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Enhancement of retention and cytotoxicity of 2-chlorodeoxyadenosine in cultured human leukemic lymphoblasts by nitrobenzylthioinosine, an inhibitor of equilibrative nucleoside transport

Leukemia volume 14, pages 52–60 (2000)Cite this article

Abstract

In leukemic cells exposed to 2-chlorodeoxyadenosine (2-CdA), levels of the nucleoside drug and its phosphate metabolites decay with time in the absence of external 2-CdA; an intrinsic part of this process is the efflux of 2-CdA. The effects of nitrobenzylthioinosine (NBMPR) and of dipyridamole (DPM), both potent inhibitors of es (e, equilibrative; s, sensitive to NBMPR) nucleoside transport processes, were studied in four lines of cultured leukemic lymphoblasts. Suspensions of 2-CdA-loaded cells were diluted 10-fold with 2-CdA-free medium to initiate the cellular 2-CdA decay processes, which followed a biexponential time course. When diluting media contained NBMPR or DPM, intracellular levels of 2-CdA and its metabolites were substantially increased (P < 0.001) compared with cells in media lacking the transport inhibitors, and 2-cda loss followed a monoexponential time course. As a consequence, the aucs (area under time-course plots of intracellular 2-cda and its metabolites) were significantly (P < 0.001) lower in untreated control cells compared to inhibitor-treated cells. These results suggest that nucleoside transport processes contribute to the efflux of 2-cda from the cultured lymphoblasts. The cytotoxicity of 1-h exposure to 2-cda of reh-a2 and ccrf-cem cells was enhanced three-fold by subsequent exposure to 0.5 μM NBMPR relative to that of control cells subjected to the same manipulations without NBMPR exposure. However, before such a strategy may be considered to have a therapeutic application, careful examination of effects in normal lymphocytes and ex vivo leukemic lymphoblasts must first be undertaken.

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Acknowledgements

This work was supported by the Alberta Cancer Board and the Alberta Heritage Foundation for Medical Research. AMPW was the recipient of an AHFMR Studentship award, which she held during the course of this work.

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  1. Department of Pharmacology, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada

    AMP Wright, WP Gati & ARP Paterson

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Wright, A., Gati, W. & Paterson, A. Enhancement of retention and cytotoxicity of 2-chlorodeoxyadenosine in cultured human leukemic lymphoblasts by nitrobenzylthioinosine, an inhibitor of equilibrative nucleoside transport. Leukemia 14, 52–60 (2000). https://doi.org/10.1038/sj.leu.2401633

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