Preclinical profile of docetaxel (taxotere): efficacy as a single agent and in combination

Docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) is a new taxoid currently being studied in phase II and III clinical trials worldwide, with promising activity in breast cancer. Docetaxel was evaluated as a single agent against against seven mammary tumors, five from mice and two of human origin. Six of the seven models were found to be sensitive to docetaxel, exhibiting regressions of advanced-stage disease in murine models (MA16/C, MA13/C), and long tumor growth delays (Calc18) and cures (MX-1) in human tumor xenografts. In combination studies in tumor-bearing mice, synergism with docetaxel was observed with cyclophosphamide, 5-fluorouracil, etoposide, vinorelbine (Navelbine; Pierre Fabre Oncologie, Boulogne, France), and methotrexate. A similar level of efficacy was obtained in the cases of docetaxel/vincristine and docetaxel/mitomycin C, compared with the activity of the best single agent. Good activity was obtained with the docetaxel/doxorubicin, docetaxel/vinblastine, and docetaxel/cisplatin combinations; however, the activity of these combinations was lower than that of the best agent in the combination when tested in monotherapy. In terms of tolerance, 60% to 70% of the highest nontoxic dose of each agent could be administered in combination, except for vinca alkaloids, in which 80% to 100% of the maximum tolerated dose did not cause additional toxicity. Although docetaxel is a very potent agent when used in monotherapy, the above results suggest that it also will have a key role in clinical combination chemotherapy.