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

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Biotherapy

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 growthin 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 H2O2by 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-1αin vivo.

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Abbreviations

ATP:

adenine triphosphate

GSH:

glutathione

HBSS:

Hanks Balanced Salt Solution

H2O2 :

hydrogen peroxide

IC90 :

concentration to inhibit activity by 90%

IL-1α:

human recombinant interleukin-1α

PMA:

4-beta-phorbol-12-beta-myristate 13-acetate

TCA:

trichloroacetic acid

TNF:

tumor necrosis factor

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Authors and Affiliations

  1. Department of Radiation Oncology Division of Gynecologic Oncology University of Miami School of Medicine The Sylvester Comprehensive Cancer Center, University of Miami, PO Box 016960, 33101, Miami, Florida

    Paul G. Braunschweiger, Dayna Cameron, Laura Sharpe, Octavio Santos & Arnold M. Markoe

  2. Department of Obstetrics and Gynecology Division of Gynecologic Oncology University of Miami School of Medicine The Sylvester Comprehensive Cancer Center, University of Miami, PO Box 016960, 33101, Miami, Florida

    James P. Perras & Bernd-Uwe Sevin

  3. Michigan Cancer Foundation, 48201, Detroit, MI

    Vathsala S. Basrur

Authors
  1. Paul G. Braunschweiger
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  2. Vathsala S. Basrur
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  3. Dayna Cameron
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  4. Laura Sharpe
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  5. Octavio Santos
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  6. James P. Perras
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  7. Bernd-Uwe Sevin
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  8. Arnold M. Markoe
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Braunschweiger, P.G., Basrur, V.S., Cameron, D. et al. Modulation of cisPlatin cytotoxicity by interleukin-1α and resident tumor macrophages. Biotherapy 10, 129–137 (1997). https://doi.org/10.1007/BF02678540

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  • DOI: https://doi.org/10.1007/BF02678540

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