ROLE OF NITRIC-OXIDE AND SUPEROXIDE ANION IN ELIMINATION OF LOW METASTATIC HUMAN COLORECTAL CARCINOMAS BY UNSTIMULATED HEPATIC SINUSOIDAL ENDOTHELIAL-CELLS

Human colorectal carcinoma (CRC) cell survival For the first 24 h afte r implantation in the hepatic sinusoid determines its potential to col onize the liver, Nearly 10-fold more highly metastatic CX-1 cells surv ive within the livers of nude mice 24 h after Intrasplenic injection t han weakly metastatic clone A cells. Because CRCs contact sinusoidal e ndothelial cells (SECs) during implantation, we sought to determine wh ether SECs were more toxic to clone A than to CX-1 cells, When 2 x 10( 4) vital dye-labeled CRC cells mere added to murine SEC monolayers, mo re than 30% of clone A cells lost calcein AM fluorescence compared to fewer than 5% of CX-1 cells after 24 h of coculture with SECs, Kupffer cells did not mediate this effect, because neither enriched Kupffer c ells nor SECs treated with a Kupffer cell inhibitor altered the SEC-me diated toxic effect to clone A cells. Pretreatment with a nitric oxide synthase inhibitor, N-G-monomethyl-L-arginine, superoxide dismutase, or dexamethasone, blocked SEC-mediated toxicity to clone A cells, wher eas calcium chelation and catalase did not, In addition, clone A cells mere more sensitive to a superoxide donor, 3-morpholinosydnonimine N- ethylcarbamide, than were CX-1 cells, and neither cell line nas sensit ive to sodium nitroprusside, a nitric oxide donor, Thus, unstimulated murine SECs produce reactive oxygen species that are selectively toxic to weakly metastatic clone A cells. This may he a mechanism by which host liver cells eliminate weakly metastatic neoplastic cells.