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

Paul G. Braunschweiger, Vathsala S. Basrur, Dayna Cameron, Laura Sharpe, Octavio Santos, James P. Perras, Bernd Uwe Sevin, Arnold M. Markoe

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

The modulation of cisPlatin cytotoxicity by interleukin-1 (IL-1α) 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-1α in SCC-7 solid tumors. Neither IL-1α nor tumor macrophages affected the survival of clonogenic tumor cells and IL-1α had no direct effect on tumor cell growth in vitro. Macrophages had no direct effect on cisPlatin sensitivity (IC90=6.0 μM), but, the addition of IL-1α (500-2000U/ml) to co-cultures of cisPlatin pretreated tumor cells and resident tumor macrophages increased cell killing (IC90=3.1 μM). Similar responses were seen in primary cultures treated with cisPlatin before IL-1α. The modulation of cisPlatin cytotoxicity by IL-1α exhibited a biphasic dose response that paralleled the IL-1α dose dependent release of H2O2 by resident tumor macrophages. Further, IL-1α modification of cisPlatin cytotoxicity was prompt and inhibited by catalase. CisPlatin and exogenous H2O2 (50 μM) 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-1α treatment for 24 hrs, before cisPlatin, produced drug resistance (IC90 = 11.1 μM). Our study shows that IL-1α 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 explanation for the synergistic antitumor activity of cisPlatin and IL-1α in vivo.

Original languageEnglish (US)
Pages (from-to)129-137
Number of pages9
JournalBiotherapy
Volume10
Issue number2
DOIs
StatePublished - Jan 1 1997

Keywords

  • cisPlatin
  • Drug resistance
  • IL-1α
  • Tumor macrophages

ASJC Scopus subject areas

  • Pharmacology

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    Braunschweiger, P. G., Basrur, V. S., Cameron, D., Sharpe, L., Santos, O., Perras, J. P., Sevin, B. U., & Markoe, A. M. (1997). Modulation of cisPlatin cytotoxicity by interleukin-1α and resident tumor macrophages. Biotherapy, 10(2), 129-137. https://doi.org/10.1007/BF02678540