title: A preclinical therapeutic schedule optimizing docetaxel plus estramustine administration in prostate cancer.
abstract: 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.
authors.affiliation: Department of Translational Research, Laboratory of Preclinical Investigation, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Dahmani
authors.forename: Ludmilla
authors.initials: L
authors.lastname: de Plater
authors.forename: Charlotte
authors.initials: C
authors.lastname: Guyader
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Fontaine
authors.forename: Aurélie
authors.initials: A
authors.lastname: Berniard
authors.forename: Franck
authors.initials: F
authors.lastname: Assayag
authors.forename: Philippe
authors.initials: P
authors.lastname: Beuzeboc
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Marangoni
authors.forename: Fariba
authors.initials: F
authors.lastname: Némati
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Poupon
authors.forename: Christophe
authors.initials: C
authors.lastname: Pasik
authors.forename: Stéphane
authors.initials: S
authors.lastname: Oudard
authors.forename: Didier
authors.initials: D
authors.lastname: Decaudin
mesh_terms: D000368:Aged; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D015897:Comorbidity; D000077143:Docetaxel; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D004961:Estramustine / Q000494:pharmacology*; D005767:Gastrointestinal Diseases / Q000453:epidemiology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000097:blood / Q000188:drug therapy / Q000453:epidemiology; D009919:Orchiectomy; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000453:epidemiology; D015996:Survival Rate; D043823:Taxoids / Q000494:pharmacology*; D014652:Vascular Diseases / Q000453:epidemiology; D020246:Venous Thrombosis / Q000139:chemically induced; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D043823:Taxoids; D000077143:Docetaxel; D004961:Estramustine; D017430:Prostate-Specific Antigen