Effects of indomethacin, cytokines, and cyclosporin A on tumor growth and the subsequent development of cancer cachexia
Gelin, J.; Andersson, C.; Lundholm, K.
Cancer Research 51(3): 880-885
1991
ISSN/ISBN: 0008-5472 PMID: 1988128 Document Number: 368614
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.alpha. IL-1.beta. (21 ng/g), IL-2 (21 ng/g), and tumor necrosis factor .alpha. (21 ng/g) or s.c. injections of cyclosporin A (60 .mu.g/g) or indomethacin (1 .mu.g/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 .mu.g/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.alpha. and IL-1.beta. suppressed tumor growth in vivo, which tumor necrosis factor .alpha., 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 diseases. 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".