WO1997015571A1 - Procede de traitement du cancer au moyen de promedicaments a base de sels d'onium taxoïdes - Google Patents

Procede de traitement du cancer au moyen de promedicaments a base de sels d'onium taxoïdes Download PDF

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WO1997015571A1
WO1997015571A1 PCT/US1995/013902 US9513902W WO9715571A1 WO 1997015571 A1 WO1997015571 A1 WO 1997015571A1 US 9513902 W US9513902 W US 9513902W WO 9715571 A1 WO9715571 A1 WO 9715571A1
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taxol
group
alkyl
bridging
aryl
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PCT/US1995/013902
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English (en)
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Wolfgang Wrasidlo
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The Scripps Research Institute
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Priority to AU40135/95A priority Critical patent/AU4013595A/en
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Publication of WO1997015571A1 publication Critical patent/WO1997015571A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems

Definitions

  • the invention relates to a medical use of taxoid onium salt prodrugs for treating patients with tumors or other cancers.
  • Taxol (paclitaxel; Bristol-Myers Squibb Co, Wallingford CT) is a diterpene compound of novel structure which has been isolated from the bark ofthe Northwestern or Japanese yew tree Taxus brevifolia (Rowinsky et. al. J. Natl Cancer Inst. 1990 82, 1247). In vitro, taxol has been shown to promote the assembly of microtubules (Schiff et. al. Nature 1979, 227, 655) and to stabilize tubulin polymers against depolymerization (Schiff et. al. Proc. Natl. Acad. Sci.
  • antimicrotubular agents act primarily by inhibiting the microtubular system; however, taxol exerts its effect on the G 2 and M phases ofthe cell cycle by binding to tubulin, thus enhancing the rate and extent of microtubular polymerization and stabilizing formed microtubules. The result is a rigid microtubular network that resists depolymerization and inhibits cellular replication
  • Taxol has been shown to activate macrophages to express TNF-a and IL-1 and to downregulate TNF- receptors; both of these activities are shared by bacterial LPS (Manthey et. al. J. Immunology 1992 149, 2459; Ding et. al. Science 1990, 248, 370). This cytokine stimulatory activity of taxol may contribute to its antitumor properties. Taxol has recently been approved for clinical use in the treatment of refractory ovarian and breast cancers in the United States (Markman et. al. Yale Journal of Biology and Medicine 1991 64, 583; McGuire et. al. Ann. Intern. Med.
  • Taxol dose intensity has been shown to be an important factor in the treatment of patients with ovarian cancer (Sarosy et. al. J. Natl Med Assoc 1993, 85, 427).
  • a phase I study was undertaken by the National Cancer Institute which examined taxol dose intensification with a granulocyte colony-stimulating factor (G- CSF) support (Sarosy et. al. J. Clinical Oncology 1992 10, 1165).
  • G- CSF granulocyte colony-stimulating factor
  • taxol-cisplatin dose level 200 mg/m 2 to 75 mg/m 2
  • the mean neutrophil count nadir was 98D ⁇ L and hospitalization for neutorpenia and fever was required in 64% of courses.
  • the starting doses of taxol (110 mg/m 2 ) and cisplatin (50 mg/m 2 ) were doses that produce minimal toxicity when either drug was administered as a single agent.
  • the doses of both agents were then escalated to within a conventional range, focusing on dose escalation of taxol.
  • the dose levels were 135/50, 110/75, 135/75, 170/75, and 200/75 mg/m 2
  • Taxol was supplied as a concentrated sterile solution (6mg/mL) in a 5 mL ampule in 50% polyoxyethylated castor oil (Cremophor EL) and 50% dehydrated alcohol. Because of stability considerations 25% ofthe total dosage was reconstituted immediately before use in 250 mL of 5% dextrose in water and was infused over 6 hours for four treatments. Glass bottles and polyethylene-lined nitro glycerin tubing were use to administer taxol due to possible problems with Cremophor-induced leaching of plasticizers.
