5-aza-2'-deoxycytidine delays androgen-independent disease and improves survival in the transgenic adenocarcinoma of the mouse prostate mouse model of prostate cancer.
OBJECTIVE
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.


METHODS
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.
Zorn
Christoph S
CS
Department of Urology, University of Michigan, Ann Arbor, Michigan 48109-0944, USA.
Wojno
Kirk J
KJ
McCabe
Michael T
MT
Kuefer
Rainer
R
Gschwend
Juergen E
JE
Day
Mark L
ML
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000601:surgery; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002369:Castration; D003131:Combined Modality Therapy; D000077209:Decitabine; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000601:surgery
D000964:Antimetabolites, Antineoplastic; D000077209:Decitabine; D001374:Azacitidine