Discussion: Some comments on the potential carcinogenicity of the clinically useful antitumor agents
Discussion: Some comments on the potential carcinogenicity of the clinically useful antitumor agents
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讨论：对临床上有用的抗肿瘤药物潜在致癌性的一些评论
作者：
S. Sieber;R. Adamson
化疗可能在癌症患者的第二原发肿瘤的病因学中起作用，这一点越来越引起人们的关注。然而，在抗肿瘤药物和这些第二肿瘤之间建立因果关系之前，必须获得额外的基础实验数据。Marquardt博士总结了体外筛选系统在这方面的应用。Weisburger和Schmzhl介绍了从临床有用的抗肿瘤药物的啮齿动物生物测定中获得的致癌性数据。在我们实验室几年前开始的研究中，我们使用非人类灵长类动物，主要是恒河猴和食蟹猴，来评估各种抗肿瘤药物的致癌潜力。迄今为止，丙卡嗪和甲基亚硝基脲（MNU）已被证明是强致癌物（表1）。在平均6.5年的潜伏期后，丙卡嗪在18%的治疗猴子中诱发了肿瘤，10个恶性肿瘤中有6个是急性白血病。在接受MNU治疗的猴子中，11%的猴子在平均6年的时间里患上了口咽鳞状细胞癌。使用阿霉素、1-PAM （melphalan）和Imuran等其他药物的研究直到最近才开始，接受治疗的猴子还没有出现肿瘤。我们还试图在猴子身上确定已知的肝癌致癌物二乙基亚硝胺（DENA）是否存在致癌阈值剂量。五组猴子每两周接受40至1mg /kg剂量的DENA腹腔注射。在三组已经发生肿瘤的猴子中，我们发现潜伏期随着mg/kg剂量的减少而增加；此外，总DENA剂量在1.2
T IS CLEAR T H A T THERE IS INCREASING CONI cern about the possibility that chemotherapy may play a role in the etiology of second primary tumors in cancer patients. However, before a causal relationship can be established between antineoplastic agents and these second tumors, additional basic experimental data must be acquired. Dr. Marquardt has summarized the utility of in uitro screening systems for this purpose, and Drs. Weisburger and Schmzhl have presented data obtained from rodent bioassays on the carcinogenicity of clinically useful antitumor agents. In studies initiated at our laboratory several years ago, we are using nonhuman primates, primarily rhesus and cynomolgus monkeys, to evaluate the carcinogenic potential of various antitumor agents. To date, both procarbazine and methylnitrosourea (MNU) have proved to be potent carcinogens (Table 1 ). Procarbazine has induced neoplasms in 18% of treated monkeys after an average latent period of 6.5 years, and six of the 10 malignancies that developed were acute leukemia. MNU induced squamous cell carcinomas of the oropharynx in 11% of monkeys receiving this agent for an average of 6 years. Studies with the other agents, Adriamycin, 1-PAM (melphalan) and Imuran have only recently been initiated, and none of the treated monkeys have as yet developed tumors. We are also trying to establish in monkeys whether there is a threshold carcinogenic dose for the known hepatocarcinogen diethylnitrosamine (DENA). Five groups of monkeys are receiving biweekly intraperitoneal injections of DENA at doses ranging from 40 to 1 mg/kg. In the three groups of monkeys in which tumors have developed, we have found that the latent period increases as the mg/kg dose decreases; furthermore, a total DENA dose between 1.2