  • Cremophor EL polyoxyethylated castor oil
  • taxol was administered over 24 hours with the following premedications: 1) dexamethasone, 20 mg intravenously (IV) or orally, 14 and 7 hours before taxol; (2) diphenhydramine, 50 mg (IV) 30 minutes before taxol; and either one ofthe H 2 -histamine antagonists, ranitidine 50 mg IV or famotidine 20 mg IV, 30 minutes before taxol. Continuous ECG telemetry was performed during the infusion of taxol. (Rowinsky et. al. J. of Clinical Oncology 1991 9, 1692).
  • Taxol was supplied as a concentrated sterile solution in 50% polyoxyethylated castor oil (Cremophor EL) and 50% dehydrated ethanol.
  • taxol was administered as a 24 hour continuous intravenous (IV) infusion in 5% dextrose at an initial concentration of 0.5 mg/mL.
  • IV intravenous
  • Dose escalation above the starting dose 200 mg/m2 proceeded in 20% increments (240, 290, 350, and 420 mg/m2) until dose-limiting toxicity was reached.
  • the dose-limiting toxicity was neurotoxicity which occurred at a dose of
  • Taxotere N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl Taxol; RP 56976; ⁇ SC 628503, Rhone Poulenc Rorer Research Development ) is a semisynthetic analogue of taxol which is twice as active in inhibiting tubuline depolymerization and has demonstrated better in vivo activity on B 16 melanoma with responses in several advanced adenocarcinomas.
  • a phase I study sixty five patients (49 women, 16 men), with a median age of 57 years, each received 248 courses of Taxotere administered as a 1-2 hour I.V. infusion every 2 or 3 weeks. Ten distinct dosage levels from 5 to 115 mg/m 2 were studied (Extra et. al. Cancer
  • the taxotere used for the study was supplied by Rhone Poulenc Rorer laboratories in 15 mg/ml vials in 50% polysorbate 80 (Tween 80) and 50% dehydrated alcohol.
  • the vials were reconstituted just prior to use in 50 cc of 5% dextrose in water and the amount of Taxotere was further diluted in 5% dextrose in water, so that the maximum Taxotere concentration was 0.3 mg/ml to ensure that polysorbate 80 concentration would not exceed 1%.
  • No pretreatment medication to prevent gastrointestinal toxicity or anaphylactic reactions was given. Taxotere was give at intervals of 2 weeks and then at an interval of 3 weeks when side-effects were observed, which was doses greater than 55 mg/m 2 . Treatment was stopped in cases of severe toxicity; a cohort of 3 patients was studied at each dose level until significant toxicity was observed. (Extra et. al. Cancer Research, 1993 53, 1037.)
  • taxol A generally recognized shortcoming of taxol is its low solubility in aqueous media conventionally employed for administering drugs.
  • the low solubility of taxol necessitates its formulation in mineral oil suspensions, e.g., Cremophor EL, in order to achieve concentrations sufficient to administer an effective dose.
  • mineral oil suspensions e.g., Cremophor EL
  • taxol and taxotere prodrugs having superior antitumor activities, low toxicity, and good solubility.
  • C-2' onium salts of taxol and taxotere achieve good solubility while maintaining a high level of anti-tumor activity and low toxicity in vivo.
  • C-2' onium salts of taxol and taxotere release taxol and taxotere respectively upon exposure to plasma, thereby serving as a prodrug ofthe parent compound.
  • the in vivo anti-tumor activity of C-2' substituted taxoids depends upon the pharmacokinetics of prodrug reversion to the parent compound.
  • the pharmacokinetics ofthe prodrug are determined by a balance between in vivo hydrolytic stability, bioavailability, and the rate of elimination.
  • the nature ofthe substituents for a given position as well as the location of a given substituent at different positions in the molecule have profound effects on the antitumor activity ofthe compounds. This could not be predicted from the in vitro data.
  • the 7-substituted pyridinium salt of taxol (3) was as effective as taxol in inhibiting calcium induced microtubule disassembly and showed cytotoxicities comparable to taxol on human tumor cell lines. However, these same 7-substituted pyridinium salts completely failed to inhibit the growth of these tumors in nude mice.
