Enhancement of methotrexate cytotoxicity by modulation of proliferative activity in normal and neoplastic T lymphocytes and in a myeloid leukemia cell line.

Abstract

Recent advances in the modulation of cell kinetics with growth factors suggest that the effect of cycle-specific cytostatic drugs can be enhanced by combination with such factors. The truth of this hypothesis was investigated by studying the effect of phytohemagglutinin and/or interleukin 2 on the sensitivity to methotrexate (MTX) of normal T lymphocytes and of lymphoblasts of a patient with acute T-cell lymphoid leukemia. In both cases, inhibition of proliferation by MTX was increased from less than 30% in resting cells or those suboptimally stimulated, in the case of leukemic blasts, to 68-83% in maximally stimulated cells. Similar results were observed when the AML 193 human myeloid leukemia line was stimulated with human recombinant granulocyte macrophage colony stimulation factor (GM-CSF). Under basal proliferation conditions, the addition of 1 microgram/ml and 10 micrograms/ml MTX was followed by 48% and 72% inhibition respectively. When 1 ng/ml GM-CSF (40 I.U./ml) was present, these figures rose to 89% and 91%. It is thus clear that growth factor-induced cell proliferation increases sensitivity to cycle-specific cytostatic agents. There is thus a biological premise for new perspectives in antineoplastic therapy.