Effect of methotrexate on NAD kinase activity in leukaemic mice.

Abstract

IN the course of treatment of leukaemia L1210 in mice using an antifolate compound, methotrexate (MTX), the leukaemic cells are affected early during treatment and later, while becoming resistant1, show impaired retention and decreased permeability to the drug2–4. Some antifolate-resistant sub-lines of leukaemia .L1210 have substantial dihydrofolate reductase (1.5.1.3) (DHR) activities5–7 and use NADPH to reduce folate to tetrahydrofolate8,9. Some authors have therefore considered the possibility of using the level of DHR activity to measure the effectiveness of the action of a drug on MTX-resistant leukaemic cells10,11. The extent to which the capacities to synthesize NADP and NADPH are influenced by the antifolate treatment is, however, unknown. Waravdekar et al.12 reported that livers of mice bearing various transplantable tumours showed impaired capacities to synthesize NAD. Furthermore, differences in the ratio of NAD to NADH2 are known to reflect the extent of oxidative metabolism and reductive synthesis in the livers of different species13. In the present experiments, the effects of daily treatment with MTX on hepatic and splenic NAD kinase (2.7.1.23) were examined in mice implanted with leukaemia L1210.