Marie-Christine Bissery

Combined Effects of Docetaxel and Angiostatin Gene Therapy in Prostate Tumor Model

The anti-tumor effects of adenovirus-delivered angiostatin (AdK3) in association with docetaxel (Taxotere) have been evaluated in a human-origin prostate tumor model. In vitro, human endothelial cells were 50- to 100-fold more sensitive to docetaxel than prostate cell lines (PC3, LNCaP, and DU145), and the combination regimen of docetaxel and AdK3 was significantly more cytotoxic for endothelial cells than either treatment alone. PC3 cells, which display the highest sensitivity to docetaxel, were then grafted onto athymic mice for an evaluation of the combined regimen as a therapy. The combination of a single intratumoral injection of AdK3 (2 x 10(9) pfu) and a single intravenous injection of docetaxel (15 mg/kg) was compared with the injection of AdK3 alone on preestablished mice bearing PC3-derived tumors with a mean tumor volume of 60 +/- 11 or 205 +/- 46 mm3. Significant antitumoral effects were observed only in mice receiving the combined treatment. We showed that all PC3 tumors regressed in the AdK3-docetaxel combination group and that 40 to 83% totally regressed. In all cases, this regimen was tightly correlated with a marked decrease in intratumoral vascularization. Our experimental data show that attacking both endothelial and tumoral compartments is an efficient and logical strategy, making this bitherapy approach clinically promising.