ENDOGENOUS TUMOR-NECROSIS-FACTOR INHIBITS THE CYTOTOXICITY OF EXOGENOUS TUMOR-NECROSIS-FACTOR AND ADRIAMYCIN IN PANCREATIC-CARCINOMA CELLS

Pancreatic carcinoma is one of the most devastating neoplasms with reg ard to its resistance to conventional therapy. In a previous report, w e found that endogenous tumor necrosis factor (enTNF) exerts an intrac ellular protective effect against exogenous TNF- and Adriamycin (ADM)- induced cytotoxicity by scavenging oxygen free radicals (OFR) with ind uced manganous superoxide dismutase (MnSOD). We also know that glutath ione S-transferase pi (GST-pi) and glutathione (GSH) also scavenge OFR . It remains unclear to what extent enTNF and MnSOD induced by enTNF r egulate the sensitivity to ADM and exogenous TNF among different carci noma cells. In this study, we examined the relationship between ADM an d exogenous TNF sensitivity and enTNF expression and MnSOD activity in four pancreatic carcinoma lines. We determined whether ADM and exogen ous TNF sensitivity could be predicted by measuring enTNF expression a nd MnSOD activity in the carcinoma cells. The sensitivity to TNF and A DM varied with the cell lines, and TNF sensitivity correlated well wit h Adriamycin sensitivity. Moreover, enTNF expression and MnSOD activit y correlated positively with resistance to ADM and exogenous TNF. When MIAPaCa-2 cells, which had the lowest enTNF expression and the highes t sensitivity to exogenous TNF and ADM, were transfected with the nons ecretory-type human TNF gene (pTNF Delta pro) to increase enTNF synthe sis, their intracellular MnSOD activity and exogenous TNF and ADM resi stance were increased. These findings suggest that MnSOD plays a criti cal role in scavenging OFR induced by ADM and exogenous TNF. enTNF is the most important factor that regulates the production of MnSOD. Ther efore, it is plausible that inhibition of enTNF expression or MnSOD ac tivity in pancreatic carcinoma would improve the efficacy of therapies for pancreatic carcinoma.