LOSS OF NORMAL P53 FUNCTION CONFERS SENSITIZATION TO TAXOL BY INCREASING G2 M ARREST AND APOPTOSIS/

The anticancer agent paclitaxel (Taxol(R)) stabilizes tubulin polymeri zation resulting in arrest in mitosis and apoptotic cell death. Normal human fibroblasts depleted of functional p53 by SV40 T antigen or HPV -16 E6, and primary embryo fibroblasts from p53 null mice showed seven - to ninefold increased cytotoxicity by paclitaxel. Reduced levels of p53 correlated with increased G2/M phase arrest, micronucleation, and p53-independent paclitaxel-induced apoptosis. Surviving cells with int act p53 progressed through mitosis and transiently accumulated in the subsequent G1 phase, coincident with increased p53 and p21(cip1,waf1) protein levels. These results are in contrast to studies linking p53 l oss with resistance to DNA damaging anticancer agents.