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.