Abstract
Hormone-refractory prostate cancer continues to be associated with a very poor prognosis. Agents that interact with the nuclear matrix have been demonstrated to have activity against hormone-refractory prostate cancer. It was the aim of this study to assess the activity of estramustine, an estradiol-nitrogen mustard conjugate, and 9-aminocamptothecin (9-AC), a topoisomerase I inhibitor, in a preclinical model of hormone-refractory prostate cancer. We used the Dunning rat prostatic adenocarcinoma model to demonstrate that the combination of estramustine and 9-AC interacts at the level of the nuclear matrix to inhibit the growth of prostate cancer cells. We demonstrate that the combination of these two agents at pharmacologically achievable doses are cytotoxic to rat and human prostate cancer cells in vitro and in vivo in the rat. The combination of the two drugs was significantly more cytotoxic than either drug alone. We have instituted a Phase II clinical trial in patients with hormone-refractory prostate cancer using 9-AC based on these preclinical findings.
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