p53-mediated regulation of expression of a rabbit liver carboxylesterase confers sensitivity to 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11).
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.
Wierdl
Monika
M
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105,USA.
Morton
Christopher L
CL
Harris
Linda C
LC
Danks
Mary K
MK
Schuetz
John D
JD
Potter
Philip M
PM
D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000633:toxicity; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D000077146:Irinotecan; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D011817:Rabbits; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D004791:Enzyme Inhibitors; D016159:Tumor Suppressor Protein p53; D000077146:Irinotecan; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase; D002166:Camptothecin