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

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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.