title: Effect of cyclooxygenase and nitric oxide synthase inhibitors on tumor growth in mouse tumor models with and without cancer cachexia related to prostanoids.
abstract: The potential interaction between cyclooxygenase (Cox) and NO metabolic pathways in the control of local tumor growth was evaluated. Mice bearing either a sarcoma-derived tumor (C57B1; MCG 101) or a malignant melanoma (C3H/HeN; K1735-M2) were used. These models were principally different because they demonstrate, in tumor hosts, conditions with and without cancer cachexia, seemingly related to high and low production of prostanoids, respectively. Cox inhibitors (Cox-1 and Cox-2) decreased tumor growth by 35-40% in MCG 101-bearing mice but had no such effect on melanoma-bearing mice, despite the expression of the Cox-2 protein in melanoma cells. Indomethacin reduced prostanoid production in both tumor (MCG 101) and host tissues and reduced tumor cell proliferation, mainly in vivo. Nitric oxide synthase (NOS) inhibitors (N(omega)-nitro-L-arginine methyl ester and N(omega)-nitro-L-arginine) reduced tumor growth in vivo by approximately 50% in both tumor models. Tumor growth reduction, related to NOS inhibition, was unrelated to prostanoid production and was an in vivo phenomenon in both tumor models. Specific inhibitors of inducible NOS activity, unexpectedly, had no effect in any tumor model, although inducible NOS protein was present in tumor tissues in large amounts. A combination of Cox and NOS inhibitors had no additive effect on tumor growth (MCG 101). Cox inhibition increased tumor tissue (MCG 101) expression of cNOS mRNA but had no significant effect on tumor tissue expression of the transferrin receptor, vascular endothelial growth factor, or basic fibroblast growth factor. NOS inhibition increased tumor tissue content of cNOS mRNA but showed as well a trend to increase mRNA content of the transferrin receptor and vascular endothelial growth factor. Our results suggest that NOS inhibitors can decrease the local growth of tumors that are either responsive or unresponsive to Cox inhibition. This effect may reflect cross-talk between Cox and NOS pathways within or among tumor cells, or it may represent unrelated effects on tumor and host cells. Whether NO inhibition may be used therapeutically in clinical tumors that are unresponsive to eicosanoid intervention remains to be evaluated.
authors.affiliation: Department of Surgery, Sahlgrenska University Hospital, Göteborg, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Cahlin
authors.forename: J
authors.initials: J
authors.lastname: Gelin
authors.forename: D
authors.initials: D
authors.lastname: Delbro
authors.forename: C
authors.initials: C
authors.lastname: Lönnroth
authors.forename: C
authors.initials: C
authors.lastname: Doi
authors.forename: K
authors.initials: K
authors.lastname: Lundholm
mesh_terms: D000818:Animals; D002100:Cachexia / Q000097:blood / Q000209:etiology*; D015232:Dinoprostone / Q000097:blood; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006133:Growth Substances / Q000235:genetics; D007150:Immunohistochemistry; D007189:Indans / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007457:Iodine Radioisotopes; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009374:Neoplasms, Experimental / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011453:Prostaglandins / Q000097:blood*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D006133:Growth Substances; D007189:Indans; D007457:Iodine Radioisotopes; C093700:L 745337; D011453:Prostaglandins; D012333:RNA, Messenger; D019335:Nitroarginine; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin