Yu D C, Chen Y, Dilley J, Li Y, Embry M, Zhang H, Nguyen N, Amin P, Oh J, Henderson D R
Calydon, Incorporated, Sunnyvale, California 94089, USA.
Cancer Res. 2001 Jan 15;61(2):517-25.
CV787, a PSA+ prostate cell-specific adenovirus variant, is currently in Phase I/II clinical trials for the treatment of prostate cancer. We have previously demonstrated that a single administration of CV787 at 1 x 10(11) particle/animal could eliminate established tumors within 6 weeks in nude mouse xenografts (Yu et al., Cancer Res., 59: 4200-4203, 1999). We now demonstrate that CV787-mediated 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 points by 3-[4,5-dimethylthiazole-2-4]-2,5-diphenyl-2H-tetrazolium bromide assay, and virus yield was examined by plaque assay. Addition of taxane to CV787 resulted in a synergistic increase of cytotoxicity toward the human prostate cancer cell line LNCaP, regardless of the timing of administration. There was no reduction in virus replication or specificity of CV787-based cytopathogenicity for prostate cancer cells (approximately 10,000 to 1) with the taxanes. p53 expression was significantly elevated in the cells treated 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 docetaxel in combination eliminates large preexistent distant tumors. Toxicity studies do not show a synergistic increase of toxicity of CV787 and taxane. These experiments demonstrate a synergistic antitumor efficacy for CV787 when combined with taxane and demonstrate an in vivo single-dose curative therapeutic index for CV787 of over 1000:1.
CV787是一种前列腺特异性抗原（PSA）阳性的腺病毒变体，目前正处于治疗前列腺癌的I/II期临床试验阶段。我们之前已经证明，以1×10¹¹颗粒/动物的剂量单次给予CV787，可在6周内消除裸鼠异种移植瘤中已形成的肿瘤（Yu等人，《癌症研究》，59: 4200 - 4203，1999）。我们现在证明，CV787介导的依赖复制的细胞毒性在体外和体内均与化疗药物紫杉醇（泰素）或多西他赛（泰索帝）具有协同作用。在体外，细胞在紫杉烷处理前24小时用CV787预处理，在CV787处理前24小时用紫杉烷预处理，或同时用两种药物处理。通过3 - [4,5 - 二甲基噻唑 - 2 - 4] - 2,5 - 二苯基 - 2H - 四氮唑溴盐试验在不同时间点测定细胞活力，并通过噬斑试验检测病毒产量。无论给药时间如何，在CV787中添加紫杉烷都会导致对人前列腺癌细胞系LNCaP的细胞毒性协同增加。紫杉烷对CV787的病毒复制或基于CV787的对前列腺癌细胞的细胞病变效应特异性（约为10,000比1）没有降低。在用CV787和紫杉烷处理的细胞中，p53表达显著升高。在体内，使用前列腺癌的PSA阳性LNCaP异种移植模型，静脉内单次给予1×10⁸颗粒的CV787和多西他赛联合使用可消除预先存在的大的远处肿瘤。毒性研究未显示CV787和紫杉烷的毒性协同增加。这些实验证明了CV787与紫杉烷联合使用时具有协同抗肿瘤功效，并证明了CV787在体内的单剂量治愈性治疗指数超过1000:1。
