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Research Articles: Therapeutics, Targets, and Development

The effect of a novel transition state inhibitor of methylthioadenosine phosphorylase on pemetrexed activity

Departments of ¹ Medicine and Molecular Pharmacology, and ² Biochemistry, Albert Einstein College of Medicine, Bronx, New York

Requests for reprints: I. David Goldman, Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. Phone: 718-430-2302; Fax: 718-430-8550. E-mail: igoldman{at}aecom.yu.edu

Abstract

Pemetrexed is a new-generation antifolate inhibitor of thymidylate synthase (TS) and a weaker inhibitor of glycinamide ribonucleotide transformylase (GARFT) required for de novo purine synthesis. Methylthioadenosine phosphorylase (MTAP) salvages purines by releasing adenine from methylthioadenosine and is often deleted in mesothelioma. The current study addresses the effect of MTAP on pemetrexed activity using a highly potent transition state inhibitor of MTAP, MT-DADMe-Immucillin A (ImmA; K_i = 86 pmol/L) in the MTAP(+) NCI-H28 and MTAP(–) NCI-H2052 mesothelioma cell lines. Based on selective nucleoside protection, TS was found to be the primary pemetrexed target in both cell lines with GARFT inhibition requiring 20- to 30-fold higher pemetrexed concentrations. ImmA had no effect on pemetrexed activity but, when thymidine was added, the pemetrexed IC₅₀ decreased by a factor of 3 in MTAP(+) H28 cells with no effect in MTAP(–) H2052 cells. Conversely, the transfection of MTAP into H2052 cells increased the pemetrexed IC₅₀ by nearly 3-fold but only in the presence of thymidine; this was reversed by ImmA. An MTAP-specific short interfering RNA produced a 2-fold decrease in pemetrexed IC₅₀ in MTAP(+) HeLa cells in the presence of thymidine. These data indicate that suppression of constitutive MTAP has no effect on pemetrexed activity when the primary target is TS. There is a modest salutary effect when the pemetrexed target is GARFT alone. [Mol Cancer Ther 2006;5(10):2549–55]

Grant support: NIH, CA-82621, and the Mesothelioma Applied Research Foundation Alvin Rehbeck Memorial Grant.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 5/25/06; revised 7/20/06; accepted 8/16/06.