SUPPRESSION OF CANCER CELL-GROWTH BY ADENOVIRUS EXPRESSING P21(WAF1 CIP1) DEFICIENT IN PCNA INTERACTION/

p53 tumor suppression is deficient in the majority of human cancers, E fforts to understand this pathway have identified cyclin-dependent kin ase (CDK) inhibitors and suggested a potential for their replacement i n human cancer, In the present studies, expression of a C-terminal del etion mutant of the human p21(WAF1/CIP1) CDK inhibitor completely supp ressed the growth of colon cancer cells, whereas full-length p21 only partially suppressed growth, We prepared a replication-deficient adeno viral recombinant which expresses the p21 C-terminal mutant (Ad-WAF1-3 41) and compared its tumor suppressive abilities with Ad-p53 and Ad-La cZ. Ad-WAF1-341- and Ad-p53-infected cancer cells, but not Ad-LacZ-inf ected cancer cells, expressed a nuclear protein recognized by anti-p21 antibody and were deficient in cell cycle progression, The exogenous p21 mutant interacted with CDK2 but not proliferating cell nuclear ant igen following infection of p21-/- cancer cells, Ad-WAF1-341 was more potent than Ad-p53 in inhibiting DNA synthesis in human papillomavirus 16 E6-expressing cancer cells, Most importantly, the Ad-WAF1-341-infe cted E6-expressing cells died, whereas most of the Ad-p53-infected cel ls continued to proliferate, Endonucleolytic cleavage of DNA was obser ved in Ad-WAF1-341-infected cancer cells, These observations suggest t hat Ad-WAF1-341 should be evaluated in the treatment of human papillom avirus-associated neoplasia and other neoplasias resistant to p53.