NOVEL COMBINATION THERAPY FOR HUMAN COLON-CANCER WITH ADENOVIRUS-MEDIATED WILD-TYPE P53 GENE-TRANSFER AND DNA-DAMAGING CHEMOTHERAPEUTIC AGENT

Alteration of the wild-type (wt) p53 gene by mutation, deletion or re- arrangement is a major factor in the development of human colon cancer . Recent studies have demonstrated that p53 might be an essential comp onent of the apoptotic pathway triggered by DNA-damaging stimuli such as chemotherapeutic agents and ionizing radiation. We examined the ant i-tumor effects of adenovirus-mediated wt-p53 gene transfer in combina tion with a chemotherapeutic drug on the human colon cancer cell line WiDr, which is homozygous for a mutation in the p53 gene. Treatment wi th the chemotherapeutic drug cisplatin following infection with a repl ication-deficient, recombinant adenoviral vector expressing wt-p53 (te rmed AdCMVp53) significantly suppressed the growth of WiDr cells compa red to single treatments alone. To evaluate the in vivo efficacy of Ad CMVp53 and cisplatin given sequentially, WiDr cells were inoculated s. c. in nu/nu mice. After 3 days, AdCMVp53 was injected s.c. into the ar ea where tumor cells were implanted, followed by i.p. administration o f cisplatin. Analysis of initial growth inhibition at 21 days demonstr ated a profound therapeutic cooperativity, though administration of ei ther AdCMVp53 or cisplatin alone was followed only by a slowing of gro wth. Our results suggest that gene therapy using wt-p53-expressing ade novirus in combination with a chemotherapeutic DNA-damaging drug could be a useful strategy for treating human colon cancer. (C) 1997 Wiley- Liss, Inc.