Modulation of the growth of transformed cells by human tumor necrosis factor-alpha and interferon-gamma.
Recombinant human tumor necrosis factor-alpha (rHuTNF-alpha) inhibited growth of the cervical carcinoma cell line, ME-180neo, at doses greater than 50 units/ml, but stimulated the growth of these cells at low doses (0.1-10 units/ml). ME-180neo variants selected for resistance to the cytotoxic effects of rHuTNF-alpha retained the ability to be growth stimulated at all concentrations tested. ME-180neo cells and the rHuTNF-alpha-resistant ME-180neo variants possessed equivalent steady state numbers of TNF-alpha receptors with similar Kd values. Recombinant human interferon-gamma (rHuIFN-gamma) augmented the rHuTNF-alpha-induced cytotoxic response of ME-180neo cells and overcame the resistance of the ME-180neo variants to rHuTNF-alpha cytotoxicity. In separate experiments we were able to show that the number of TNF-alpha binding sites on both rHuTNF-alpha-sensitive and -resistant ME-180neo cells was similar and was increased by treatment with rHuIFN-gamma. These results suggest that the growth stimulation of tumor cells mediated by rHuTNF-alpha can be dissociated from the cytotoxic response and that these responses are not related to the number or affinity of TNF-alpha binding sites.
Lewis
G D
GD
Department of Pharmacological Sciences, Genentech, Inc., South San Francisco, California 94080.
Aggarwal
B B
BB
Eessalu
T E
TE
Sugarman
B J
BJ
Shepard
H M
HM
D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007700:Kinetics; D011956:Receptors, Cell Surface / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D002583:Uterine Cervical Neoplasms / Q000473:pathology*
D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma