Enhancement of methotrexate cytotoxicity by modulation of proliferative activity in normal and neoplastic T lymphocytes and in a myeloid leukemia cell line.
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.
Ciaiolo
C
C
Amedeo di Savoia Hospital, Turin, Italia.
Ferrero
D
D
Pugliese
A
A
Biglino
A
A
Marletto
G
G
Tonello
M
M
Colzani
G
G
Marietti
G
G
D002455:Cell Division / Q000187:drug effects; D003115:Colony-Stimulating Factors / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008727:Methotrexate / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D003115:Colony-Stimulating Factors; D006133:Growth Substances; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D008727:Methotrexate