In vitro correlates of clinical response to methotrexate in acute leukaemia and Burkitt's lymphoma

Abstract

The response of drug-resistant patients with acute leukaemia and Burkitt's lymphoma to treatment with a 24 h infusion of methotrexate (MTX) followed, in some cases,by cytosine arabinoside was correlated with in vitro measurements of total intracellular MTX, exchangeable intracellular MTX, and suppressibility of deoxyuridine (UdR) incorporation in isolated marrow blast cells at extracellular MTX concentrations of 10(-8)M, 10(-7)M, 10(-6)M and 10(-5)M. Total intracellular MTX levels and exchangeable intracellular MTX levels were not significantly different in responding or non-responding patients at any MTX concentration, but increased four-fold for every ten-fold concentration increment studied. Extracellular MTX levels in excess of 10(-7)M appeared necessary to allow accumulation of exchangeable intracellular MTX. UdR incorporation at 10(-6)M and 10(-5)M differed significantly between responding and non-responding patients, with responders having less than 20% of control values and non-responders having greater than 40% of control values. Further, increasing the extracellular MTX concentration from 10(-6)M to 10(-5)M produced no significant decrease in UdR incorporation in either group. The therapeutic implications of this apparent threshold are discussed.