Abstract
Prostate cancer is the most common urological malignancy involving multiple factors. Enzymes for detoxification and growth factors might also play a role in the formation of prostate cancer. The aim of part one study was to investigate whether polymorphisms of glutathione S-transferase M1 (GST M1), insulin-like growth factor-2 (IGF-2) and epidermal growth factor (EGFR) genes could be used as genetic markers for association with prostate cancer. We compared the frequency of the polymorphisms of GST M1, IGF-2, and EGFR genes between 96 patients with prostate cancer and 121 healthy male volunteers from the same area (age, > 60 years). There was significant distribution of the genotype of GST M1 gene between prostate cancer group and control group (p = 0.042). Percentage of null GST M1 gene was significantly higher in the cancer group (59.4 %) than control (45.5 %). However, the result revealed no significant association between the prostate cancer and IGF-2 or EGFR genotype distribution. In part two, we screened the anti-tumor effects of FK228 (depsipeptide) on human prostate cancer. In NOD-SCID mice implanted with these cells, 50 mg/kg FK228 given orally thrice a week led to inhibition of tumor growth and metastasis, tumor regression in >25 % of animals and increased survival. Median time to the experimental end point (tumor volume 2 cm3 or death) in the untreated was 52 days, and average tumor volume was 0.8 ± 0.18 cm3. At the same time, 94.4 % of FK228-treated mice survived and had average tumor volumes of 0.37 ± 0.1 cm3. Sizeable metastases positively stained for PSA and limited air gaps were found in lungs of untreated mice. In animals treated with FK228, lung morphology appeared normal. Primary tumors of treated animals were highly positive for PSA and had an elevated level of p21 and the proapoptotic protein, Bax. Sections taken from FK228-treated animals, examined under an electron microscope, exhibited condensed chromatin and apoptotic bodies. PSA serum levels were higher in untreated compared to treated animals and correlated with tumor volume. Since prolonged oral administration with 50 mg/kg or a single oral dose of 1.2 g/kg FK228 did not cause adverse effects and the former exhibited significant anticancer activity. In summarizes, this study suggests that the GST M1 gene may be associated with susceptibility of prostate cancer in the Taiwan population and FK228 is likely to display a high therapeutic index and may be beneficial for prostate cancer patients.