Effects of indomethacin, cytokines, and cyclosporin A on tumor growth and the subsequent development of cancer cachexia.
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), and tumor necrosis factor alpha (21 ng/g) or s.c. injections of cyclosporin A (60 micrograms/g) or indomethacin (1 micrograms/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 micrograms/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/10(6) cells versus 3700 +/- 922 pg/10(6) cells). Lipopolysaccharide stimulated macrophages from tumor-bearing mice to produce significantly more prostaglandin E2 in vitro compared with control macrophages (39,500 +/- 4208 pg/10(6) cells versus 12,500 +/- 4330 pg/10(6) cells).(ABSTRACT TRUNCATED AT 400 WORDS)
Gelin
J
J
Department of Surgery, University of Gothenburg, Sweden.
Andersson
C
C
Lundholm
K
K
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002100:Cachexia / Q000209:etiology*; D003524:Cyclosporins / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D005260:Female; D007213:Indomethacin / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D008748:Methylcholanthrene; D051379:Mice; D008810:Mice, Inbred C57BL; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D003524:Cyclosporins; D007375:Interleukin-1; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D008748:Methylcholanthrene; D007213:Indomethacin