Effect of cyclooxygenase and nitric oxide synthase inhibitors on tumor growth in mouse tumor models with and without cancer cachexia related to prostanoids

The potential interaction between cyclooxygenase (Cox) and NO metabolic pat hways in the control of local tumor growth was evaluated. Mice bearing eith er a sarcoma-derived tumor (C57BI; MCG 101) or a malignant melanoma (C3H/He N; K1735-M2) were used. These models were principally different because the y 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 1 01-bearing mice but had no such effect on melanoma-bearing mice, despite th e expression of the Cox-2 protein in melanoma cells. Indomethacin reduced p rostanoid production in both tumor MCG 101) and host tissues and reduced tu mor cell proliferation, mainly in vivo. Nitric oxide synthase (NOS) inhibit ors N-omega-nitro-L-arginine methyl ester and N-omega-nitro-L-arginine redu ced tumor growth in vivo by similar to 50% in both tumor models, Tumor grow th reduction, related to NOS inhibition, was unrelated to prostanoid produc tion and was an in vivo phenomenon in both tumor models. Specific inhibitor s of inducible NOS activity, unexpectedly, had no effect in any turner mode l, although inducible NOS protein was present in tumor tissues in large amo unts, A combination of Cox and NOS inhibitors had no additive effect on tum or growth (MCG 101). Cox inhibition increased tumor tissue (MCG 101) expres sion of cNOS mRNA but had no significant effect on tumor tissue expression of the transferrin receptor, vascular endothelial growth factor, or basic f ibroblast growth factor. NOS inhibition increased tumor tissue content of c NOS mRNA but showed as well a trend to increase mRNA content of the transfe rrin receptor and vascular endothelial growth factor, Our results suggest t hat NOS inhibitors can decrease the local growth of tumors that are either responsive or unresponsive to Cor inhibition. This effect may reflect cross -talk between Cox and NOS pathways within or among tumor cells, or it may r epresent unrelated effects on tumor and host cells. Whether NO inhibition m ay be used therapeutically in clinical tumors that are unresponsive to eico sanoid intervention remains to be evaluated.