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 cyclespecific cytostatic drugs can be enhanced by combination with such factors. The truth of this hypothesis was investigated by studying the effect of phytohemoagglutinin and/or interlenkin 2 on the sensitivity to methotrexate (MTX) of normal T lymphocytes and of lymphoblastis 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 sub-optimally 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 μg/ml and 10 (μ/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 cyclespecific cytostatic agents. There is thus a biological premise for new perspectives in antineoplastic therapy.