PROTECTION OF MICE AGAINST LETHAL DOSAGES OF NEBULARINE BY NITROBENZYLTHIOINOSINE, AN INHIBITOR OF NUCLEOSIDE TRANSPORT

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  • 1 January 1979
    • journal article
    • research article
    • Vol. 39  (9) , 3607-3611
Abstract
In the presence of nitrobenzylthioinosine (NBMPR) a potent inhibitor of nucleoside transport, Roswell Park Memorial Institute [RMPI] 6410 cells [human lymphoblastoid] proliferating in culture were protected from otherwise inhibitory concentrations of 9-.beta.-D-ribofuranosylpurine (nebularine); cellular uptake of nebularine was greatly reduced under these circumstances. Initial rates of nebularine uptake by RMPI 6410 cells were inhibited by NBMPR, indicating that the latter interfered with nebularine transport. NBMPR protected mice against potentially lethal treatment regimens with nebularine, 4-amino-7-(.beta.-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine (tubercidin) or 4-amino-5-cyano-7-(.beta.-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine (toyocamycin); protection resulted when NBMPR was administered i.p. in advance of or simultaneously with nebularine, but not when NBMPR followed nebularine by 1 h. Both NBMPR and its 5''-monophosphate protected mice against nebularine lethality when administered s.c. [These findings have application to the use of a combination of NBMPR and Nebutarine in human cancer therapy.].