Alternative Antiandrogen Therapy Research Articles

Antiandrogen withdrawal syndrome and alternative antiandrogen therapy associated with the W741C mutant androgen receptor in a novel prostate cancer xenograft

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). 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whether AWS was observed in this model, bicalutamide (BCL) was orally administered to the castrated mice and then withdrawn.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. 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. 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.

Current topics and perspectives relating to hormone therapy for prostate cancer

Prostate cancer is androgen-dependent, and hormone therapy, mainly achieved by androgen deprivation, has been one of the main treatment modalities in the clinical management of prostate cancer patients for more than six decades. In the 1980s, luteinizing hormone-releasing hormone agonists, which reduce testosterone to castration levels, were introduced Also, after the 1980s, nonsteroidal antiandrogens were developed in addition to steroidal antiandrogens. Since then, so-called maximum androgen blockade (MAB)/combined androgen blockade (CAB), which is a combination of surgical or medical castration and oral antiandrogens, has been developed. More recently, novel treatment modalities have been developed, such as intermittent androgen suppression, nonsteroidal antiandrogen monotherapy, and alternative antiandrogen therapy after relapse from initial MAB/CAB, The present article focuses on these treatment modalities to review current topics and perspectives with respect to hormone therapy for prostate cancer.

Clinical efficacy of alternative antiandrogen therapy in Japanese men with relapsed prostate cancer after first‐line hormonal therapy

To confirm the effectiveness of alternative antiandrogen therapy (AAT) in Japanese patients with prostate cancer relapse after first-line hormonal therapy. A total of 80 patients who had successive serum prostate-specific antigen (PSA) progression after first-line hormonal therapy (luteinizing hormone-releasing hormone agonist alone: 21 cases; combined antiandrogen blockade therapy: 59 cases) were enrolled. We evaluated the positive ratio of antiandrogen withdrawal syndrome (AWS), the PSA responses with second- and third-line AAT, and cause-specific survival in terms of the effectiveness of AAT. The overall positive AWS ratio after first-line therapy was 33%, while that after second-line therapy was 7%. There was no correlation between the first-line PSA response and the positive AWS. Of the 10 positive and the 20 negative AWS cases, secondary antiandrogen administration was effective in 50% and 60% of cases, respectively. The positive PSA responders at second- and third-line therapy were 51% and 13%, respectively. For second-line therapy, the effective rates from steroidal to non-steroidal, from non-steroidal to non-steroidal antiandrogen, and from non-steroidal to steroidal were 83%, 43%, and 14%, respectively. The cause-specific survival of the second-line responders was significantly better than that of the non-responders. There was a substantial number of patients who found second-line AAT to be modestly effective. Flutamide was effective as an alternative antiandrogen for the patients' relapse treatment with bicalutamide in Japanese men.