title: Modulation of cisPlatin cytotoxicity by interleukin-1 alpha and resident tumor macrophages.
abstract: 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.
authors.affiliation: Department of Radiation Oncology, University of Miami School of Medicine, Sylvester Comprehensive Cancer Center, Florida 33101, USA.
authors.forename: P G
authors.initials: PG
authors.lastname: Braunschweiger
authors.forename: V S
authors.initials: VS
authors.lastname: Basrur
authors.forename: D
authors.initials: D
authors.lastname: Cameron
authors.forename: L
authors.initials: L
authors.lastname: Sharpe
authors.forename: O
authors.initials: O
authors.lastname: Santos
authors.forename: J P
authors.initials: JP
authors.lastname: Perras
authors.forename: B U
authors.initials: BU
authors.lastname: Sevin
authors.forename: A M
authors.initials: AM
authors.lastname: Markoe
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology*; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D006861:Hydrogen Peroxide / Q000378:metabolism; D007375:Interleukin-1 / Q000008:administration & dosage / Q000494:pharmacology*; D007700:Kinetics; D008264:Macrophages / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D016877:Oxidants / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D007375:Interleukin-1; D016877:Oxidants; D006861:Hydrogen Peroxide; D002945:Cisplatin