Antiandrogen withdrawal syndrome and alternative antiandrogen therapy associated with the W741C mutant androgen receptor in a novel prostate cancer xenograft.
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whether AWS was observed in this model, bicalutamide (BCL) was orally administered to the castrated mice and then withdrawn.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.
Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Naoki
N
Terada
Yosuke
Y
Shimizu
Toru
T
Yoshida
Atsushi
A
Maeno
Tomomi
T
Kamba
Takahiro
T
Inoue
Eijiro
E
Nakamura
Toshiyuki
T
Kamoto
Osamu
O
Ogawa
D000284:Administration, Oral; D000726:Androgen Antagonists / Q000008:administration & dosage* / Q000009:adverse effects; D000728:Androgens / Q000378:metabolism; D000813:Anilides / Q000008:administration & dosage; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage* / Q000009:adverse effects; D003545:Cysteine; D004334:Drug Administration Schedule; D005485:Flutamide / Q000008:administration & dosage; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation; D009570:Nitriles / Q000008:administration & dosage; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000187:drug effects / Q000235:genetics*; D019233:Retreatment; D013375:Substance Withdrawal Syndrome; D014105:Tosyl Compounds / Q000008:administration & dosage; D014183:Transplantation, Heterologous; D014364:Tryptophan
D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; D018931:Antineoplastic Agents, Hormonal; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D005485:Flutamide; D014364:Tryptophan; C053541:bicalutamide; D003545:Cysteine