Synergistic antiproliferative effects of the combination of interleukin-1 alpha and doxorubicin against human melanoma cells.
We have investigated the antiproliferative effects of recombinant human interleukin-1 alpha (IL-1) combined with the cytotoxic antitumor drug doxorubicin against A375 human melanoma IL-1-sensitive (C6) and IL-1-resistant (C5) clonal cell lines. Growth inhibition was assessed by the MTT assay, and C5 cells were 10-fold less sensitive to IL-1 than the C6 cells, but both cell lines were equally sensitive to doxorubicin. Synergistic antitumor activity between the two agents was evaluated by median effects/combination index analysis, and IL-1 and doxorubicin were strongly synergistic over a broad range of drug concentrations. The strongest synergism occurred when C6 cells were exposed to IL-1 prior to doxorubicin, and when C5 cells were pretreated with doxorubicin for 6 hr prior to IL-1 additions. An examination of various ratios of the two agents revealed a maximum 20-fold potentiation of doxorubicin, and a 30-fold potentiation of IL-1 median dose values in the combination compared to the median dose values obtained with doxorubicin or IL-1 alone. Doxorubicin treatment enhanced the binding and internalization of [125I]IL-1 after 24 and 48 hr at 37 degrees C, but IL-1 binding to cells incubated on ice was increased only marginally by doxorubicin pretreatment. Treatment of C6 cells with IL-1 for 24 hr did not alter the cellular accumulation of doxorubicin. A recombinant protein IL-1 receptor antagonist that binds to both the 80 kDa type I and the 65 kDa type II IL-1 receptors, blocked the cytostatic effects of IL-1 and abrogated the synergism with doxorubicin. In cells synchronized following release from aphidicolin block, doxorubicin caused a G2 + M accumulation, IL-1 alone had no effect, and the combination of both agents resulted in a G2 + M block similar in magnitude to that caused by doxorubicin alone. These results provide preclinical evidence that doxorubicin combined with IL-1 may be beneficial in the clinical treatment of malignant melanoma and possibly other types of solid tumors.
Mimnaugh
E G
EG
Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Monti
E
E
Sebers
S
S
Stetler-Stevenson
M
M
Sinha
B K
BK
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D004317:Doxorubicin