  • the 2'-substituted acyl derivative of taxol (7) which exhibits a high cytotoxicity profile and behaves as a prodrug, completely fails to exhibit any antitumor effects in vivo.
  • the 2'- onium salt (2) exhibited no tubulin binding, and in competition assays of intact cells showed affinity profiles three orders of magnitude below that ofthe parent taxol.
  • this compound produced tumor regression with a high percentage of animals being free of measurable tumor masses at the end ofthe experiments.
  • this compound was well tolerated, showing no visible toxic side effects and no significant weight loss in tumor bearing nude mice.
  • taxol was administered in mice on an equal molar basis, both visual toxicity and animal weight losses were observed.
  • taxol was administered at somewhat lower doses, its efficacy was significantly diminished, indicating that taxol exhibits a relatively narrow therapeutic window.
  • the much higher plasma affinity ofthe onium salts may be one reason for their improved tolerance in animals.
  • one aspect ofthe invention is directed to a method for treating a mammal having a tumor or other cancer.
  • the tumor is treated by administering an aqueous solution of a taxoid onium salt prodrug.
  • the route of administration may be by injection or infusion.
  • the taxoid onium salt prodrug is represented by the following structure:
  • S " is selected from the group consisting of OAc “ , Cl “ , Br “ , I “ , BF 4 ' , ClO 4 “ , ArSO 3 “ , and AlkylSO 3 "
  • R 1 is selected from the group consisting of phenyl and tBuO
  • R 2 is selected from the group consisting of OAc and OH
  • R 3 is selected from the group consisting of R 3 , and R 3 2 .
  • R 3 is represented by the following structure:
  • P is selected from the group consisting of N and S,
  • Z is selected from the group consisting of C, N, S, and O,
  • R 4 is selected from the group consisting of H, alkyl, allyl, arenzyl, propargyl, bridging aryl and bridging alkyl
  • R 5 is selected from the group consisting of H, alkyl, allyl, arenzyl, propargyl, bridging aryl and bridging alkyl
  • R 6 is selected from the group consisting of H, alkyl, allyl, arenzyl, aryl, propargyl, O-alkyl
  • R 7 is selected from the group consisting of H, alkyl, allyl, arenzyl, aryl, propargyl, O-alkyl
  • R 8 is selected from the group consisting of H, alkyl, allyl, arenzyl, aryl, propargyl, O-alkyl, and OH.
  • R 3 2 is represented by the following structure:
  • P is selected from the group consisting of N and S
  • Z is selected from the group consisting of C, N, S, and O
  • R 9 is selected from the group consisting of H, alkyl, allyl, arenzyl, propargyl, bridging aryl and bridging alkyl
  • R 10 is selected from the group consisting of H, alkyl, allyl, arenzyl, propargyl, bridging aryl and bridging alkyl
  • R u is selected from the group consisting of H, alkyl, allyl, arenzyl, aryl, propargyl, O-alkyl, OH, halogen, bridging aryl, and bridging alkyl
  • R 12 is selected from the group consisting of H, alkyl, allyl, arenzyl, aryl, propargyl, O-alkyl, and OH, halogen, bridging aryl, and bridging alkyl.
  • the method ofthe invention may be employed with any mammal, including human tumor or cancer patients.
  • the mammal is sensitive and/or intolerant to a side effect of taxol.
  • Taxol-2'-MPA is much less toxic in vivo than taxol or taxotere.
  • a preferred dosage for treating tumors and other cancers is approximately 50 -300 mg/m 2 .
  • the preferred dosage is approximately 50 - 4,900 mg/m 2 .
  • the preferred dosage is approximiately 50 - 21,000 mg/m 2 and in some cases approximately 50 - 28,000 mg/m 2 .
  • the method ofthe invention is particularly useful for treating tumors or other cancers that are refractory and/or insensitive to taxol.
