Bevacizumab plus 5-fluorouracil induce growth suppression in the CWR-22 and CWR-22R prostate cancer xenografts

Abstract

Prostate cancer is the most common malignancy in men. Although patients with metastatic prostate cancer can benefit from androgen ablation, most of them will die of prostate cancer progression to an androgen-refractory state. In the present study, the effects of docetaxel, bevacizumab, 5-fluorouracil (5-FU), bevacizumab plus docetaxel, and bevacizumab plus 5-FU on the growth of human CWR-22 (androgen-dependent) and CWR-22R (androgen-independent) prostate carcinoma xenografts were investigated. We report that i.p. administration of 10 mg/kg docetaxel at 1-week interval, 5 mg/kg/ bevacizumab once every 2 weeks, or 12.5 mg/kg 5-FU, bevacizumab/docetaxel, or bevacizumab/5-FU weekly to severe combined immunodeficient mice bearing prostate cancer xenografts (12 mice per treatment group) for 21 days resulted in 22.5 +/- 8%, 23 +/- 7%, 31 +/- 8%, 22 +/- 6%, and 81 +/- 5% growth inhibition, respectively. Greatest growth suppression was observed in bevacizumab/5-FU treatment. Bevacizumab/5-FU-induced growth suppression was associated with reduction in microvessel density, inhibition of cell proliferation; up-regulation of phosphatase and tensin homologue, p21(Cip1/Waf1), p16(INK4a), and p27(Kip1); hypophosphorylation of retinoblastoma protein; and inhibition of Akt/mammalian target of rapamycin pathway. Our data indicate that bevacizumab/5-FU effectively inhibits angiogenesis and cell cycle progression and suggest that bevacizumab/5-FU may represent an alternative treatment for patients with prostate cancer.