A possible role for methotrexate in the treatment of childhood acute myeloid leukaemia, in particular for acute monocytic leukaemia

Acute myeloid leukaemia (AML) is thought to be methotrexate (MTX)-resistant . However, a small study suggested that acute monocytic leukemia (AML-MS) i s sensitive to MTX. We measured MTX accumulation/polyglutamylation in 20 AM L-nonM5, 37 AML-MS and 83 common/preB-acute lymphoblastic leukaemia (c/preB -ALL) samples. Membrane transport was determined in 11 childhood AMLs (incl uding 3 AML-MS) and in 25 c/preB-ALL samples. MTX sensitivity was determine d in 23 AML-nonMS, 15 AML-MS and 63 common/preB-ALL samples using the thymi dylate synthase (TS) inhibition assay. MTX transport was higher in AML samp les compared with c/preB-ALL precluding a transport defect in AML. Accumula tion of long-chain polyglutamates MTX-Glu(4-6) was 3-fold lower for AML-non MS compared with c/preB-ALL cells (median 268 versus 889 pmol MTX-Glu(4-6)/ 10(9) cells; P less than or equal to0.001); for AML-MS samples, median accu mulation of MTX-Glu(4-6) was 0 pmol/10(9) cells (P less than or equal to0.0 01). After short-term MTX exposure, AML-nonMS was 6-fold more resistant to MTX compared with c/preB-ALL cells (2.16 versus 0.39 muM; P < 0.001), while AML-MS was 2-fold more resistant (P = 0.02). In both AML-nonMS and AML-MS cells, MTX resistance was circumvented by continuous MTX exposure (median T SI50 values: 0.052 and 0.041 <mu>M, respectively) compared with a c/preB-AL L value of 0.066 muM. In conclusion, AML-MS is relatively sensitive to MTX compared with other AML-subtypes even though polyglutamylation of MTX is po or. Using continuous exposure, AML-nonMS and AML-MS cells were at least as sensitive to MTX as c/preB-ALL cells. This report suggests that MTX might b e an overlooked drug in the treatment of childhood AML, (C) 2001 Elsevier S cience Ltd. All rights reserved.