  • the method ofthe invention may employ any counter ion S " that is classified as generally regarded as safe (GRAS) by the U.S. Food and Drug Administration.
  • GRAS counter ion S
  • Preferred routes of administration include injection of a bolus and infusion.
  • the administration may be intravenous or intraperitoneal.
  • a preferred taxoid onium salt prodrug taxol-2'-MPA is represented by the following structure:
  • taxotere-2'-MPA represented by the following structure:
  • Figure 1 illustrates the chemical structures of taxol, taxotere, and C-2', C-7, and C-2 substitutes derivatives.
  • Figure 2 illustrates tubulin polymerization-depolymerization measurements which disclose that calcium chloride promoted depolymerization is suppressed by taxol and taxoI-7-MPA but not by taxol-2'-MPA.
  • Data points for the negative control are indicated by (D); data points for the positive control using taxol are indicated by (0); data points for taxol-7-MPA are indicated by ( ⁇ ); data points for taxol-2'-MPA are indicated by (O).
  • Figure 3 illustrates the competition by nonradioactive taxol or c-2'-MPA- taxol for the binding of 1 x 10 "9 M tritiated compounds by intact Molt-4 cells.
  • Figure 4 illustrates the in vivo efficacy of protaxol in human lung adenocarcinoma tumor xenograft nude mouse models.
  • Data points for mice treated with D5W (control) are indicated by ( ⁇ ); data points for mice treated with 2'-acyl sulfone taxol are indicated by (D); data points for mice treated with taxol are indicated by (O); data points for mice treated with taxol-2'-MPA are indicated by
  • Figure 5 illustrates the in vivo efficacy of protaxols in Ovcar 3 tumor xenograft nude mouse models. Data points for mice treated with D5W alone
  • FIG. 6 illustrates the in vivo efficacy of protaxols in prostate tumor xenograft nude mouse models. Data points for mice treated with D5W alone (control) are indicated by (O); data points for mice treated with taxol-2'-MPA are indicated by (D); data points for mice treated with taxol are indicated by ( ⁇ ).
  • C-2'-MPA-Taxol (1 mM in 0.9% saline solution, 400 ⁇ L) was injected along with tritiated taxol at 32000 cpm into normal BALB/C mice (4 mice each) housed in metabolic cages and the urine and feces were measured periodically in a scintillation counter using Achillea scintillation fluid.
  • All cell lines described herein were obtained from the ATCC and maintained in media formulations as recommended by the supplier. The cell lines were tested for mycoplasma contamination prior to incubation at 37° C in 5% carbon dioxide. Normal human dermal fibroblasts, peripheral blood lymphoblasts and mammary epithelial cells were obtained from Clonogenic Cor., San Diego, California and were maintained under the above incubation conditions in special media provided by the supplier.
  • Antiproliferative activities ofthe onium salts were determined using the XTT dye binding assay.
  • Cells were harvested with trypsin/EDTA (Irvine Scientific), washed, resuspended in the appropriate medium, and counted in a hemocytometer using Trypan Blue to determine viability. Then IO 4 cells/well were added to 96 well microtiter plates and incubated for 24 hours before addition of drug at concentrations in the range of 10 "4 to IO "13 molar by direct addition from DMSO solutions. After 72 hours, XTT binding dye was added and incubation was continued for 4 hours. The inhibition of cell proliferation was quantified using a
  • the absorbance of XTT was measured at 450 nM.
  • the concentration of drug which inhibited growth of cells by 50% was calculated from duplicated determinations.
  • the fraction of ethyl acetated extractable material was between 18 and 23% for all onium salts and 95% for the present compounds. Since the partition coefficient for the organic-water phases for these compounds are greater than 50, the relatively low ethyl acetate extractable values given in Table II are most likely due to strong affinity ofthe onium salts for plasma proteins.
  • Table I illustrates IC 50 values of six taxoids against a panel of human and murine tumor cell Iines and, for comparison, against several untransformed cells.
