INHIBITION OF PROSTATE-CANCER GROWTH BY ESTRAMUSTINE AND ETOPOSIDE - EVIDENCE FOR INTERACTION AT THE NUCLEAR MATRIX

Metastatic prostate cancer which is refractory to hormone therapy rema ins an incurable disease for which there is no effective therapy. We h ave begun to investigate the nuclear matrix, the RNA-protein network o f the nucleus that plays an important role in DNA replication and gene expression, as a target for cancer chemotherapy. It was postulated th at estramustine phosphate (EMP), an estradiol-nitrogen mustard conjuga te that binds to the nuclear matrix, might enhance the cytotoxicity of etoposide (VP-16), a topoisomerase II inhibitor that acts at the leve l of the nuclear matrix. In a nascent DNA synthesis assay, EMP and eto poside interact to selectively inhibit new DNA synthesis on the nuclea r matrix. In vitro, EMP and etoposide appeared to act synergistically to inhibit the growth of the metastatic Dunning rat prostate adenocarc inoma cell line Mat-LyLu as well as the metastatic human prostate aden ocarcinoma cell line PC-3. In vivo, EMP and etoposide inhibited prosta te adenocarcinoma growth in the Dunning Copenhagen rat model. These da ta have formed the basis of a Phase I/II clinical trial to examine the effect of EMP and etoposide in patients with stage D hormone-refracto ry prostate cancer.