Antitumor synergy of CV787, a prostate cancer-specific adenovirus, and paclitaxel and docetaxel

CV787, a PSA(+) prostate cell-specific adenovirus variant, is currently in Phase I/II clinical trials for the treatment of prostate cancer, We have pr eviously demonstrated that a single administration of CV787 at 1 x 10(11) p article/animal could eliminate established tumors within 6 weeks in nude mo use xenografts (Yu et al,, Cancer Res,, 59: 4200-4203, 1999), We now demons trate that CV787-mediatcd replication-dependent cytotoxicity is synergistic with the chemotherapeutic agents paclitaxel (Taxol) or docetaxel (Taxotere ) both in vitro and in vivo, In vitro, cells were pretreated with CV787 24 h before taxane, pretreated with taxane 24 h before CV787, or treated with both agents simultaneously. Cell viability was determined at various time p oints by 3-[4,5-dimethylthiazole-2-4]-2,5-diphenyl-2H-tetrazolium bromide a ssay, and virus yield was examined by plaque assay, Addition of taxane to C V787 resulted in a synergistic increase of cytotoxicity toward the human pr ostate cancer cell line LNCaP, regardless of the timing of administration, There was no reduction in virus replication or specificity of CV787-based c ytopathogenicity for prostate cancer cells (approximately 10,000 to 1) with the taxanes, p53 expression was significantly elevated in the cells treate d with CV787 and taxane, In vivo, using the PSA(+) LNCaP xenograft model of prostate cancer, a single i.v. dose of 1 x 10(8) particles CV787 and docet axel in combination eliminates large preexistent distant tumors, Toxicity s tudies do not show a synergistic increase of toxicity of CV787 and taxane, These experiments demonstrate a synergistic antitumor efficacy for CV787 wh en combined with taxane and demonstrate an in vivo single-dose curative the rapeutic index for CV787 of over 1000:1.