  • the cytotoxic potencies of these analogs were comparable to their parent compounds within one to two logs of clear molar concentrations with medium values for tumor cell lines being in the nanomolar range.
  • IC 50 values above the median were obtained for metastatic melanoma, melanoma, breast, ovarian, lung prostate and colon carcinomas, metastatic neuroblastoma and leukemia.
  • Cell lines which gave relatively low cytotoxicities were melanoma, CNS cancer, and renal cell adenocarcinoma and untransformed cells.
  • Taxotere (5) and its C-2' MPA salt (6) gave cytotoxicities about 10-fold higher than taxol or its onium salts, and the C-2'- MPA isomer of taxol (2) gave on average about 10-fold higher values than the C-7- isomer (3).
  • Figure 2 illustrates the results of GTP induced polymerization and calcium chloride induced depolymerization of tubulin in the presence of taxol and the 2'- and 7-MPA substituted derivatives.
  • the curves show that both taxol and its 7-MPA salt cause essentially complete inhibition of depolymerization of microtubules to tubulin, while the GTP controls and the 2' isomer showed the characteristic calcium induced depolymerization profiles, with about 70% reversal to tubulin.
  • Figure 3 illustrates a competition assay ofthe C-2'-MPA isomer of taxol (2) in comparison to the parent taxol (1) for the suspension cell line Molt-4.
  • the binding constants for taxols (1) and (2) calculated from the slopes ofthe linear portions ofthe curves in Figure 3 were 5xl0 "9 and 3X10 "6 respectively. It can be seen from these curves that binding is progressively inhibited at increasing concentrations of competitor until a plateau is reached. The plateau corresponds to nonspecific background binding.
  • the curve obtained for the MPA-derivative parallels that for taxol but with an approximately 1000-fold lower specific binding affinity.
  • the data agree with the results obtained from the microtubule assay suggesting that the cellular target for this drug is tubulin. Since the microtubule assay for compound (2) indicated no tubulin binding, the data in Figure 3 suggests that the specific binding effect observed for this compound may involve a secondary target of lower affinity.
  • the antitumor activity ofthe onium salts of taxol were assessed in nude mice bearing tumors of human A-549 lung adenocarcinomas, Ovcar-3 ovarian carcinoma, and PC-3 prostate carcinoma cells.
  • the data in Figure 4 for the lung tumor model (A549) showed large differences in antiproliferation activity between two 2'-substituted protaxols. While the 2 -MPA derivative (2) inhibited tumor growth nearly completely, the 2'-acylsufone derivative (7) showed no significant growth inhibition, yielding a tumor growth curve very similar to the 5DW control.
  • Figure 5 illustrates antiproliferation results for 2'-MPA-3-thiophene-taxol (4) and 2'MPA taxol (2) for the Ovcar-3 human tumor xenograft. Under the conditions given in this figure, compound 2 gave complete inhibition of tumor growth, with 100% survival of animals.
  • Figure 6, summarizes the results for a PC-3, prostate tumor model study. Taxol was compared with both the 2'- and 7-substituted oxonium salts. The taxol (1) control and the 2'-MPA salt (2) gave regression of established tumors. The 7-MPA isomer (3) showed essentially no antitumor activity as indicated by a tumor growth curve which followed the 5DW controls.
  • mice Most significantly, however, only 3 out of 8 mice survived the taxol treatment, while all ofthe mice given either the 2'- or 7-isomers survived and 5 out of 8 animals given the 2 - isomer showed complete remission with no palpable tumor mass at the termination ofthe trial (after 24 days).
  • Tritiated taxol and 2'MPA-taxol were used in drug elimination experiments in normal BALB/C mice. In both groups of mice of four animals each, only 4-5% ofthe administered radioactivity was measured in the combined urine and feces 24 hours after injection.
  • Tubulin was isolated from calf brain according to a procedure disclosed by Williams et al. (Methods in Enzymology, vol. 85, pages 376-392.) The tubulin was then stored at a concentration of 5.5 mg/ml in liquid nitrogen. 96- Well microplates were charged with 30 ⁇ l of PEM buffer and 10 ml DMS A containing the drug. Then 35 ⁇ l of tubulin solution (2 mg/ml) and 8 ⁇ l of GTP (1 mM) in water was added.
