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

The established antitumor efficacy of paclitaxel against a variety of human tumors has led to preclinical and clinical studies to develop the paclitax el-based combination regimens, We examined in vivo the antitumor activity a nd 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 CDF, mice. Paclitaxel given intravenously at 24 mg /kg/day on a schedule of consecutive daily injections for 5 days (d1-5) ind uced reproducibly, in 6 experiments, a significant (37-52%) increase in the survival time of tumor-bearing mice over saline-treated control mice. Cisp latin at 4 and 2 mg/kg/day) given intravenously on the same treatment sched ule 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 o f the survival time of tumor-bearing mice compared with the group given pac litaxel alone. On the other hand, treatment with these drugs on the reverse sequence caused toxic deaths of all mice, Such sequence-dependent toxic de ath of mice was also observed with the combination of paclitaxel and carbop latin, etoposide or methotrexate, The combination of paclitaxel and adriamy cin, cyclophosphamide, ranimustine or vinblastine (VLB) showed a sequence-i ndependent antitumor activity and a more-than-additive therapeutic effect w as observed with the combination of paclitaxel and either VLB or ranimustin e. Although the drug administration schedules used here may not be directly applicable to the clinic, knowledge of the nature of the sequence-dependen cy in paclitaxel-based combination chemotherapy should be useful in the des ign of clinical trials.