Activity of Docetaxel With or Without Estramustine Phosphate Versus Mitoxantrone in Androgen Dependent and Independent Human Prostate Cancer Xenografts

No AccessJournal of UrologyCLINICAL UROLOGY: Original Articles1 May 2003Activity of Docetaxel With or Without Estramustine Phosphate Versus Mitoxantrone in Androgen Dependent and Independent Human Prostate Cancer Xenografts STEPHANE OUDARD, MARIE-EMMANUELLE LEGRIER, KARINE BOYÉ, RUI BRAS-GONÇALVES, GONZAGUE DE PINIEUX, PATRICIA DE CREMOUX, and MARIE-FRANCE POUPON STEPHANE OUDARDSTEPHANE OUDARD , MARIE-EMMANUELLE LEGRIERMARIE-EMMANUELLE LEGRIER , KARINE BOYÉKARINE BOYÉ , RUI BRAS-GONÇALVESRUI BRAS-GONÇALVES , GONZAGUE DE PINIEUXGONZAGUE DE PINIEUX , PATRICIA DE CREMOUXPATRICIA DE CREMOUX , and MARIE-FRANCE POUPONMARIE-FRANCE POUPON View All Author Informationhttps://doi.org/10.1097/01.ju.0000062500.75703.2cAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: Prostate cancer is known to be refractory to chemotherapy with only mitoxantrone showing some benefit. Recent clinical data indicate the antitumoral efficacy of taxanes alone or combined with estramustine phosphate. We compared the response to these treatments of hormone dependent and independent human prostate cancer xenografts. Materials and Methods: PAC120, an androgen dependent human prostate cancer xenograft, and several HIDs, which are androgen independent variants, were established in nude mice. Human gene expression was determined by semiquantitative reverse transcriptase-polymerase chain reaction. Androgen deprivation was achieved by surgical castration. Tumor bearing mice received 20 mg./kg. docetaxel on day 2, 1 mg./kg. hydrocortisone on days 1 to 3, 4 mg./kg. estramustine phosphate on days 1 to 4 or 1 mg./kg. mitoxantrone on day 1 by the intraperitoneal route for 3-week cycles. Relative tumor volume and growth delay were evaluated. Histological examination of tumors was done before and after treatment. Results: Mitoxantrone transiently decreased the growth rate of HID xenografts but did not affect that of PAC120. Estramustine phosphate alone inhibited the growth of PAC120 but not that of HID variants. Docetaxel inhibited the growth of all prostate cancer xenografts (PAC120 and HIDs) and increased survival. PAC120 showed distinct response patterns during prolonged treatment. Efficacy was significantly decreased by splitting docetaxel into 2 doses given at a 7-day interval (p =0.01). The docetaxel effect was potentiated by estramustine phosphate in 1 of the 2 HID variants tested. In castrated mice docetaxel induced a greater growth delay than in intact male mice (p =0.01). High Her2/neu and β2-tubulin transcripts were detected in all samples. Prostate specific antigen, androgen receptor and multidrug related protein-1 mRNA did not correlate with the drug response, while CYP3A4 mRNA inversely correlated with the response. Docetaxel treated tumors had an increased number of mitotic cells with centrosome alterations and multinuclei, an increased number of Ki67 labeled cells and a strong decrease in β-tubulin without evidence of apoptosis. Conclusions: Docetaxel showed a significant antitumoral effect on hormone dependent and tumors, which was largely superior to that of mitoxantrone. Estramustine phosphate alone had a modest effect. The drug response was associated with high Her2/neu expression, low CYP3A4 expression and the induction of numerous mitotic abnormalities. References 1 : Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol1996; 14: 1756. Google Scholar 2 : Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the cancer and leukemia group B 9182 study. J Clin Oncol1999; 17: 2506. Google Scholar 3 : Phase I trial of docetaxel with estramustine in androgen-independent prostate cancer. J Clin Oncol1999; 17: 958. Google Scholar 4 : Daily oral estramustine and intermittent intravenous docetaxel (Taxotere) as chemotherapeutic treatment for metastatic, hormone-refractory prostate cancer. Semin Oncol1999; 26: 34. Google Scholar 5 : Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: a final report of CALGB 