  • the plates were then shaken on a titer plate shaker for 10 seconds and placed in the microplate reader. Absorbance was measured in 1 minute intervals at 340 nm at a plate temperature of 37° C. After 15 minutes of reaction time, 10 ⁇ l of calcium chloride (10 mM) was added and the reaction was continued for another 10 minutes.
  • the positive control included both tubulin (1.0 mg.ml) with taxol (IO "6 M), CaCl 2 (0.25 mM) added at 15 minutes.
  • the taxol-2'-MPA measurements included both tubulin (1.0 mg.ml) with taxol-2'-MPA (10 " * M), CaCl 2 (0.25 mM) added at 15 minutes.
  • the taxol-7-MPA measurement included both tubulin (1.0 mg.ml) with taxol-2'-MPA (IO *6 M), CaCl 2 (0.25 mM) added at 15 minutes. Turbidity was measured as optical density at 340 nm using a microplate reader
  • PRPMI media to which IO '9 M ofthe radiolabeled taxol or taxol onium salt was added together with increasing concentrations of nonradiolabeled compound. After 30 minutes, the cells were centrifuged, washed with PBS and 1% SDS was added. The radioactivity of lysed cells was then read by means of a LKB Model 1219 scintillation counter. Altematively, the cells may be lysed by sonication.
  • Taxol (1) was purchased from Napro Biotherapeutics Co. (Boulder Colorado). Taxotere (5) was synthesized from deacetyl-bacatin III according to conventional methods or obtained from Rhone Poulenc Rorer Research Development. C-7-MPA taxol (3) was synthesized according to the method of Paloma et al. ⁇ Chemistry and Biology, 1994: vol. 1, pp 107-1 120.) The C-2'-methylpyridinium acetate salts (MPA) of taxol (2) and taxotere (6) and the 2-substituted thiophene analog (4) were synthesized according to the method of Nicolaou et al.
  • MPA C-2'-methylpyridinium acetate salts
  • Taxol (1) is formulated with Cremophor EL in order to enhance its solubility. Conventional formulations of taxol (1) with Cremophor EL exhibit a
  • Preferred therapeutic dose for the C-2'-MPA prodrugs of taxol (2) and taxotere (6) ranges between 5 and 70 mg/kg (approximately 1, 120 - 1,260 mg/m 2 ). However, for highly refractory tumors, the dose may be increased to 300 mg/kg
  • the dose may be administered as a bolus injection or by i.v. infusion.
  • Bolus injections may be administered intraveneously (i.v.) or intraperitoneally (i.p ).
  • Bolus injections may be administered in a 10 ml volume.
  • the dose may be administered by infusion in a much larger volume over a preferred period of three hours.
  • the preferred interval between administrations is three weeks. However, for highly refractory tumors, the interval between administrations may be shortened.
  • C-2'-MPA prodrugs of taxol (2) or taxotere (6) is dissolved in 2-3 ml of ethanol, followed by dilution with 10-14 ml of 5% dextrose solution or by 10-15 ml of 5% dextrose.
  • Formulations intended for infusion may contain other counter ions, e.g., lactated ringer solutions. Formulation may also include nitrates. The preferred counter ion is acetate. However, alterative counter ions include OAc “ , Cl “ , Br “ , I “ , BF 4 “ , ClO 4 “ , ArSOj “ , and AlkylSO 3 " . More generally, any counter ion classified by the U.S. Food and Drug Administration as generally regarded as safe (GRAS) for injection may be employed in the formulation.
  • GRAS safe
  • C-2'-MPA prodrugs of taxol (2) and taxotere (6) are stable and may stored without significant loss in 1-2% Tween #80 or Tween #20 (Sigma Chemical Co., St Louis Mo.) with or without ethyl alcohol.
