title: A role for the interleukin 1 receptor in the synergistic antitumor effects of human interleukin 1 alpha and etoposide against human melanoma cells.
abstract: To investigate the possibility that anticancer drugs combined with cytokines may show increased activity, human tumor cells were treated with combinations of human recombinant interleukin 1 alpha (rIL-1 alpha) and etoposide (VP-16). The cytotoxicity of these combinations was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay using rIL-1 alpha-sensitive A375-C6 melanoma cells and A375-C5 cells, a clonal variant line that is resistant to IL-1 alpha. Data were analyzed for synergism by the median effect principle of T-C. Chou and P. Talalay (J. Biol. Chem., 252: 6438-6442, 1977). At a dose ratio of VP-16 to rIL-1 alpha of 12 nM:1 unit/ml in either simultaneous or sequential exposure (VP-16 first), the calculated combination index values indicated synergistic cytotoxicity toward both A375-C6 cells and A375-C5 cells. IL-1 alpha treatment 24 h prior to VP-16 exposure had no advantage over simultaneous treatment. Surface IL-1 alpha receptors on both A375-C6 and A375-C5 cells were measured using 125I-radiolabeled rIL-1 alpha binding; A375-C6 cells had 701 +/- 128 (SD) receptor molecules/cell and A375-C5 cells only had 58 +/- 33 receptor molecules/cell. The dissociation constants for IL-1 alpha were similar in both cell types (19 +/- 6 pM for A375-C6 and 17 +/- 2 pM for A375-C5). The specific binding of rIL-1 alpha to the surface IL-1 alpha receptors of both sensitive and resistant cells was significantly increased in a dose-dependent fashion by the prior treatment with VP-16 (1.75-fold on A375-C6 cells and 3.5-fold on A375-C5 cells). VP-16 also enhanced the internalization of receptor-bound rIL-1 alpha, suggesting that a possible mechanism of the synergistic cytotoxicity of rIL-1 alpha and VP-16 might be related to the modulation of rIL-1 alpha receptors by VP-16, resulting in increased internalization of rIL-1 alpha.
authors.affiliation: Clinical Pharmacology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892.
authors.forename: N
authors.initials: N
authors.lastname: Usui
authors.forename: E G
authors.initials: EG
authors.lastname: Mimnaugh
authors.forename: B K
authors.initials: BK
authors.lastname: Sinha
mesh_terms: D004334:Drug Administration Schedule; D004357:Drug Synergism; D005047:Etoposide / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D008545:Melanoma / Q000378:metabolism; D011971:Receptors, Immunologic / Q000187:drug effects / Q000378:metabolism*; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000378:metabolism
chemical_list: D007375:Interleukin-1; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D005047:Etoposide