EFFECTS OF ECTOPIC OVEREXPRESSION OF P21WAF1 CIP1 ON ANEUPLOIDY AND THE MALIGNANT PHENOTYPE OF HUMAN BRAIN-TUMOR CELLS/

p21(WAF1/CIP1) is downstream effector of the p53 tumor suppressor gene and a universal cyclin-dependent kinase (CDK) inhibitor. To determine the ability of p21(WAF1/CIP1) to function as a tumor suppressor, we c onstructed a replication-defective adenovirus vector containing p21(WA F1/CIP1) (Adp21(WAF1/CIP1)) to effect ectopic overexpression in a p53- defective human astrocytoma cell line, U-373MG. We observed a marked d ecrease in CDC2 and CDK2 kinase activity associated with a correspondi ng decrease in the amount of CDC2 but not CDK2 protein; a decreased gr owth potential of Adp21(WAF1/CIP1)-infected cells demonstrated by dimi nished [H-3]thymidine incorporation, increased cell doubling time and G(1)-arrested cell cycle; an association between Adp21(WAF1/CIP1)-infe cted cells and inhibition of aneuploid cell accumulation; and an alter ation of the malignant phenotype of cells was evidenced by the loss of anchorage-independent growth in soft agar and the failure to induce t umorigenesis in both peripheral and intracerebral xenograft models, in cluding the prevention of tumor formation AdP21(WAF1/CIP1) infection 2 days post tumor cell implantation. AdP21(WAF1/CIP1). AdP21(WAF1/CIP1) appears to be a strong candidate for gene therapy studies based on th ese studies indicating that Adp21(WAF1/CIP1) inhibits proliferation, t umorigenicity and aneuploidy in human brain tumor cells.