Cytotoxic effect of diphtheria toxin used alone or in combination with other agents on human renal cell carcinoma cell lines

Abstract

Treatment of renal cell carcinoma (RCC) by conventional chemotherapy and 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 aeruginosa exotoxin A (PEA) and ricin. Furthermore, DTX in combination with tumor necrosis factor-alpha (TNF-alpha) resulted in synergistic cytotoxic activity. The mechanism of synergy was examined. A possible mechanism of resistance to TNF-alpha in tumor cells is the expression of TNF-alpha mRNA or protein. R11 cells did not constitutively express mRNA for TNF-alpha, however, treatment of R11 cells with TNF-alpha induced 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 TNF-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 enhanced cytotoxicity seen with the combination of DTX and TNF-alpha. Furthermore, the combination treatment might also potentiate the antitumor host responses. The implications of these findings in clinical therapy are discussed.