Effects of rGM-CSF and rG-CSF on the cisplatin sensitivity of the blast cells of acute myeloblastic leukemia.

Recombinant growth factors have been shown to alter the sensitivity of acute myeloblastic leukemia (AML) blast cells to cytosine arabinoside (ara-C) in culture. The mechanism is controversial and suggestions for it include changes in ara-C metabolism, changes in cell cycle parameters, and changes in the balance between self-renewal and determination in blast stem cells. We addressed this issue by measuring the cisplatin sensitivity of freshly obtained AML blasts in rG-CSF, rGM-CSF, or the two together. For comparison, simultaneous measurements of ara-C sensitivity were made. We found that exposure to different factors in suspension altered the cisplatin sensitivity of AML blasts in the same direction as the change observed in ara-C sensitivity. Similar changes in cisplatin sensitivity were seen when cells were briefly exposed to the drug, washed, and then grown in suspension in the presence of different growth factors. Control experiments showed that the conditions in suspension, not in the clonogenic assay in methylcellulose, were responsible for the changes in cisplatin sensitivity. The capacity of high specific activity to inactivate clonogenicity was tested at several times under growth conditions which altered the sensitivity of cells to cisplatin. Whereas changes in survival after 3HTdR and cisplatin both were seen with time, growth conditions that altered cisplatin sensitivity were not associated with changes in 3HTdR toxicity. The data do not support explanations of the effects of growth conditions on drug toxicity which depend either on drug metabolism or cell cycle effects. Instead, the findings are consistent with a model that postulates an association between drug sensitivity and the balance between self-renewal and differentiation in the blast population.