A preclinical therapeutic schedule optimizing docetaxel plus estramustine administration in prostate cancer.

Androgen-dependent and castration-resistant prostate cancer (PC) is usually sensitive to docetaxel chemotherapy. Nevertheless, docetaxel resistance frequently appears after several cycles of treatment, raising the problem of salvage treatment for docetaxel-resistant PC patients. Although the combination of docetaxel and estramustine prolongs metastasis-free and overall survival of patients with androgen-independent PC, the use of this modality remains limited in elderly patients or patients with several comorbidities, especially vascular disease or gastrointestinal toxicity, because of unacceptable toxicity including venous thrombosis. The aims of this study were therefore (i) to evaluate the in-vivo efficacy of estramustine combined with docetaxel since initial tumor growth and following the appearance of docetaxel resistance in the androgen-dependent human PC xenograft PAC120, and (ii) to evaluate the efficacy of estramustine in six human androgen-independent PC models derived from PAC120. In docetaxel-resistant tumor-bearing mice, estramustine alone induced a TGD2 of 18 days, whereas the combination of docetaxel and estramustine induced a TGD2 of 50 days (P<0.05) with no significantly different overall survival of mice treated by docetaxel and estramustine since day 1 or since the onset of resistance to docetaxel. Among the six human androgen-independent tumors treated with estramustine alone, two highly sensitive models, two intermediate responding tumors, and two resistant models were observed. Altogether, these results suggest that estramustine should be combined with docetaxel in PC patients, but the use of this treatment could be limited, particularly in elderly patients, to docetaxel-resistant cases.

Estramustine phosphate enhances the effects of hyperthermia and induces the small heat shock protein HSP27 in the human prostate carcinoma cell line PC-3.

The antimicrotubule drug estramustine phosphate (EMP) has been shown to sensitize prostate carcinoma cells to radiation via synchronization at the G2/M phase of the cell cycle. This synchronization may also render cells more sensitive to hyperthermia, providing a rationale for multimodal treatment approaches. We have investigated the effects of EMP and hyperthermia, as well as the regulation of heat shock proteins (HSP) in the PC-3 prostatic carcinoma cell line. Cells were incubated with four doses of EMP for 48 h followed by a 1-h hyperthermia treatment ranging from 41 degrees C to 44 degrees C. Cell cycle distribution at the end of the EMP incubation was investigated by flow cytometry. Cytotoxicity was assessed by colony formation assays. HSP accumulation was investigated by Western immunoblotting. Doses of 1, 5, 10 and 15 microM EMP synchronized 27, 28, 46, and 68% of PC-3 cells at G2/M. With 5, 10 and 15 microM, a sensitizing effect of EMP was assessed at hyperthermic temperatures of 42, 43 and 44 degrees C. EMP did not alter the expression of HSP72, but substantially induced the synthesis of HSP27 in PC-3 cells. Our data show that EMP sensitizes PC-3 cells to hyperthermia induced cytotoxicity. This observation supports the rationale for multimodal treatment approaches in locally advanced prostate cancer.