Overexpression of a rabbit liver carboxylesterase sensitizes human tumor cells to CPT-11.
CPT-11 [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin ] is a prodrug that is converted to the active metabolite SN-38 by carboxylesterases. In its active form, the drug inhibits topoisomerase I, causes DNA damage, and induces apoptosis. Data in this study show metabolism of CPT-11 to SN-38 (7-ethyl-10-hydroxycamptothecin) by a rabbit liver carboxylesterase in vitro and growth-inhibitory activity of the products of the reaction. Additionally, stable expression of the cDNA encoding this protein in Rh30 human rhabdomyosarcoma cells increased the sensitivity of the cells to CPT-11 8.1-fold. We propose that this prodrug/enzyme combination can be exploited therapeutically in a manner analogous to approaches currently under investigation with the combinations of ganciclovir/herpes simplex virus thymidine kinase and 5-fluorocytosine/cytosine deaminase.
Danks
M K
MK
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Morton
C L
CL
Pawlik
C A
CA
Potter
P M
PM
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism* / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D000077146:Irinotecan; D008099:Liver / Q000201:enzymology*; D011355:Prodrugs / Q000378:metabolism* / Q000627:therapeutic use; D011817:Rabbits; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D011355:Prodrugs; D000077146:Irinotecan; D002265:Carboxylic Ester Hydrolases; D002166:Camptothecin