Gene Therapy for Colon Cancer with Adenoviral Vector Expressing Tumor Suppressor p53 Gene

野生型p53基因的突变、缺失或重排是导致人类结肠癌发生的主要因素。最近的研究表明，p53可能是由DNA损伤刺激如化疗药物和电离辐射触发的细胞毒性途径的重要组成部分。我们研究了腺病毒介导的野生型p53基因转移结合化疗药物对人结肠癌细胞系WiDr的抗肿瘤作用，WiDr具有纯合突变的p53基因。与任何单一治疗相比，用化疗药物顺铂治疗，在感染复制缺陷型重组腺病毒载体表达wt-p53（称为AdCMV p53）后显著抑制WiDr细胞的生长。为了评价AdCMV p53和顺铂以顺序组合给予的体内功效，将WiDr细胞皮下接种到nu/nu小鼠中，3天后将AdCMV p53皮下注射到肿瘤细胞植入的区域中，随后腹膜内施用顺铂。在第21天对初始生长抑制的分析表明了深刻的治疗协同性，尽管单独的AdCMV p53或单独的顺铂显示出肿瘤生长的适度减缓。这些结果表明，使用wt-p53表达的腺病毒与化疗DNA损伤药物的组合的基因治疗是一个有用的策略，用于人结肠癌的治疗。

The alteration of wild-type p53 gene by mutations, deletions, or rearrangements is a major factor in the development of human colon cancer. Recent studies have demonstrated that p53 might be an essential component of the cytotoxic pathway triggered by DNA-damaging stimuli such as chemotherapeutic agents and ionizing radiation. We examined the antitumor effect of adenovirus-mediated wild-type p53 gene transfer in combination with a chemotherapeutic drug on human colon cancer cell line WiDr, which has a homozygous mutated p53 gene. The treatment with a chemotherapeutic drug, cisplatin, following the infection of a replication-deficient, recombinant adenoviral vector expressing wt-p53 (termed AdCMV p53) significantly suppressed the growth of WiDr cells compared to any single treatments. To evaluate the in vivo efficacy of AdCMV p53 and cisplatin given in a sequential combination, WiDr cells were subcutaneously inoculated in nu/nu mice, and after 3 days AdCMV p53 was subcutaneously injected into the area where tumor cells were implanted followed by intraperitoneal administration of cisplatin. Analysis of initial growth inhibition at 21 days demonstrated a profound, therapeutic cooperativity, although AdCMV p53 alone or cisplatin alone showed a modest slowing of the tumor growth. These results suggest that the gene therapy using wt-p53-expressing a denovirus in combination with a chemotherapeutic DNA-damaging drug is a useful strategy for human colon cancer therapy.