Abstract A27: Efficacy of estramustine + docetaxel in docetaxel-resistant human prostate cancer xenograft: a preclinical model of docetaxel resistance reversion

Abstract

Abstract Introduction: Androgen-dependent prostate cancers (PC) are usually sensitive to docetaxel chemotherapy. Nevertheless, docetaxel-resistance frequently appears after several cycles of treatment, raising the treatment rescue of docetaxel-resistant PC patients. If the combination of estramustine to docetaxel prolongs the metastatic-free and overall survivals of patients with androgen-dependent PC, its use remains limited in patients because of unacceptable toxicity including venous thromboses. The aims of this study were (1) to evaluate the in vivo efficacy of estramustine combined to docetaxel since initial tumor growth and since appearance of docetaxel resistance in one androgen-dependent human PC xenograft, and (2) to evaluate the efficacy of estramustine in six human androgen-independent human PC variants. Experimental procedures: The preclinical models included the androgen-dependent PAC120 tumor obtained from a Gleason-9 primary PC of a 51-years old patient (De Pinieux et al, Am J Pathol, 2001), and six hormone-independent variants derived from PAC120. Docetaxel was administrated at a dosage of 20 mg/kg every three weeks by intraperitoneal injection for at most six cycles, and estramustine was given intraperitoneally at a dosage of 12 mg/kg days 1 to 5 every 3 weeks until mice sacrifice. Tumor volume was measured twice a week and Relative Tumor Volume (RTV) from start of treatment were then calculated. In the PAC120 model, escape to docetaxel was defined at the beginning of each next cycle (n + 1) as a ratio of RTVn+1/RTVn ≥ 2. Resistant mice were then randomized into two groups, one receiving estramustine alone, and the other treated by a combination of docetaxel + estramustine, with an evaluation of the tumor growth delay for a 2-fold tumor size increase from randomisation (TGD2). In the 6 androgen-independent PC xenografts (HID), estramustine administered alone was compared to a control group. Results: Estramustine alone did not induce significant tumor growth inhibition in both PAC120 and HID xenografts. In PAC120 model, tumor growth inhibition (TGI) after docetaxel alone and docetaxel + estramustine was 81% and 95%, with a mean response duration of 29 days [21–63] and 68 days [64–74], respectively (p < 0.05). In docetaxel-resistant tumor bearing mice, estramustine alone induced a TGD2 of 18 days, whereas estramustine + docetaxel induced a TGD2 of 49 days (p < 0.05). Metastatic lesions and venous thromboses into lung of tumor-bearing mice have also been evaluated by histopathological analyses and may be presented during the meeting. Conclusions: Estramustine alone was not efficient in both human androgen-dependent and -independent PC xenografts. Inversely, the combination of estramustine + docetaxel in first treatment line and estramustine added to docetaxel in docetaxel-resistant xenografts was highly effective. These data therefore suggest that estramustine should be combined to docetaxel in PC patients, but its use could be delayed, particularly in elderly patients, to docetaxel refractory cases. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A27.