Activation of human peripheral-blood-derived monocytes by cis-diamminedichloroplatinum: enhanced tumoricidal activity and secretion of tumor necrosis factor-alpha.
The anticancer agent cis-diamminedichloroplatinum (CDDP) has been shown to have immunopotentiating and immuno-suppressive properties depending on the CDDP concentration used. Treatment of human peripheral-blood-derived monocytes (PBM) in vitro with low concentrations of CDDP resulted in a significant potentiation of antitumor cytotoxicity as assessed in an 18-hour 51Cr release assay. The potentiation of cytotoxicity by CDDP was also observed with PBM treated with recombinant interferon-gamma (rIFN-gamma). The monocyte-mediated cytotoxicity was significantly inhibited when antitumor necrosis factor (TNF) antibody was added to the assay culture. The role of TNF in the cytotoxic mechanism was further corroborated by demonstrating that significant levels of immunoreactive TNF-alpha in the supernatants were detected by ELISA. Further, supernatants derived from CDDP-treated monocytes were cytotoxic to the TNF-sensitive tumor cells and the cytotoxicity was neutralized by the addition of anti-TNF antibody. The secretion of TNF-alpha by CDDP-treated monocytes was readily detected as early as 4 h after culture and was dependent on de novo protein synthesis as inhibitors of RNA and protein synthesis abolished TNF-alpha secretion. Altogether, these results demonstrate that CDDP can potentiate monocyte-mediated antitumor cytotoxicity and stimulates TNF-alpha synthesis and secretion.
Gan
X H
XH
Department of Microbiology and Immunology, UCLA School of Medicine.
Jewett
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A
Bonavida
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B
D002945:Cisplatin / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D009000:Monocytes / Q000276:immunology*; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D002945:Cisplatin