title: Clinically relevant deoxycytidine levels are high enough to profoundly alter 9-beta-D-arabinofuranosylguanine cytotoxicity for human T-cell acute leukemia cells in vitro.
abstract: Plasma deoxycytidine levels can vary markedly during chemotherapy, from < 0.05 microM to at least 10.3 microM in T-cell acute lymphoblastic leukemia (T-ALL). This study demonstrates that clinically relevant deoxycytidine levels can dramatically protect human T-ALL cells against 9-beta-D-arabinofuranosylguanine (araG), a promising drug in this leukemia. At 0.4, 1.2, 3.6, and 10.8 microM deoxycytidine, the dose of araG required to kill 50% of MOLT3 T-ALL cells increased 4.23 +/- 1.95-(mean +/- SEM), 23.1 +/- 5.42-, 39.3 +/- 19.3-, and 67.0 +/- 11.5-fold compared to araG without deoxycytidine. Such deoxycytidine concentrations sharply reduced intracellular araG levels and blocked inhibition of DNA synthesis even in the presence of 160 and 640 microM araG. These data offer the first evidence that clinically relevant deoxycytidine levels could profoundly modulate araG toxicity in T-ALL.
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001087:Arabinonucleosides / Q000493:pharmacokinetics / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D003841:Deoxycytidine / Q000097:blood* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured