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Vol. 127 No. 11, November 1992 |
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PAPERS PRESENTED AT THE 45TH ANNUAL CANCER SYMPOSIUM OF THE SOCIETY OF SURGICAL ONCOLOGY, NEW YORK, NY, MARCH 15-18, 1992 |
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Cholera Toxin Pretreatment Protects Against Tumor Necrosis Factor Lethality Without Compromising Tumor Response to Therapy
Mark I. Block, MD;
H. Richard Alexander, MD;
Jeffrey A. Norton, MD
Arch Surg. 1992;127(11):1330-1334.
Abstract
• Antitumor therapy with tumor necrosis factor is limited by systemic toxic effects. We studied whether cholera toxin, a bacterial exotoxin that adenosine diphosphate—ribosylates the  -subunit of Gs proteins, could separate the lethal from the antitumor effects of tumor necrosis factor. A single dose of intravenous cholera toxin protected non—tumor-bearing mice from a lethal dose of Escherichia coli endotoxin administered 6 or 24 hours later. On the basis of these results, tumor-bearing mice were randomized to receive either cholera toxin or saline, followed 6 hours later by either human tumor necrosis factor (400 µg/kg) or saline. Tumor-bearing mice pretreated with cholera toxin had (1) reduced treatment-related mortality (0/11 vs 5/11 for saline controls) and (2) tumor regression similar to that of controls. In a separate experiment in tumor-bearing mice, intravenous human tumor necrosis factor treatment induced an increase in serum levels of murine tumor necrosis factor to a peak of 500 pg/mL at 1 hour in saline-pretreated controls, while a similar increase could not be detected in those mice pretreated with cholera toxin. These results suggest that pretreatment with cholera toxin can reduce the endogenous tumor necrosis factor response to administered tumor necrosis factor and separate the lethal from the antitumor effects. Cholera toxin may prove to be a useful tool for investigating the mechanisms underlying the varied effects of tumor necrosis factor.
(Arch Surg. 1992;127:1330-1334)
Author Affiliations
From the Surgical Metabolism Section, Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Md. Dr Norton is now with Washington University School of Medicine, St Louis, Mo.
Footnotes
Accepted for publication June 21, 1992.
Presented at the 45th Annual Cancer Symposium of the Society of Surgical Oncology, New York, NY, March 18, 1992.
Reprint requests to Washington University School of Medicine, Box 8109, 660 S Euclid Ave, St Louis, MO 63110 (Dr Norton).
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