Transport and metabolism of 9-beta-D-arabinofuranosylguanine in a human T-lymphoblastoid cell line: nitrobenzylthioinosine-sensitive and -insensitive influx.
Nitrobenzylthioinosine (NBMPR), dipyridamole, and dilazep, potent inhibitors of nucleoside transport, were found to be ineffective in preventing 9-beta-D-arabinofuranosylguanine (ara-G)-induced inhibition of MOLT 4 and CCRF CEM cell growth, ara-G (2.0 microM) was metabolized to 9-beta-D-arabinofuranosylguanine 5'-triphosphate in MOLT 4 cells, and the levels of this metabolite were not affected by the presence of 5.0 microM NBMPR in the incubation medium. Permeation of the MOLT 4 cell membrane by ara-G occurred primarily by means of the NBMPR-sensitive nucleoside transport system. However, a residual transport component accounting for 10-20% of the total transport activity was demonstrated in the presence of NBMPR. This component was inhibited by adenine and hypoxanthine but not by dilazep, dipyridamole, or other nucleosides. In contrast, inhibitors of nucleoside transport readily reversed the cytotoxic effect of 7-deazaadenosine (tubercidin) in both MOLT 4 and CCRF CEM cells. The levels of tubercidin 5'-triphosphate formed from 2.0 microM tubercidin in MOLT 4 cells were reduced by 80% in the presence of 5.0 microM NBMPR. The influx of tubercidin into MOLT 4 cells was found to occur primarily by means of the NBMPR-sensitive nucleoside transport system. This same system mediated the transport of ara-G into human erythrocytes.
Prus
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Wellcome Research Laboratories, Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709.
Averett
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Zimmerman
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D001087:Arabinonucleosides / Q000097:blood / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004109:Dilazep / Q000494:pharmacology; D004176:Dipyridamole / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007288:Inosine / Q000031:analogs & derivatives*; D007700:Kinetics; D015459:Leukemia-Lymphoma, Adult T-Cell; D011687:Purines / Q000494:pharmacology; D012263:Ribonucleosides / Q000494:pharmacology; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014372:Tubercidin / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D001087:Arabinonucleosides; D011687:Purines; D012263:Ribonucleosides; C028771:9-arabinofuranosylguanine; D013868:Thioinosine; D007288:Inosine; D004176:Dipyridamole; D004109:Dilazep; C001789:4-nitrobenzylthioinosine; D014372:Tubercidin