therapy for hormone refractory prostate cancer utilizing the agents estramustine and etoposide. Although neither of these agents alone is effective in the treatment of advanced hormone refractory prostate cancer, we predicted their activity when used in combination based on preclinical assays and then demonstrated their effectiveness in a Phase I/II clinical trial where they were shown to have a 50 percent complete and partial response rate in patients with bidimensionally measurable disease (Journal of Clinical Oncology, 12:2005-2012, 1994). We have demonstrated that estramustine and etoposide interact with the nuclear matrix, which is the site of DNA replication. Furthermore, we have identified that paclitaxel (taxol), a microtubule inhibitor, interacts with estramustine and etoposide and may lead to new therapeutic strategies for advanced prostate cancer. The goal of this proposal is to test in the clinical setting a new therapy for hormone refractory prostate cancer which preclinical in vitro and in vivo data suggests will be active in the treatment of patients with hormone refractory prostate cancer. We hypothesize that the combination of estramustine, etoposide and paclitaxel will be an active regimen in the treatment of patients suffering from hormone refractory prostate cancer. We have demonstrated that estramustine, a nitrogen mustard-estradiol conjugate, increases the inhibition of nuclear matrix based DNA synthesis by the topoisomerase II inhibitor etoposide. We have shown that the cytotoxic activity of these agents demonstrated in preclinical in vitro and in vivo models can be successfully translated to the clinic for the treatment of patients with hormone refractory prostate cancer. Furthermore, we and others have demonstrated that estramustine also interacts with microtubules and increases the inhibitory action of paclitaxel in the preclinical and clinical settings of hormone refractory prostate cancer. We have demonstrated in the preclinical setting that the combination of estramustine, etoposide, and paclitaxel appears to have significant cytotoxic activity in prostate cancer models. Specifically, we propose to: 1. Conduct a Phase II clinical trial of oral estramustine, oral etoposide and intravenous paclitaxel in hormone refractory prostate cancer patients. 2. Test the effect of these agents on the presence of circulating cancer cells measured by the reverse transcriptase polymerase chain reaction which will detect PSA mRNA in the on. This clinical trial and its laboratory con-elate will allow us to assess the clinical efficacy and toxicity of these agents in patients with hormone refractory prostate cancer in the Phase II setting.
