OVEREXPRESSION OF A RABBIT LIVER CARBOXYLESTERASE SENSITIZES HUMAN TUMOR-CELLS TO CPT-11

CPT-11 0-[4-(1-piperidino)-1-piperidino]carbonyloxycampto thecin] is a prodrug that is converted to the active metabolite SN-38 by carboxyle sterases. In its active form, the drug inhibits topoisomerase I, cause s DNA damage, and induces apoptosis, Data in this study show metabolis m of CPT-11 to SN-38 (7-ethyl-10-hydroxycamptothecin) by a rabbit live r carboxylesterase in vitro and growth-inhibitory activity of the prod ucts of the reaction, Additionally, stable expression of the cDNA enco ding this protein in Rh30 human rhabdomyosarcoma cells increased the s ensitivity of the cells to CPT-11 8.1-fold. We propose that this prodr ug/enzyme combination can be exploited therapeutically in a manner ana logous to approaches currently under investigation with the combinatio ns of ganciclovir/herpes simplex virus thymidine kinase and 5-fluorocy tosine/cytosine deaminase.