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Effects of Indomethacin, Cytokines, and Cyclosporin A on Tumor Growth and the Subsequent Development of Cancer Cachexia¹

Department of Surgery, Institution I, University of Gothenburg, Sahlgrenska Hospital, S-413 45 Gothenburg, Sweden

C57BL/6J mice bearing a low or undifferentiated rapidly growing tumor were treated daily with either i.p. injections of the recombinant cytokines interleukin(IL)-1, IL-1ß (21 ng/g), IL-2 (21 ng/g), and tumor necrosis factor (21 ng/g) or s.c. injections of cyclosporin A (60 µg/g) or indomethacin (1 µg/g). In some experiments, indomethacin was administered in the drinking water corresponding to the amount of s.c. injections. Survival and the time course of tumor growth and food and water intake were measured. The nutritional state (body composition) of the animals was registered at spontaneous death in the course of tumor disease.

Indomethacin prolonged survival from 14 ± 1 to 22 ± 1 days in tumor-bearing mice when administered either in the drinking water or as s.c. injections. This effect, which was due to tumor growth inhibition, was equally effective irrespective of whether indomethacin was instituted on Day 1, 5, 7, or 9 following tumor implantation. Indomethacin did not inhibit tumor cell growth in vitro. Indomethacin-treated tumor-bearing mice were also less anorectic than untreated tumor-bearing mice, and their nutritional state, particularly lean body mass, was significantly improved by indomethacin at doses (1 µg/g) that did not influence the food intake or body composition in non-tumor-bearing mice. At spontaneous death, indomethacin-treated tumor-bearing mice had a significantly larger tumor burden when accounting for their degree of malnutrition as compared with untreated tumor bearers. Indomethacin did not decrease the elevation in hepatic concentrations of RNA seen in response to tumor progression. Adherent peritoneal macrophages from tumor-bearing mice had a lower prostaglandin E₂ synthesis compared with macrophages from non-tumor-bearing controls in the basal state (1100 ± 150 pg/10⁶ cells versus 3700 ± 922 pg/10⁶ cells). Lipopolysaccharide stimulated macrophages from tumor-bearing mice to produce significantly more prostaglandin E₂ in vitro compared with control macrophages (39,500 ± 4208 pg/10⁶ cells versus 12,500 ± 4330 pg/10⁶ cells). IL-1 and IL-1ß suppressed tumor growth in vivo, which tumor necrosis factor , IL-2, or cyclosporin A did not, but this effect of IL-1 was probably secondary to potentiating anorexia in tumor-bearing mice. IL-1 had no effect on survival in tumor disease.

We conclude that many previously reported effects on tumor growth by cytokines can be ascribed to alterations in food intake and host substrate metabolism if not otherwise confirmed, which was done for indomethacin in this study. Positive host effects and tumor inhibition by indomethacin in this model represent so far an outstanding monodrug experimental therapy that has no equal alternative that we know of. We also conclude that immune control of tumor growth is insignificant in this model, although the tumor is highly "immunogenic."

¹ Supported in part by grants from the Swedish Cancer Society (93-B89-22XA, 2014-B88-01XA, 2147-B89-04XA), the Medical Research Council (B89-17X-00536-25A, B89-17K-08712-01A), Tore Nilson Foundation, Assar Gabrielsson Foundation (AB Volvo, Sweden), Jubileumskliniken Foundation, Ingabritt and Arne Lundbergs Research Foundation, Swedish and Gothenburg Medical Societies, and the Medical Faculty, University of Gothenburg, Sweden.

² To whom requests for reprints should be addressed, at Department of Surgery, Sahlgrenska Hospital, S-413 45 Gothenburg, Sweden.

Received 5/ 7/90. Accepted 11/ 9/90.

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