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[Cancer Research 58, 20-22, January 1, 1998]
© 1998 American Association for Cancer Research
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Overexpression of a Rabbit Liver Carboxylesterase Sensitizes Human Tumor Cells to CPT-111

Mary K. Danks, Christopher L. Morton, Cynthia A. Pawlik and Philip M. Potter2

Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

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.

1 This work was supported in part by NIH Grants CA-66124 and CA-63512, the Cancer Center Core Grant P30-CA-21765, and the American Lebanese Syrian Associated Charities.

2 To whom requests for reprints should be addressed, at Department of Molecular Pharmacology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105. Phone: (901) 495-3440; Fax: (901) 521-1668; E-mail: phil.potter@stjude.org.

Received 10/24/97. Accepted 11/11/97.




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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
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Annual Meeting Education Book Meeting Abstracts Online
Copyright © 1998 by the American Association for Cancer Research.