Effect of PEDF on survival and in vivo antitumor activities of low-dose chemotherapy in castration-refractory prostate cancer.

Abstract

e15103 Background: The development of metronomic/low-dose treatment with conventional chemotherapeutic drugs has recently shown promise in the treatment of castration-refractory prostate cancer (CPRC). Pigment Epithelium-Derived Factor (PEDF) is a natural angio-inhibitor which is downregulated in prostate cancer. Previously we demonstrated that overexpression of PEDF in human CRPC PC3 cells decreased tumor growth in vivo. In the present study, we further validate PEDF anti-tumor properties in highly metastatic CRPC LNCaP-derivative CL1 cells. We also hypothesized that PEDF may enhance the cytotoxic effects of low-dose docetaxel (Doc) and cyclophosphamide (CTX) chemotherapies in vivo. Methods: Human PC3 and CL1 cell lines were genetically modified to stably express fluorescent DsRed Express protein with PEDF. Resulting cells were characterized in vitro for PEDF expression by western blot and for proliferation by growth curves and clone formation in Matrigel. PEDF anti-tumor effects were assessed on established SC xenografts in mice treated with Doc (5mg/kg IP every 4 days, 1mg/kg IP daily for 10 days, 0.5mg/kg IP every other day), CTX (10-20mg/kg in drinking water) or placebo. Survival studies were performed by injecting CL1 cells that express PEDF or control into the left lobe of the dorsal prostate of anesthetized mice. Results: We showed that PEDF inhibits proliferation and induces differentiation of all CPRC cells tested in vitro. Similarly, PEDF expression decreases by 85% and 70% the development of SC PC3 and CL1 tumors, respectively. In the survival study, we found that PEDF expression prolongs significantly (p=0.01; 95% confidence interval) median survival of CL1 tumor-bearing mice (53±0.001 days versus 57±1). Most importantly, we demonstrated that PEDF enhances the cytotoxic effects of low-dose chemotherapy on established tumors (best Doc dose: 1mg/kg for PC3 and 5mg/kg for CL1; best CTX dose: 10mg/kg for PC3 and CL1). Conclusions: This data reinforces the significance of PEDF as a potential new target when treating advanced prostate cancer. It also emphasizes PEDF as a promising new agent to enhance the anti-tumor efficacy of low-dose Doc and CTX chemotherapies.