CYTOTOXIC EFFECT OF DIPHTHERIA-TOXIN USED ALONE OR IN COMBINATION WITH OTHER AGENTS ON HUMAN RENAL-CELL CARCINOMA CELL-LINES

Treatment of renal cell carcinoma (RCC) by conventional chemotherapy a nd immunotherapy has resulted in minimal remissions. Alternative forms of therapy are therefore being sought. The present study investigated the sensitivity of RCC cell lines to several toxins used alone and in combination with other agents. RCC lines were relatively sensitive to the direct cytotoxic effect of diphtheria toxin (DTX), Pseudomonas ae ruginosa exotoxin A (PEA) and ricin. Furthermore, DTX in combination w ith tumor necrosis factor-alpha (TNF-alpha) resulted in synergistic cy totoxic activity. The mechanism of synergy was examined. A possible me chanism of resistance to TNF-alpha in tumor cells is the expression of TNF-alpha mRNA or protein. R11 cells did not constitutively express m RNA for TNF-alpha, however, treatment of R11 cells with TNF-alpha indu ced the expression of TNF-alpha mRNA. When DTX was used in combination with TNF-alpha, the level of TNF-alpha mRNA induced by TNF-alpha was markedly reduced. These studies suggest that DTX in combination with T NF-alpha can overcome the resistance of RCC lines and that the marked downregulation of TNF-alpha mRNA by DTX may play a role in the enhance d cytotoxicity seen with the combination of DTX and TNF-alpha. Further more, the combination treatment might also potentiate the antitumor ho st responses. The implications of these findings in clinical therapy a re discussed.