Reduced expression of p53 and p21WAF1/CIP1 sensitizes human breast cancer cells to paclitaxel and its combination with 5-fluorouracil
Johnson, K.R.; Fan, W.
Anticancer Research 22(6a): 3197-3204
2002
ISSN/ISBN: 0250-7005 PMID: 12530065 Document Number: 545042
The favorable clinical activity of paclitaxel has prompted considerable interest in combining this agent with other clinically effective antineoplastic agents including the antimetabolite 5-fluorouracil (5-FU). Our previous studies indicated that simultaneous exposure or pretreatment with 5-FU could significantly interfere with the cytotoxic effects of paclitaxel on both mitotic arrest and apoptosis. Biochemical examination also revealed that 5-FU inhibited expression of p21WAF1/CIP1 that may contribute to paclitaxel cytotoxicity. In this study, human breast cancer BCap37 cells were transfected with either sense or antisense p53 or p21WAF1/CIP1. The established stable transfectants were then analyzed for an altered sensitivity to paclitaxel, 5-FU or the combinations of these drugs using a series of cytotoxic and apoptosis assays. Tumor cells transfected with antisense p53 or p21WAF1/CIP1 exhibited a significant increase in their sensitivity to paclitaxel. The reduced protein levels of p53 and p21WAF1/CIP1 were also found to abrogate the inhibitory effects of 5-FU on paclitaxel-induced mitotic arrest and apoptosis. These findings suggest that the status of p53 and p21WAF1/CIP1 might play an important role in tumor cell susceptibility to paclitaxel and its combination with other drugs such as 5-FU.