Modulation of cisplatin cytotoxicity by interleukin-1α and resident tumor macrophages

• Published in: Biotherapy (Dordrecht) Vol. 10; no. 2; pp. 129 - 137
• Main Authors: BRAUNSCHWEIGER, P. G, BASRUR, V. S, CAMERON, D, SHARPE, L, SANTOS, O, PERRAS, J. P, SEVIN, B.-U, MARKOE, A. M
• Format: Journal Article
• Language: English
• Published: Dordrecht Kluwer 01.01.1997
• Subjects: Animals; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Biological and medical sciences; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - pathology; Cisplatin - administration & dosage; Cisplatin - pharmacology; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); Drug Synergism; Female; Hydrogen Peroxide - metabolism; Interleukin-1 - administration & dosage; Interleukin-1 - pharmacology; Kinetics; Macrophages - metabolism; Macrophages - physiology; Medical sciences; Mice; Mice, Inbred C3H; Oxidants - metabolism; Pharmacology. Drug treatments; Tumor Cells, Cultured; Antineoplastic agent; Drug combination; Cytokine; Rodentia; Interleukin 1α; Cytotoxicity; In vitro; Cisplatin; Vertebrata; Mixed cell culture; Mammalia; Mouse; Animal; Mechanism of action; Tumor cell; Macrophage; Platinum II Complexes
• ISSN: 0921-299X; 1573-8280
• DOI: 10.1007/BF02678540

The modulation of cisPlatin cytotoxicity by interleukin-1 (IL-1 alpha) was studied in cultures of SCC-7 tumor cells with and without tumor macrophages to examine potential mechanisms for the synergistic antitumor activity of cisPlatin and IL-1 alpha in SCC-7 solid tumors. Neither IL-1 alpha nor tumor macrophages affected the survival of clonogenic tumor cells and IL-1 alpha had no direct effect on tumor cell growth in vitro. Macrophages had no direct effect on cisPlatin sensitivity (IC90 = 6.0 microM), but, the addition of IL-1 alpha (500-2000U/ml) to co-cultures of cisPlatin pretreated tumor cells and resident tumor macrophages increased cell killing (IC90 = 3.1 microM). Similar responses were seen in primary cultures treated with cisPlatin before IL-1 alpha. The modulation of cisPlatin cytotoxicity by IL-1 alpha exhibited a biphasic dose response that paralleled the IL-1 alpha dose dependent release of H2O2 by resident tumor macrophages. Further, IL-1 alpha modification of cisPlatin cytotoxicity was prompt and inhibited by catalase. CisPlatin and exogenous H2O2 (50 microM) produced more than additive SCC-7 clonogenic cell kill and hydroxyl radicals played an important role in the response. Interleukin-1 modulation of cisPlatin cytotoxicity was schedule dependent. IL-1 alpha treatment for 24 hrs, before cisPlatin, produced drug resistance (IC90 = 11.1 microM). Our study shows that IL-1 alpha can stimulate tumor macrophages to release pro-oxidants that modify cellular chemosensitivity in a schedule and dose dependent fashion. Our findings may also provide a mechanistic explantation for the synergistic antitumor activity of cisPlatin and IL-1 alpha in vivo.