16-16-dimethylprostaglandin-e2 and Lung-Neoplasms

The effects of a prostaglandin synthesis inhibitor, indomethacin (Indo), on the growth of Lewis lung carcinoma (LLC) growing as primary subcutaneous tumors in either conventional C57BL/6 mice, T cell deficient nude mice, or natural killer (NK) cell deficient beige mice were studied. In conventional mice, Indo, when continuously administered in the drinking water, consistently and significantly inhibited, in a dose-related fashion, the growth of LLC implanted either subcutaneously in the footpad or in the inguinal region; however, the degree of inhibition of footpad tumor appeared to be greater than that of inguinal tumor. Maximum inhibition was found when Indo was initiated before detectable or measurable tumor developed. If Indo treatment was initiated after tumor growth was evident, then Indo was found to be less effective, although significant inhibition was still observed. Indo also effectively inhibited LLC growing either in the footpad or in the inguinal region of nude or beige mice. The degree of inhibition of both footpad and inguinal tumors in both these mice was comparable to that seen in conventional C57BL/6 mice, indicating that mature T cells, NK cells, or soluble products produced only by these cells are not involved in mediating or modulating the inhibitory effects of Indo on LLC growth. Although Indo treatment significantly inhibited LLC growth in vivo, continuous treatment of cultured LLC cells with Indo in vitro did not decrease the growth of cultured cells. These results indicate that the inhibitory effect of Indo in vivo is not the result of a direct inhibitory effect of Indo on these tumor cells. Lastly, this inhibitory effect of Indo in vivo could not be reversed or negated, not even in part, by the simultaneous, daily i.p. administration of 16,16-dimethyl-PGE2. This finding suggests that the inhibitory effect of Indo involves a mechanism other than the inhibition of prostaglandin E2 production.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Cell Division; Female; Indomethacin; Lung Neoplasms; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Mice, Nude; Neoplasms, Experimental; Tumor Cells, Cultured

The role of prostaglandin E2 (PGE2) in directly stimulating metastatic spread by Lewis lung carcinoma (LLC) cells was examined with the use of an in vitro migration model for tumor dissemination. The extent to which cloned metastatic and nonmetastatic LLC cells migrated out of glass capillary tubes in vitro reflected their capacity to form pulmonary metastases in vivo. The addition of PGE2 to metastatic LLC cells further stimulated their migration. Other cyclooxygenase products, besides PGE2, did not stimulate the migration of metastatic LLC cells. Nonmetastatic LLC cells did not migrate out of capillary tubes, even in the presence of exogenous PGE2. The amount of PGE2 secreted by cloned LLC cells was quantitated by a radioimmunoassay. Nonmetastatic LLC cells secreted more PGE2 than did the metastatic LLC cells. When the nonmetastatic LLC cells were either mixed with or placed adjacent to cloned metastatic LLC cells, the migration by the metastatic LLC cells was stimulated. The migration-stimulatory capacity of the nonmetastatic LLC cells was minimized in the presence of indomethacin, a prostaglandin synthesis inhibitor. Studies were conducted to relate these in vitro results to tumor metastasis in vivo. Injection of a mixture of metastatic and nonmetastatic LLC cells into mice s.c. resulted in a greater number of lung metastases than did injection of metastatic cells alone. This increase in metastasis formation was prevented by indomethacin. Formation of pulmonary metastases was also augmented when irradiated nonmetastatic LLC cells were injected into metastatic LLC-bearing mice. The results of our studies suggest that nonmetastatic LLC cells, by producing PGE2, can augment in vitro migration and in vivo dissemination of metastatic LLC cells. Thus, the response of tumor cells to PGE2, rather than simply their production of PGE2, appears to be important in regulating tumor dissemination.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Clone Cells; Dinoprostone; Indomethacin; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Radioimmunoassay