Effect of Recombinant Tumor Necrosis Factor a in vitro and Its Modulation by a and y Interferons

The effect of recombinant human tumor necrosis factor a (rTNF-a) on human myelogenous leukemia clonogenic cells growing either in semisolid media or in suspension cultures was studied and compared with the effect on normal granulocyte-macrophage progenitors (GM-CFC). Exposure of cells to a range of rTNF-a doses including pharmacologically achievable plasma concentrations revealed a large heterogeneity in the response of leukemic clonogenic growth to rTNF-a. Only one of 13 specimens was highly resistant to rTNF-a. Eight of ten leukemic samples were significantly more sensitive than were normal GM-CFC. particularly within the in vivo achievable dose range (1 x 100 to 1 x 102 ng/mL). No significantly increased inhibition of either normal or leukemic clonogenic growth could be achieved by increasing the rTNF-a concentration above 250 ng/mL. Proliferation of leukemic clonogenic cells (L-CFC) was studied in suspension cultures. In five cases the clonogenic cells were signifIcantly inhibited by rTNF-a while in one case no inhibition was observed. The inhibition of L-CFC growth by rTNF-a was dose dependent between 1 x 100 and 1 x 1O ng/mL. In suspension cultures. the TNF effect on L-CFC was a function of time of exposure. particularly with low concentrations of TNF. A remarkably higher inhibition of L-CFC as compared with

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