In vitro evaluation of a p53-expressing adenovirus as an anti-cancer drug.
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 beta-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 p21WAFI/CIPI, 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 p21WAFI/CIPI 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.
Blagosklonny
M V
MV
Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania Comprehensive Cancer Center, Philadelphia, USA.
el-Deiry
W S
WS
D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism*; D000258:Adenovirus Infections, Human / Q000235:genetics / Q000378:metabolism / Q000821:virology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000628:therapy / Q000821:virology; D003110:Colonic Neoplasms / Q000235:genetics / Q000628:therapy / Q000821:virology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000032:analysis; D018432:Drug Resistance, Multiple; D005069:Evaluation Studies as Topic; D016158:Genes, p53; D005909:Glioblastoma / Q000235:genetics / Q000628:therapy / Q000821:virology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000628:therapy / Q000821:virology; D009369:Neoplasms / Q000235:genetics / Q000628:therapy* / Q000821:virology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53