In vitro evaluation of ap53-expressing adenovirus as an anti-cancer drug

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Abstract
Deficiency in p53‐mediated cell death is common in human cancer, contributing to both tumorigenesis and chemoresistance. In an attempt to restore p53, we evaluated in vitro infectivity and cytotoxicity of a wild type (w.t.) p53‐expressing adenovirus (Ad‐p53) toward a panel of human cancer cell lines (n = 19). At a multiplicity of infection of 30, both Ad‐p53 and adenovirus expressing β‐galactosidase (Ad‐LacZ) infected greater than 99% of cells derived from brain, lung, breast, ovarian, colon, and prostate cancer, but failed to infect leukemia or lymphoma cells. Ad‐p53, but not Ad‐LacZ, infection of cancer cells was followed by nuclear accumulation of the CDK inhibitor p21WAF1/CIP1, cell cycle arrest and loss of viability. Ad‐p53 induced apoptotic death in cancer cells that express mutant p53, including multi‐drug resistant cells, but fewer deaths were observed in some w.t. p53 expressing cells. Ad‐p53‐infected SKBr3 breast cancer cells were more sensitive to cytotoxicity of the DNA damaging drugs mitomycin C or Adriamycin, but not the M‐phase specific drug vincristine. Our results suggest that Ad‐p53 is capable of infecting and killing cancer cells of diverse tissue origins (including multi‐drug resistant cancer cells), that p21WAF1/CIP1 may be a useful marker of p53 infectivity and that there may be synergy between Ad‐p53 and either mitomycin C or Adriamycin induced cell death in tumors with p53 mutations. © 1996 Wiley‐Liss, Inc.