Enhancement of tumorigenicity of B16 melanoma in heterogenetic mice by administration of copper chelates.

Exogenous copper was found to enhance tumorigenicity of B16 melanoma in heterogenetic mice that were treated with either the cupric chelate of nitrilotriacetic acid (NTA-Cu+2) or the cuprous chelate of neocuproine (NC-Cu+1). Both copper chelates were nontoxic to host mice given in the treatment schedule used here. Transplanted B16 melanoma cells were rejected after ip inoculation into CDF1 mice unless they were pretreated with copper chelates, which permitted 100% tumor takes. A limited number of tumor takes were observed in untreated NIH Swiss mice, and treatment with copper chelates doubled the number of ip tumor takes. Treatment with NC-Cu+1 enhanced tumor pigmentation and inhibited tumor encapsulation, a characteristic not shared with NTA-Cu+2. Tumors without capsules grew as unrestrained ascites and this was associated with an earlier onset of morbidity and decreased survival. Only mice treated with copper chelates permitted sc tumor takes. Treatment with NC-Cu+1 caused a reversible suppression of body weight, indicating that tumors grew slowly and independently of host body weight accretion until treatment was stopped. Treatment with NC-Cu+1 enhanced tumorigenicity of sc tumors as evidenced by an earlier onset of palpability, enhanced tumor takes in NIH Swiss mice, decreased final tumor weight and tumor burden, and shortened host survival. These results suggest that copper chelates alter the biological growth characteristics of B16 melanoma in both a murine and copper chelate-specific manner, and that the growth-promoting activity of NC-Cu+1 on tumors is related to the oxidation state of copper in chelates and enhanced copper nutriture of tumors. The potentially adverse interaction of elevated plasma copper levels in cancer patients with chemotherapeutic agents is discussed.