Effect of high-dose methotrexate on plasma hypoxanthine and uridine levels in patients with acute leukemia or non-Hodgkin lymphoma in childhood.

We investigated the effect of high dose methotrexate (HDMTX) therapy on plasma hypoxanthine (Hx) and uridine (UR) concentrations in 12 children with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL). The initial plasma Hx level before the first administration of HDMTX (1 g/m2) was significantly higher in patients (25.5 +/- 17.5 microM) than that in healthy adult controls (4.0 +/- 1.4 microM). By 48 or 72 hours after the beginning of MTX infusion, the Hx concentration had decreased to 7.9 +/- 7.7 microM and 4.7 +/- 4.1 microM, respectively. This decrease of plasma Hx concentration after MTX infusion was also observed with the second course of HDMTX (3 g/m2) therapy. On the other hand, the plasma UR level did not change significantly. The in vitro treatment with 2 microM MTX of hypoxanthine-guanine phosphoribosyltransferase (HGPRT)-deficient mutant cells selected from HL-60 lowered the excretion of Hx into the culture medium. These data suggest a possible new explanation of the synergism of HDMTX and 6-thiopurines, for example 6-mercaptopurine and 6-thioguanine, since plasma Hx is considered to counteract 6-thiopurine toxicity through competition at the level of HGPRT.