Reduced expression of p53 and p21WAF1/CIP1 sensitizes human breast cancer cells to paclitaxel and its combination with 5-fluorouracil.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Johnson
Korey R
KR
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425, USA.
Fan
Weimin
W
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics; D016373:DNA, Antisense / Q000008:administration & dosage / Q000235:genetics; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D017239:Paclitaxel / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000091402:Prohibitins; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016373:DNA, Antisense; C000717331:PHB2 protein, human; D000091402:Prohibitins; D016159:Tumor Suppressor Protein p53; D017239:Paclitaxel; D005472:Fluorouracil