Mechanism of resistance to cyclopentenyl cytosine (CPE-C) in Molt-4 lymphoblasts

Biochemical Pharmacology
S M BlaneyD G Poplack

Abstract

Cyclopentenyl cytosine (CPE-C), a carbocyclic analogue of cytidine, has preclinical antineoplastic activity against ara-C resistant murine leukemias and a broad spectrum of human tumor xenografts. CPE-C is a prodrug and requires intracellular phosphorylation to cyclopentenyl cytosine triphosphate (CPE-CTP) which depletes endogenous CTP pools. The initial step in this activation process is catalyzed by uridine/cytidine kinase. We studied the mechanism of resistance to CPE-C in a Molt-4 T-cell leukemia line made resistant to CPE-C (Molt-4R) by culturing it in the continuous presence of increasing concentrations of CPE-C. Using a tetrazolium based colorimetric assay to assess cytotoxicity, the IC90 for the parent Molt-4 cells (Molt-4WT) was 0.5 microM after a 24 hr drug exposure. In contrast, cytotoxicity was not observed at concentrations as high as 1 mM in the Molt-4R cells. Following a brief exposure to 1 microM CPE-C, parent drug could be detected intracellularly in the resistant and sensitive cell lines. However, CPE-CTP formation was reduced markedly in the resistant cell line. Measurement of the activity of anabolic and catabolic enzymes in the Molt-4WT and Molt-4R cells revealed equivalent activities of alkaline and acid p...Continue Reading

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Citations

Mar 4, 1999·Biological Chemistry·A C VerschuurA B Van Kuilenburg
Oct 18, 1996·The Journal of Biological Chemistry·G M Hatch, G McClarty
Sep 20, 2016·Chembiochem : a European Journal of Chemical Biology·Gregory D McCluskeyStephen L Bearne
Sep 30, 2021·Proceedings of the National Academy of Sciences of the United States of America·Eric M LynchJustin M Kollman
Dec 17, 2009·Bioorganic & Medicinal Chemistry Letters·Alexander C RoyStephen L Bearne

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