RT Journal Article
SR Electronic
T1 p53-Mediated Regulation of Expression of a Rabbit Liver Carboxylesterase Confers Sensitivity to 7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11)
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 699
OP 705
DO 10.1124/jpet.102.044149
VO 304
IS 2
A1 Monika Wierdl
A1 Christopher L. Morton
A1 Linda C. Harris
A1 Mary K. Danks
A1 John D. Schuetz
A1 Philip M. Potter
YR 2003
UL http://jpet.aspetjournals.org/content/304/2/699.abstract
AB We have exploited the ability of wild-type (wt) p53 to repress gene expression and produce tumor-selective cytotoxicity using viral-directed enzyme prodrug therapy. Vectors containing either the cytomegalovirus or Rous sarcoma virus promoter regulating transcription of a rabbit liver carboxylesterase (CE) have been constructed. Upon transfection of these plasmids into cells expressing either wt or mutant p53, differential expression of the CE has been observed, resulting in sensitization of the cells expressing the latter protein to the anticancer prodrug irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carb- onyloxycamptothecin (CPT-11). Transduction of isogenic cell lines with adenovirus containing CE under control of the Rous sarcoma virus promoter confirmed the decreased sensitization of cells expressing wtp53 to CPT-11. These studies indicate that the inactivation of wtp53 by mutant p53 in human tumor cells may be sufficient enough to generate a therapeutic window for enhanced cytotoxicity with CPT-11. The American Society for Pharmacology and Experimental Therapeutics