Metabolism and selective cytotoxicity of 9-beta-D-arabinofuranosylguanine in human lymphoblasts.
The selective toxicity of purine deoxyribonucleosides for T-lymphoblasts appears to be mediated by the selective accumulation of the corresponding deoxyribonucleoside triphosphates in these cells. This finding has led to a search for deoxyribonucleoside analogues which may have clinical utility in T-cell lymphoproliferative disorders. 9-beta-D-arabinofuranosylguanine (ara-G) is a 2'-deoxyguanosine analogue which is 70-fold more inhibitory to the growth of T- than of B-lymphoblasts. It is less potent than ara-C but far more selective in its cytotoxic effect on T-cells. ara-G is not significantly degraded by purine nucleoside phosphorylase (EC 2.4.2.1) activity in T-lymphoblasts and is metabolized to 9-beta-D-arabinofuranosylguanine 5'-triphosphate. The accumulation of this metabolite directly correlates with inhibition of DNA but not of RNA or protein synthesis. MOLT-4 T-lymphoblasts were selected for ara-G resistance, and six clones were identified which exhibited a major degree of resistance to 2'-deoxyguanosine but little or none to ara-C. Further characterization of clone 24B3 revealed a 600-fold increase in ara-G resistance, a 36-fold increase in 2'-deoxyguanosine resistance, and only a 4-fold increase in 1-beta-D-arabinofuranosylcytosine resistance. The 24B3 cell line accumulated less than 10% of 9-beta-D-arabinofuranosylguanine 5'-triphosphate and 2'-deoxyguanosine 5'-triphosphate from the corresponding nucleosides as compared to wild-type MOLT-4 cells; in contrast, 1-beta-D-arabinofuranosylcytosine 5'-triphosphate accumulation was approximately 30% of control values. Thus, ara-G differs from 1-beta-D-arabinofuranosylcytosine in its selectivity for cultured T-lymphoblasts and may be of use as a chemotherapeutic or immunosuppressive agent.
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001087:Arabinonucleosides / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D003561:Cytarabine / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D004351:Drug Resistance; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism
D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D003561:Cytarabine; C028771:9-arabinofuranosylguanine; D004247:DNA