Combinatorial chemoprevention of prostate cancer

Improved understanding of the molecular biology of prostate cancer has lead to the identification and development of a number of agents which may be well suited to the task of chemoprevention. In the work described here, two novel agents, resveratrol and gefitinib, have been evaluated for their anticancer effects using in vitro and in vivo models of prostate cancer. Specifically, the hypothesis that these two agents can act synergistically to achieve a greater antineoplastic effect has been tested. Resveratrol is a diet-derived naturally-occurring polyphenol which displays anti-oxidant and anti-inflammatory properties. Gefitinib (ZD1839. "Iressa", AstraZeneca Pharmaceuticals) is a small molecule inhibitor of the epidermal growth factor (EGFR) tyrosine kinase. EGFR is increasingly implicated in prostatic carcinogenesis. The results presented here demonstrate that both resveratrol and gefitinib inhibit the proliferation of hormone-sensitive and hormone-resistant cells in vitro, although there was no synergy between these two compounds. Both compounds modulate cell cycle kinetics causing arrest in various phases of the cycle. Gefitinib was shown to effectively abrogate EGFR phosphorylation in prostate cancer cell lines. No effect of resveratrol on oxidative DNA damage in prostate cancer cells was observed and its effects on COX-2 expression could not be evaluated. Gefitinib potently inhibited the development of DU145 xenografts in a nude mouse model of prostate cancer. No significant effect of resveratrol could be seen in the same mouse model. These results suggest that gefitinib may well have a role to play in the chemotherapy and chemoprevention of prostate cancer. Despite its potent in vitro antiproliferative effects, further in vivo evaluation of resveratrol is required prior to its use alone or in combination with other agents can be recommended in prostate cancer.