Premium
Antiandrogen withdrawal syndrome and alternative antiandrogen therapy associated with the W741C mutant androgen receptor in a novel prostate cancer xenograft
Author(s) -
Terada Naoki,
Shimizu Yosuke,
Yoshida Toru,
Maeno Atsushi,
Kamba Tomomi,
Inoue Takahiro,
Nakamura Eijiro,
Kamoto Toshiyuki,
Ogawa Osamu
Publication year - 2009
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.21058
Subject(s) - antiandrogen , flutamide , bicalutamide , prostate cancer , antiandrogens , androgen receptor , medicine , androgen , in vivo , prostate , endocrinology , cancer , cancer research , biology , hormone , microbiology and biotechnology
Abstract BACKGROUND The mechanisms underlying antiandrogen withdrawal syndrome (AWS) and alternative antiandrogen therapy (AAT) effectiveness were assumed to be mutations in the androgen receptor (AR), which resulted in an altered response to antiandrogens. The aim of the present study was to test this assumption using the novel prostate cancer xenograft model KUCaP‐1 harboring the W741C mutant AR (Yoshida et al., Cancer Res 2005; 65(21): 9611–9616). METHODS Mice bearing xenograft tumors were castrated, and the long‐term sequential changes in tumor volume were observed. To determine whether AWS was observed in this model, bicalutamide (BCL) was orally administered to the castrated mice and then withdrawn. The effect of flutamide (FLT) on the W741C mutant AR was examined with transactivation assays in vitro and with the oral administration of FLT to non‐castrated mice harboring KUCaP‐1 in vivo. The AAT efficacy against KUCaP‐1 was evaluated by changing BCL with FLT. RESULTS KUCaP‐1 regressed significantly after castration and did not re‐grow. KUCaP‐1 treated with BCL continued to grow even after castration and started regressing 2 months after BCL withdrawal, replicating clinically recognized AWS. The antagonistic effect of FLT against the W741C mutant AR was revealed in vitro and in vivo. AAT with FLT suppressed tumor growth after BCL withdrawal. CONCLUSIONS KUCaP‐1 was an entirely androgen‐dependent xenograft and mimicked the clinical phenomena of AWS and AAT caused by the agonistic and antagonistic activity of BCL and FLT, respectively. KUCaP‐1 could be an in vivo model for screening novel antiandrogens for the treatment of BCL resistant prostate cancer harboring the W741C mutation in the AR. Prostate 70: 252–261, 2010. © 2009 Wiley‐Liss, Inc.