Weisbart Richard H, Hansen James E, Chan Grace, Wakelin Rika, Chang Sophia S, Heinze Emil, Miller Carl W, Koeffler Phillip H, Yang Fusheng, Cole Greg M, Min Yoon S, Nishimura Robert N
Division of Rheumatology, Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System, Sepulveda, CA 91343, USA.
Int J Oncol. 2004 Dec;25(6):1867-73.
Some human cancers are caused by functional defects in p53 that are restored by gene therapy with wild-type p53. To circumvent the use of viral vectors, we reconstituted cancer cell lines with p53 by protein transduction. A fusion protein was produced from cDNA constructed from the Fv fragment of an antibody that penetrates living cells and wild-type p53 (Fv-p53). Fv-p53 penetrated and killed cancer cells that do not express p53. Additionally, Fv-p53 killed cancer cells that were malignant as a result of mutations within p53, nuclear exclusion of p53 and over-expression of MDM2. Non-specific toxicity was excluded by showing that Fv-p53 penetrated but did not kill primary cells and cancer cells unresponsive to p53. Fv fragments alone were not cytotoxic, indicating that killing was due to transduction of p53. Fv-p53 was shown to penetrate cancer cells engrafted in vivo. These results support continued efforts to evaluate the potential efficacy of Fv-p53 for the treatment of certain cancers in vivo.
一些人类癌症是由p53的功能缺陷引起的，而野生型p53基因治疗可恢复这些缺陷。为了避免使用病毒载体，我们通过蛋白质转导用p53重建癌细胞系。一种融合蛋白由从穿透活细胞的抗体Fv片段和野生型p53构建的cDNA产生（Fv-p53）。Fv-p53穿透并杀死不表达p53的癌细胞。此外，Fv-p53还能杀死因p53内突变、p53核排除和MDM2过表达而恶变的癌细胞。通过表明Fv-p53穿透但不杀死原代细胞和对p53无反应的癌细胞，排除了非特异性毒性。单独的Fv片段没有细胞毒性，表明杀伤是由于p53的转导。Fv-p53被证明能穿透体内移植的癌细胞。这些结果支持继续努力评估Fv-p53在体内治疗某些癌症的潜在疗效。
