Pierson H F
Cancer Treat Rep. 1985 Nov;69(11):1283-91.
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.
在外源性铜被发现能增强B16黑色素瘤在异种小鼠中的致瘤性，这些小鼠用次氮基三乙酸的铜螯合物（NTA-Cu+2）或新铜试剂的亚铜螯合物（NC-Cu+1）进行处理。在此处使用的治疗方案中，这两种铜螯合物对宿主小鼠均无毒。将移植的B16黑色素瘤细胞腹腔接种到CDF1小鼠中后会被排斥，除非它们预先用铜螯合物处理，这使得肿瘤形成率达到100%。在未处理的NIH瑞士小鼠中观察到有限数量的肿瘤形成，而用铜螯合物处理使腹腔肿瘤形成数量增加了一倍。用NC-Cu+1处理可增强肿瘤色素沉着并抑制肿瘤包膜形成，这是NTA-Cu+2所没有的特征。没有包膜的肿瘤以不受限制的腹水形式生长，这与发病更早和存活率降低有关。只有用铜螯合物处理的小鼠才允许皮下肿瘤形成。用NC-Cu+1处理导致体重可逆性抑制，表明肿瘤生长缓慢且独立于宿主体重增加，直到治疗停止。用NC-Cu+1处理增强了皮下肿瘤的致瘤性，这表现为可触及肿瘤的时间更早、NIH瑞士小鼠中的肿瘤形成增加、最终肿瘤重量和肿瘤负荷降低以及宿主存活期缩短。这些结果表明，铜螯合物以小鼠和铜螯合物特异性的方式改变B16黑色素瘤的生物学生长特性，并且NC-Cu+1对肿瘤的生长促进活性与螯合物中铜的氧化态以及肿瘤铜营养的增强有关。还讨论了癌症患者血浆铜水平升高与化疗药物之间潜在的不良相互作用。
