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Inhibition of prostate cancer growth by estramustine and etoposide: evidence for interaction at the nuclear matrix
1Meyer L. Prentis Comprehensive Cancer Center, Wayne State University School of Medicine, Detroit, Michigan.
Abstract:
Metastatic prostate cancer which is refractory to hormone therapy remains an incurable disease for which there is no effective therapy. We have begun to investigate the nuclear matrix, the RNA-protein network of the nucleus that plays an important role in DNA replication and gene expression, as a target for cancer chemotherapy. It was postulated that estramustine phosphate (EMP), an estradiol-nitrogen mustard conjugate that binds to the nuclear matrix, might enhance the cytotoxicity of etoposide (VP-16), a topoisomerase II inhibitor that acts at the level of the nuclear matrix. In a nascent DNA synthesis assay, EMP and etoposide interact to selectively inhibit new DNA synthesis on the nuclear matrix. In vitro, EMP and etoposide appeared to act synergistically to inhibit the growth of the metastatic Dunning rat prostate adenocarcinoma cell line Mat-LyLu as well as the metastatic human prostate adenocarcinoma cell line PC-3. In vivo, EMP and etoposide inhibited prostate adenocarcinoma growth in the Dunning Copenhagen rat model. These data 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-refractory prostate cancer.
Insights
Estramustine phosphate (EMP) and etoposide (VP-16) show promise in treating hormone-refractory metastatic prostate cancer. This combination therapy targets the nuclear matrix, inhibiting cancer cell growth in preclinical models and advancing to clinical trials.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Metastatic prostate cancer refractory to hormone therapy lacks effective treatments.
- The nuclear matrix, crucial for DNA replication and gene expression, is explored as a chemotherapy target.
- Estramustine phosphate (EMP) binds to the nuclear matrix.
Purpose of the Study:
- To investigate the potential synergistic effect of estramustine phosphate (EMP) and etoposide (VP-16) in treating hormone-refractory prostate cancer.
- To determine if EMP enhances the cytotoxicity of etoposide (VP-16) by targeting the nuclear matrix.
Main Methods:
- In vitro studies using nascent DNA synthesis assays.
- In vitro evaluation of cell growth inhibition in rat (Mat-LyLu) and human (PC-3) prostate cancer cell lines.
- In vivo studies using the Dunning Copenhagen rat model of prostate adenocarcinoma.
Main Results:
- EMP and etoposide were found to selectively inhibit new DNA synthesis on the nuclear matrix.
- The combination of EMP and etoposide demonstrated synergistic inhibition of prostate cancer cell growth in vitro.
- Combined EMP and etoposide treatment inhibited prostate adenocarcinoma growth in vivo.
Conclusions:
- Estramustine phosphate (EMP) and etoposide (VP-16) exhibit synergistic activity against hormone-refractory prostate cancer.
- The nuclear matrix is a viable target for novel prostate cancer chemotherapies.
- These findings support the ongoing Phase I/II clinical trial of EMP and etoposide in patients with advanced prostate cancer.