Synergistic interactions of etoposide and interleukin-1 alpha are not due to DNA damage in human melanoma cells.

Several possible mechanisms of the synergistic interactions of IL-1 alpha and VP-16 against A375-C6 human melanoma cells were investigated. Studies indicate that IL-1 alpha did not increase topoisomerase II-dependent VP-16-mediated DNA damage, nor did IL-1 alpha inhibit the repair of VP-16-induced DNA damage in these cells. Furthermore, IL-1 alpha by itself or in combination with VP-16 did not cause significant fragmentation of cellular DNA into oligomers, indicating programmed cell death (apoptosis) was not involved in the mechanism of synergy. In contrast, an IL-1-specific receptor antagonist significantly decreased IL-1 alpha toxicity toward the melanoma cells and nearly eliminated the synergistic interactions of IL-1 alpha with VP-16. These results strongly indicate that synergism of IL-1 alpha with VP-16 was dependent upon an IL-1-receptor-mediated processes. DNA-strand breakage was unlikely to be a primary intracellular target for IL-1 alpha cytotoxicity and synergism with VP-16.