Lack of correlation between mitotic arrest or apoptosis and antitumor effect of docetaxel

Purpose: To determine, as we did for paclitaxel, whether mitotic arrest and apoptosis induced in murine tumors in vivo by docetaxel correlate with the drug's antitumor effect and whether the antitumor efficacy of docetaxel de pends on p53 mutational status of tumors. Methods: C3Hf/Kam mice were impla nted with one of the following 15 syngeneic tumors: seven adenocarcinomas ( MCa-4, MCa-29, MCa-35, MCa-K, OCa-I, ACa-SG, and HCa-I), two squamous cell carcinomas (SCC-IV and SCC-VII), five sarcomas (FSa, FSa-II, Sa-NH, NFSa, a nd Sa-4020) and one lymphoma (Ly-TH). When the tumors had grown to 8 mm in diameter, the mice were treated with 31.3 mg/kg docetaxel i.v. Tumor growth delay was the endpoint of docetaxel's antitumor effect. In separate groups of mice, mitotic arrest and apoptosis were determined micromorphometricall y 1 to 72 h after docetaxel treatment. Tumors were assayed for their p53 st atus by sequence analysis of RNA prepared from freshly excised tumors. Resu lts: Docetaxel caused statistically significant growth delay in six of seve n adenocarcinomas, three of five sarcomas, and the lymphoma, but not in eit her of the squamous cell carcinomas. The drug induced mitotic arrest in all tumor types, but to various degrees ranging from 6.4 +/- 0.4% to 25.1 +/- 0.1%. In contrast, docetaxel induced appreciable apoptosis in only 5 of 15 tumors, with 10.3 +/- 1.6% being the highest apoptotic value. Neither mitot ic arrest nor apoptosis were significantly correlated with tumor growth del ay. However, tumors that responded to docetaxel by significant tumor growth delay histologically displayed massive cell destruction by cell lysis, and four of these tumors also showed marked infiltration with mononuclear lymp hoid cells. Of the 15 tumors only 3 had mutant p53. Conclusions. Docetaxel exhibited a strong antitumor effect in two-thirds of murine tumors, and on a milligram per kilogram basis was more effective than paclitaxel against t he same tumors. The drug was a potent inducer of mitotic arrest but a weak inducer of apoptosis, neither of which correlated with its antitumor effect . Tumor cell lysis appeared to be a major mode of tumor cell destruction an d can be regarded as the main mechanism underlying antitumor efficacy of do cetaxel. In contrast, paclitaxel's antitumor efficacy is related to its abi lity to induce apoptosis. At the molecular level, there was no dependency o f antitumor efficacy of docetaxel on p53 mutational status of tumors.