Schedule-dependent and -independent antitumor activity of paclitaxel-based combination chemotherapy against M-109 murine lung carcinoma in vivo

Abstract

The established antitumor efficacy of paclitaxel against a variety of human tumors has led to preclinical and clinical studies to develop the paclitaxel-based combination regimens. We examined in vivo the antitumor activity and toxicity of the combination of paclitaxel and each of 8 antitumor agents, currently in clinical use, against M-109 murine lung carcinoma implanted subcutaneously into male CDF1 mice. Paclitaxel given intravenously at 24 mg/kg/day on a schedule of consecutive daily injections for 5 days (d1-5) induced reproducibly, in 6 experiments, a significant (37-82%) increase in the survival time of tumor-bearing mice over saline-treated control mice. Cisplatin at 4 and 2 mg/kg/day given intravenously on the same treatment schedule showed no significant antitumor activity when given alone; however, the combination of paclitaxel at 24 mg/kg/day (d1-5) followed by cisplatin at a dose of 2 mg/kg/day (d6-10) induced a significant (P < 0.05) prolongation of the survival time of tumor-bearing mice compared with the group given paclitaxel alone. On the other hand, treatment with these drugs on the reverse sequence caused toxic deaths of all mice. Such sequence-dependent toxic death of mice was also observed with the combination of paclitaxel and carboplatin, etoposide or methotrexate. The combination of paclitaxel and adriamycin, cyclophosphamide, ranimustine or vinblastine (VLB) showed a sequence-independent antitumor activity and a more-than-additive therapeutic effect was observed with the combination of paclitaxel and either VLB or ranimustine. Although the drug administration schedules used here may not be directly applicable to the clinic, knowledge of the nature of the sequence-dependency in paclitaxel-based combination chemotherapy should be useful in the design of clinical trials.