Methotrexate Metabolism by Bone Marrow Cells from Patients with Leukemia

Summary

Bone marrow cells from children with leukemia in remission and lymphoblasts and myeloblasts from children with early and late-stage leukemia all accumulated methotrexate during short-term culture and converted it to poly-γ-glutamyl derivatives. This metabolism was time and dose-dependent. Leukemia cells from two patients with chronic myelocytic leukemia also synthesized methotrexate polygluta-mates. Patients varied one from another in the quantity of total non-exchangeable methotrexate and methotrexate polyglutamates present in cells, but highest levels of each of these were seen in late acute lymphoblastic leukemia and in acute myeloblastic leukemia.

Co-incubation of leukemic cells with both methotrexate and a ten-fold excess of folinic acid decreased accumulation and poly-glutamylation of methotrexate to the same extent as chieved by reducing methotrexate concentration ten-fold. Co-incubation with methotrexate and a ten-fold excess of vincristine did not increase total cell methotrexate and methotrexate polyglutamates in leukemic cells in culture. Such an increase had been anticipated from earlier studiese with other cells. Indeed, levels of methotrexate and its derivatives were modestly reduced.