9780. Cancer and Leukemia Group B. J Clin Oncol2001; 19: 2509. Google Scholar 6 : Phase I trial of weekly paclitaxel plus oral estramustine phosphate in patients with hormone-refractory prostate cancer. Urology2001; 58: 59. Google Scholar 7 : Clinical and experimental progression of a new model of human prostate cancer and therapeutic approach. Am J Pathol2001; 159: 753. Google Scholar 8 : HER-2/neu as a therapeutic target in non-small cell lung cancer, prostate cancer, and ovarian cancer. Semin Oncol2000; 27: 53. Google Scholar 9 : Estramustine depolymerizes microtubules by binding to tubulin. Cancer Res1993; 53: 4573. Google Scholar 10 : Treatment of androgen-independent prostate cancer using antimicrotubule agents docetaxel and estramustine in combination: an experimental study. Prostate2000; 44: 275. Google Scholar 11 : Hepatic biotransformation of docetaxel (Taxotere) in vitro: involvement of the CYP3A subfamily in humans. Cancer Res1996; 56: 1296. Google Scholar 12 : Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst1998; 90: 1225. Google Scholar 13 : The effect of an individual's cytochrome CYP3A4 activity on docetaxel clearance. Clin Cancer Res2000; 6: 1255. Google Scholar 14 : Chemosensitivity of prostate cancer cell lines and expression of multidrug resistance-related proteins. Eur J Cancer1999; 35: 664. Google Scholar 15 : Expression of a multidrug resistance gene in human cancers. J Natl Cancer Inst1989; 81: 116. Google Scholar 16 : Regulation of expression of the multidrug resistance protein MRP1 by p53 in human prostate cancer cells. J Clin Invest2000; 105: 1261. Google Scholar 17 : The role of MAP4 expression in the sensitivity to paclitaxel and resistance to vinca alkaloids in p53 mutant cells. Oncogene1998; 16: 1617. Google Scholar 18 : The role of HER-2 oncoprotein in drug-sensitivity in breast cancer (review). Oncol Rep2002; 9: 3. Google Scholar 19 : c-erbB-2 oncoprotein: a potential biomarker of advanced prostate cancer. Prostate1997; 30: 195. Google Scholar 20 : Survey of gene amplifications during prostate cancer progression by high-throughout fluorescence in situ hybridization on tissue microarrays. Cancer Res1999; 59: 803. Google Scholar 21 : A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med1999; 5: 280. Google Scholar 22 : Centrosome and spindle pole microtubules are main targets of a fluorescent taxoid inducing cell death. Cell Motil Cytoskeleton2001; 49: 1. Google Scholar 23 : Preliminary results of a phase II randomized trial of docetaxel, estramustine and prednisone-two schedules-versus mitoxantrone and prednisone in patients with metastatic hormone-refractory prostate cancer. Pro Am Soc Clin Oncol2002; 21: 177. Google Scholar 24 : Results of a phase II randomized trial of docetaxel, estramustine and prednisone-two schedules-versus mitoxantrone and prednisone in patients with metastatic hormone-refractory prostate cancer (HRPC). Ann Oncol2002; 325: 90. Google Scholar From the Institut Curie, Section de Recherche and Section Médicale, Hôpital Européen Georges Pompidou, Service de Cancérologie Médicale, Paris, France© 2003 by American Urological Association, Inc.FiguresReferencesRelatedDetailsCited ByHUANG D, GUH J, HUANG Y, CHUEH S, CHIANG P and TENG C (2018) INDUCTION OF MITOTIC ARREST AND APOPTOSIS IN HUMAN PROSTATE CANCER PC-3 CELLS BY EVODIAMINEJournal of Urology, VOL. 173, NO. 1, (256-261), Online publication date: 1-Jan-2005. Volume 169Issue 5May 2003Page: 1729-1734 Advertisement Copyright & Permissions© 2003 by American Urological Association, Inc.Keywordsprostatedrug evaluationgene expressiontransplantation, heterologousadenocarcinomaMetricsAuthor Information STEPHANE OUDARD Equal study contribution. More articles by this author MARIE-EMMANUELLE LEGRIER Equal study contribution. More articles by this author KARINE BOYÉ More articles by this author RUI BRAS-GONÇALVES More articles by this author GONZAGUE DE PINIEUX More articles by this author PATRICIA DE CREMOUX More articles by this author MARIE-FRANCE POUPON More articles by this author Expand All Advertisement PDF DownloadLoading ...