  • the in vivo efficacy of protaxols in human lung adenocarcinoma tumor xenograft nude mouse models is illustrated in Figure 4.
  • the tumor model was generated from A549 cell line, an ATTC that was maintained under standard cell proliferation conditions (37°C, 5% carbon dioxide in sterile air).
  • Each cohort was comprised of six randomly chosen female athymic nude mice, for a total population size of twenty four mice. Hemocytometer counted cells, suspended in Hanks minimn (Gibco, Grand Island NY) were implated S.C. (IO 6 cells in 0.4 mL per mouse). Solid tumor growth was measured on each third day. Equimolar amounts ofthe test compounds (1.0 mM, 400 ⁇ L) were injected i.p. on days 1, 3, 5, 7, 9, and 11 using the following media:
  • the in vivo efficacy of protaxols in Ovcar 3 tumor xenograft nude mouse models is illustrated in Figure 5.
  • the tumor model was generated from an ATTC
  • Ovcar 3 carcinoma cell line that was maintained under standard cell proliferation conditions, viz. 37°C, 5% carbon dioxide in sterile air.
  • Each cohort was comprised of eight randomly chosen female athymic nude mice, for a total population size of twenty four. Hemocytometer counted cells, suspended in Hanks medium (Gibco, Grand Island NY) were implanted S.C. (IO 6 cells in 0.4 mL per mouse). Solid tumor growth was measured on each third day. Equimolar amounts ofthe test compounds (1.0 mM, 400 ⁇ L) were injected i.p. on days 1, 3, 5, 7, 9, and 11 using the following media:
  • the in vivo efficacy of protaxols in prostate tumor xenograft nude mouse models is illustrated in Figure 6.
  • the tumor model was generated from an ATTC PC-3 prostate carcinoma cell line that was maintained under standard cell proliferation conditions, viz. 37°C, 5% carbon dioxide in sterile air.
  • Each cohort was comprised of eight randomly chosen female athymic nude mice, for a total population size of twenty four. Hemocytometer counted cells, suspended in Hanks minimn (Gibco, Grand Island NY) were implanted S.C. (IO 6 cells in 0.4 mL per mouse). Solid tumor growth was measured on each third day. Equimolar amounts ofthe test compounds (1.0 mM, 400 ⁇ L) were injected i.p. on days 1, 3, 5, 7, 9, and 11 using the following media:

Abstract

Les acétates de C-2'-méthylpyridinium (MPA)-taxotère sont des promédicaments ayant une bonne solubilité aqueuse, une faible toxicité et une haute activité antitumorale. Ces promédicaments sont administrés à des patients afin de traiter des tumeurs. Cette administration peut se faire par injection ou perfusion.
PCT/US1995/013902 1995-10-27 1995-10-27 Procede de traitement du cancer au moyen de promedicaments a base de sels d'onium taxoïdes WO1997015571A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1001769A1 (fr) * 1997-06-20 2000-05-24 Baker Norton Pharmaceuticals, Inc. Bioprecurseurs solubles de paclitaxel
US6153756A (en) * 1996-06-04 2000-11-28 Digenis; George A. Soluble prodrugs of paclitaxel
EP3429992A4 (fr) * 2016-03-14 2019-12-11 Sphaera Pharma Pvt. Ltd. Composés à base de trigonelline

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6153756A (en) * 1996-06-04 2000-11-28 Digenis; George A. Soluble prodrugs of paclitaxel
EP1001769A1 (fr) * 1997-06-20 2000-05-24 Baker Norton Pharmaceuticals, Inc. Bioprecurseurs solubles de paclitaxel
EP1001769A4 (fr) * 1997-06-20 2000-05-24 Baker Norton Pharma Bioprecurseurs solubles de paclitaxel
EP3429992A4 (fr) * 2016-03-14 2019-12-11 Sphaera Pharma Pvt. Ltd. Composés à base de trigonelline
US10752589B2 (en) 2016-03-14 2020-08-25 Sphaera Pharma Pvt. Ltd. Trigonelline based compounds

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