Sequence-, time- and dose-dependent synergism of methotrexate and 6-mercaptopurine in malignant human T-lymphoblasts

Effect of methotrexate polyglutamates on thioguanine nucleotide concentrations during continuation therapy of acute lymphoblastic leukemia with mercaptopurine

“…Average (per-patient) erythrocyte TGNs correlated positively with average (per-patient) erythrocyte MTX-PG 5-7 concentrations (Spearman rank test: r = 0.33 P = 0.002; n = 87; Figure 2 panel a), but not significantly with total average (per-patient) erythrocyte methotrexate polyglutamate concentrations (MTX-PG [1][2][3][4][5][6][7] : r = 0.14; P = 0.18; n = 87). Average (perpatient) MTXPG [1][2][3][4] concentrations correlated positively with TGNs concentrations but did not reach significance (r = 0.20; P = 0.06; n = 87).…”

“…In the 141 available samples, total MTX-PG concentrations ranged from 0.30 to 76.3 pmol/10 9 cells (median 27 pmol/10 9 cells) and long-chain polyglutamate concentrations (MTX-PG [5][6][7] : sum of PG5 + PG6 + PG7 polyglutamate concentrations) from 0 to 16.3 pmol/10 9 cells (median 2.2 pmol/10 9 cells).…”

“…11 Among the 87 patients, only 12 had more than two measurements of RBC TGNs and MTX-PG during continuation therapy (median of three determinations per patient, range 3-5). Among these 12 patients, the intrapatient coefficient of variation ranged from 2 to 65% (median 18%) for TGNs, from 19% to 92% (median 44%) for total MTXPGs, and from 13% to 117% for MTXPG [5][6][7] concentrations (median 42%).…”

“…5 A consequence of inhibiting de novo purine synthesis is an increase in concentrations of phosphoribosyl pyrophosphate (PRPP), a co-substrate for HPRT-catalyzed for- mation of thioinosine monophosphate. In vitro, the increase in PRPP levels by methotrexate is sequence-, time-and dosedependent, 6 although it is not clear that a higher dose of methotrexate produces higher concentrations of TGN. In vivo, methotrexate also inhibits xanthine oxidase, resulting in decreased first pass metabolism and increased mercaptopurine bioavailability.…”

The impact of high-dose methotrexate on intracellular 6-mercaptopurine disposition during interval therapy of childhood acute lymphoblastic leukemia

“…The biochemical and pharmacological basis to combine 6-MP and MTX stem from various in vivo and in vitro observations whereby de novo purine biosynthesis inhibition by MTXPG produces an elevation in cellular phosphoribosylpyrophosphate (PPPR) levels [5,6], the cofactor for HPRT. Hence, the combination of MTX with 6-MP is synergistic in enhancing the activation of 6-MP to 6-TGN that are incorporated to nucleic acids.…”