Chemotherapy with Tiazofurin and Allopurinol in Human Leukemia", pages 405-443. *
PROCEEDINGS FOR THE AMERICAN ASSOCIATION FOR CANCER RESEARCH, Vol. 34, issued March 1993, TANIKI et al., "Synergistic Action of Taxol and Tiazofurin in Human Ovarian, Pancreatic and Lung Carcinoma Cells", page 297. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6632795B1 (en) 1997-03-13 2003-10-14 Basf Aktiengesellschaft Dolastatin-15 derivatives in combination with taxanes
WO1999054445A3 (fr) * 1998-04-22 1999-12-09 Inex Pharmaceuticals Corp Traitement associe utilisant des acides nucleiques et des medicaments classiques
US6841537B1 (en) 1998-04-22 2005-01-11 Protiva Biotherapeutics Inc. Combination therapy using nucleic acids and conventional drugs
US6841538B1 (en) 1998-04-22 2005-01-11 Inex Pharmaceuticals Corporation Combination therapy using nucleic acids and radio therapy

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Publication number Publication date
AU7719994A (en) 1995-04-18
CA2129282A1 (fr) 1995-03-30

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