thioinosinic-acid and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

Methotrexate is widely administered with mercaptopurine, a prodrug requiring activation into thioguanine nucleotides (TGN) to exert antileukemic effects. In vitro, methotrexate enhances TGN formation, but in vivo, such enhancement has yet to be demonstrated. We investigated whether TGN concentrations were related to methotrexate concentrations in children with acute lymphoblastic leukemia who received a weekly intravenous methotrexate (40 mg/m(2)) dose combined with daily mercaptopurine (75 mg/m(2)). A total of 141 erythrocyte TGN concentrations were measured with erythrocyte methotrexate polyglutamates (MTX-PG) concentrations in 87 patients. Average TGN concentrations ranged from 137 to 958 pmol/8 x 10(8) cells (median 389), average total MTX-PG concentrations (MTX- PG(1-7)) from 0.60 to 97.7 pmol/10(9)cells (median 29), and average long chain polyglutamate concentrations (MTX-PG(5-7)) from 0 to 8.35 pmol/10(9) cells (median 2.43). Higher TGN concentrations correlated with higher MTX-PG(5-7) concentrations (P = 0.002). These data support the practice of administering methotrexate with mercaptopurine during continuation therapy of acute lymphoblastic leukemia.

Topics: Algorithms; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Biotransformation; Child; Drug Administration Schedule; Erythrocytes; Humans; Hypoxanthine Phosphoribosyltransferase; Inactivation, Metabolic; Injections, Intravenous; Inosine Monophosphate; Mercaptopurine; Methotrexate; Methyltransferases; Neoplasm Proteins; Nucleotides; Polyglutamic Acid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prodrugs; Thioguanine; Thionucleotides; Xanthine Oxidase