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5-Aza-2'-Deoxycytidine Delays Androgen-Independent Disease and Improves Survival in the Transgenic Adenocarcinoma of the Mouse Prostate Mouse Model of Prostate Cancer

Authors' Affiliations: ¹ Department of Urology, University of Michigan, Ann Arbor, Michigan; ² Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia; ³ Department of Urology, University of Ulm, Ulm, Germany; and ⁴ Department of Urology, Klinikum rechts der Isar, Technical University Munich, Munich, Germany

Requests for reprints: Mark L. Day, Department of Urology, University of Michigan, 6219 CCGC, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0944. Phone: 734-763-9968; Fax: 1-734-647-9271; E-mail: mday{at}umich.edu.

Purpose: We have previously shown that 5-aza-2'-deoxycytidine (5-aza) is an effective chemopreventive agent capable of preventing early disease progression in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. The purpose of this study was to determine the effect of 5-aza on preexisting TRAMP prostate cancers and prevention of androgen-independent prostate cancer.

Experimental Design: TRAMP mice with established prostate cancers were treated with 5-aza, castration, castration + 5-aza, or vehicle control (PBS). One cohort of 22 mice per treatment was euthanized after 10 weeks of treatment, whereas a second cohort of 14 mice per group was followed until death to determine survival. Histologic sections of prostate, pelvic lymph nodes, lung, and liver were blinded and analyzed by a certified genitourinary pathologist (K.J.W.).

Results: Combined treatment (castration + 5-aza) provided significant survival benefits over either single treatment (combined versus castration P = 0.029, combined versus 5-aza P = 0.036). At 24 weeks of age, 86% of mice within the PBS cohort exhibited histologic evidence of prostate cancer, whereas only 47% of the combined cohort exhibited malignant disease (P < 0.0001). Additionally, whereas 43% of the PBS treatment group exhibited lymph node metastases, these were only observed in 21% of the combined treatment mice.

Conclusions: This is the first study to examine the effect of 5-aza and combined castration + 5-aza on preexisting prostate cancer in an animal model. Based on these preclinical findings, we suggest that 5-aza treatment may prolong the time to an androgen-independent status and thus survival in a hormone-deprived setting in prostate cancer.

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