Enhancement of Intermittent Androgen Ablation Therapy by Finasteride Administration in Animal Models.

摘要

One critical issue in prostate cancer research is to slow down the transition of prostate cancer from an androgen-dependent state to a lethal androgen-refractory state. Intermittent androgen ablation therapy (IAAT) may slow down the development of androgen refractory tumors because intermittent recovery of androgens can induce differentiation of prostatic epithelial cells. However, the advantage of inducing differentiation by intermittent recovery of androgens is compromised by the disadvantage of androgenic induction of proliferation in prostate tumors. The biologically most active androgen is dihydrotestosterone (DHT), which is converted from testosterone (T) by 5 - reductase. Our recent studies showed that T is more potent than DHT in inducing the expression of growthinhibitory androgen-response genes, which led to our hypothesis that IAAT can be enhanced by finasteride, an inhibitor of T to DHT conversion. We have tested our hypothesis using LNCaP xenograft tumors in nude mice. Our experiments showed that finasteride administration during IAAT significantly reduced tumor growth rate, prolonged the life of nude mice bearing LNCaP tumors, and supra-induced the expression of growth- inhibitory androgen-response genes in the tumors.