INDUCTION OF RENAL-CELL CARCINOMA IN MALE WISTAR RATS TREATED WITH CUPRIC NITRILOTRIACETATE

Systemic administration of copper, an essential trace metal in the hum an body, has never been reported to be carcinogenic in animals. We inv estigated the induction of tumors by the cupric complex of nitrilotria cetic acid (Cu-NTA) in male Wistar rats. Thirty-two animals received i p injections of CU-NTA, 3 to 5 mg of copper/kg body weight 5 days a we ek for 12 weeks, and were kept under close observation. For comparison , 31 animals received ip injections of ferric nitrilotriacetate (Fe-NT A), 5 to 10 mg of iron/kg body weight, and 16 animals received nitrilo triacetic acid (NTA) alone at the molar dose equivalent to Cu-NTA for the same period of time. Sixteen animals were left untreated as contro ls. Fourteen animals in the Cu-NTA group died of hepatic failure durin g the treatment period, acid renal cell carcinoma (RCC) was induced in eight animals (25%). Of these, four animals died of either pulmonary metastasis or intraperitoneal hemorrhage. A total of 12 RCC were obtai ned, of which six tumors were greater than or equal to 5 mm. The Cu-NT A group yielded fewer RCC and required a longer latent period for thei r incubation than the Fe-NTA group. Furthermore, the Cu-NTA group show ed one hepatocellular carcinoma and one high-grade sarcoma of hepatic origin. No renal or hepatic tumor was observed in the NTA or control g roups. The nontumorous part of the kidney treated with Cu-NTA presente d hemosiderosis caused by copper-induced hemolytic anemia. This is the first report that systemic administration of copper compounds can ind uce malignant tumors in animals. Not only copper but also iron may pla y a role in the Cu-NTA-induced renal carcinogenesis model.