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Taxol: a review of its preclinical in vivo antitumor activity
1Experimental Therapeutics Department, Bristol-Myers Squibb Co., Wallingford, CT 06492.
Abstract:
Taxol has been demonstrated in numerous laboratories worldwide to have broad-spectrum antitumor activity against many tumor models. The susceptible tumors include murine leukemias and solid tumors, and human solid tumor xenografts. The initial findings of taxol's ineffectiveness against most distal site tumor models was probably a consequence of the insolubility of taxol in nearly all the vehicles used in those early studies. On the occasions when an ethanol-based vehicle was used to dissolve taxol, substantial distal site antitumor activity was observed. Although no definitive schedule dependency data have evolved, once-a-day or every-other-day i.v. injections for several treatments have proved to be reproducibly effective in stringent s.c. tumor models. Attempts to discern a therapeutically synergistic cytotoxic drug combination was made on two occasions without success. In the manner evaluated, taxol plus either adriamycin, cisplatin, cyclophosphamide or etoposide (VP-16) were not meaningfully more efficacious than the more effective drug in each of those combination settings.
Insights
Taxol demonstrates broad-spectrum antitumor activity in various models, particularly when using an ethanol vehicle. Combinations with other chemotherapy drugs did not enhance its efficacy.
Area of Science:
- Oncology
- Pharmacology
Background:
- Taxol exhibits broad-spectrum antitumor activity across diverse preclinical models.
- Early studies noted ineffectiveness against distal tumors, likely due to poor solubility in common vehicles.
Purpose of the Study:
- To evaluate the impact of vehicle on Taxol's efficacy.
- To assess the effectiveness of Taxol administered via different injection schedules.
- To investigate potential synergistic effects of Taxol in combination chemotherapy.
Main Methods:
- Taxol's antitumor activity was tested in murine leukemias, solid tumors, and human solid tumor xenografts.
- Efficacy was compared using different vehicles, with a focus on ethanol-based solutions.
- Administration schedules involved once-daily or every-other-day intravenous injections.
- Taxol was combined with adriamycin, cisplatin, cyclophosphamide, or etoposide (VP-16).
Main Results:
- Substantial distal site antitumor activity was observed when an ethanol-based vehicle was used.
- Once-daily or every-other-day intravenous injections proved effective in stringent subcutaneous tumor models.
- Combinations of Taxol with adriamycin, cisplatin, cyclophosphamide, or etoposide did not yield significantly greater efficacy than the individual drugs.
Conclusions:
- The choice of vehicle significantly impacts Taxol's observed antitumor efficacy.
- Optimized administration schedules can enhance Taxol's effectiveness in preclinical models.
- Taxol does not appear to offer synergistic benefits when combined with common cytotoxic agents in the evaluated settings.