Modulation of cisPlatin cytotoxicity by interleukin-1α and resident tumor macrophages
Autor: | Laura Sharpe, Octavio Santos, James P. Perras, Dayna Cameron, Vathsala S. Basrur, Bernd Uwe Sevin, Paul G. Braunschweiger, Arnold M. Markoe |
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Rok vydání: | 1997 |
Předmět: |
medicine.medical_treatment
Biology Mice Antineoplastic Combined Chemotherapy Protocols Tumor Cells Cultured medicine Animals Macrophage Cytotoxicity Clonogenic assay Pharmacology Cisplatin Mice Inbred C3H Macrophages Drug Synergism Hydrogen Peroxide Oxidants In vitro Kinetics Cytokine Cell killing Mechanism of action Immunology Carcinoma Squamous Cell Cancer research Female medicine.symptom Interleukin-1 medicine.drug |
Zdroj: | Biotherapy. 10:129-137 |
ISSN: | 1573-8280 0921-299X |
Popis: | 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. |
Databáze: | OpenAIRE |
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