Investigations of the effects of essential divalent metals, magnesium, zinc and iron, on the carcinogenicity of nickel have been continued in bioassay and biochemical studies. Immunohistochemical investigations over the first month after injection of nickel revealed that this metal transiently inhibited activity of natural killer cells in the injected muscle, while magnesium reversed this effect. In an in vitro study, nickel diminished a mitogen-stimulated incorporation of tritiated thymidine into murine T-lymphocytes, while magnesium antagonized nickel action. Thus, magnesium appears to inhibit cytotoxicity of nickel and stimulate the natural cellular defenses against nickel-transformed cells. In yet another in vitro study, nickel was found for the first time to disrupt cell-cell communication which indicated its tumor-promotional activity; magnesium partially reversed this effect. Zinc, another antagonist of nickel carcinogenesis, is much less active than magnesium. It prolonged the latency of tumors without any significant influence on their final incidence in a 1.5-yr study. Zinc does not affect nickel retention in the injected muscle and has no detectable influence on the early local necrotic/inflammatory response to nickel. In a bioassay currently underway, iron, which is chemically closer to nickel than zinc and magnesium, appears to be a much stronger inhibitor of nickel carcinogenesis than the latter two metals. A new original hypothesis on the mechanism of nickel carcinogenesis has been formulated based on the known catalytic effects of the nickel (II/nickel(III) couple on the oxidation of some polypeptides and proteins involving free-radical reactions. Experiments performed to test this hypothesis showed interstrand-DNA, DNA-histone, and histone-histone cross-linking when the substrates were incubated in vitro with nickel(II) in the presence of tetraglycine. Interactions of this type, in vivo, may damage the cellular genetic material and lead to neoplastic transformation of the cells.
