Adjuvant Action of Hepatocyte Growth Factor in Vitamin D Therapy of Androgen-Unresponsive Prostate Cancer.

摘要

This research is aimed at discovering new therapies for advanced prostate cancer and developing in preclinical models a treatment for androgen- independent prostate cancer that bolsters vitamin D's antitumor actions. We are examining separate and combined growth- regulatory actions of growth factors and hormones with vitamin D. While we are focused on paradoxical growth-inhibitory actions of hepatocyte growth factor (HGF), we are also seeking agents that act similarly with vitamin D. We concentrated initially on developing information and model systems for characterizing androgen modulation of HGF's actions and interactions with vitamin D vis-a'-vis growth inhibition and cell-cycle regulation in sublines transformed with stable androgen-receptor activity. In seeking agents similar to HGF, we discovered 2-methoxyestradiol, a normal estrogen metabolite that also exerts late cell-cycle inhibitory actions. This compound inhibits tumor progression in a transgenic mouse model of androgen- independent prostate cancer without toxic side effects. Because it is naturally occurring, readily synthesized, and reported to lack the angiogenic and other pleomorphic effects that characterize HGF activity in normal tissues, 2- methoxyestradiol could provide a cancer-cell-specific adjuvant to vitamin D therapy in prostate cancer.