5α-Reductase Inhibition Coupled with Short Off Cycles Increases Survival in the LNCaP Xenograft Prostate Tumor Model on Intermittent Androgen Deprivation Therapy

Abstract

Intermittent androgen deprivation therapy in patients with prostate specific antigen progression after localized prostate cancer treatment is an alternative to standard continuous androgen deprivation therapy. Intermittent androgen deprivation therapy allows for testosterone recovery during off cycles. This stimulates regrowth and differentiation of the regressed prostate tumor, lessens the side effects of continuous androgen deprivation therapy and potentially prolongs survival. Previously intermittent androgen deprivation therapy coupled with finasteride was shown to prolong survival in animals bearing androgen sensitive prostate tumors when the off cycle duration was not prolonged but rather fixed at 10 to 14 days. Regressed prostate tumor xenografts with testosterone replacement were initially responsive to 5α-reductase inhibition but growth resumed after several days. In shorter off cycles of testosterone recovery 5α-reductase inhibition might maximize tumor growth inhibition during intermittent androgen deprivation therapy and perhaps increase survival. We used the LNCaP xenograft tumor model to evaluate the effectiveness of short off cycles of 4 days coupled with 5α-reductase inhibition on survival and tumor regrowth while on intermittent androgen deprivation therapy. Dutasteride inhibited initial testosterone induced tumor regrowth off cycles 1 and 2, and significantly increased survival. These results further support the potential for intermittent androgen deprivation therapy combined with 5α-reductase inhibition to improve survival in patients with prostate cancer when off cycle duration is short or very short.