Diversity of the effect of recombinant tumor necrosis factors alpha and beta on human myelogenous leukemia cell lines

Abstract

In vitro characteristics of response to recombinant tumor necrosis factors alpha (rTNF-alpha) and beta (rTNF-beta) were studied in six human myelogenous leukemia cell lines. Heterogeneity of the response to rTNF was observed, and one line (K562) was resistant. No enhancement of cell growth was noted in any cell line. The dose-response curves for rTNF-alpha were characteristically sigmoid, the maximum inhibitory effect occurring between 25 and 200 ng/mL. Nonresponsiveness within this range indicated resistance that could not be overcome, even with very high doses of rTNF alpha. A similar response of sensitive and resistant lines occurred after exposure to rTNF-beta. The clonogenic cells were more sensitive than the overall population to the action of rTNF alpha, and prolonged exposure was necessary for manifestation of the effect. Concomitant exposure to recombinant interferon-alpha (rIFN-alpha) increased the response of two cell lines to rTNF-alpha, but no clear synergistic action could be demonstrated. The addition of rIFN-gamma was without effect. Variations in the rTNF-alpha-induced proliferative response could not be explained by differences in the number of binding sites per cell or their affinity for rTNF-alpha. That the clonogenic cells showed a higher sensitivity than the whole population might indicate a preferential effect on more primitive, actively proliferating cells with high growth potential.