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Regul Toxicol Pharmacol. 2010 Mar;56(2):156-65. doi: 10.1016/j.yrtph.2009.07.008. Epub 2009 Jul 23.
This study investigated if quinacrine can induce a tumorigenic response in rats when administered in a manner similar to the intended human use for female non-surgical sterilization. Young sexually mature female rats received two doses of quinacrine (or 1% methylcellulose control) into each uterine horn approximately 21 days apart, and were observed for 23 months after the second dose administration. Dose levels were 0/0, 0/0, 10/10, 70/70, and 70/250-350 mg/kg (first dose/second dose), which represent local doses in the uterus at approximate multiples of 1x, 8x and 40x the human dose (mg quinacrine/g uterine weight) used for female non-surgical sterilization. Rats were observed for viability, clinical signs of toxicity, and changes in body weight and food consumption. At necropsy, selected organs were weighed, macroscopic observations were recorded, and tissues were collected, fixed, processed, and examined for microscopic pathologic findings. Acute quinacrine toxicity was evident during the dosing period but did not affect long-term survival. Non-neoplastic findings were more common in treated animals than controls, providing evidence of the appropriateness of the bioassay. The incidence of uncommon tumors of the reproductive tract was similar to controls at doses of 10/10mg/kg but increased with dose level and was significantly greater than controls at >or=70/70 mg/kg. We conclude that two doses of quinacrine administered approximately 21 days apart into the uterus of young sexually mature rats at a local dose approximately 8 times the human dose used for non-surgical female sterilization increased the lifetime risk of tumor development in the reproductive tract.
本研究旨在探讨当以类似于女性非手术绝育的预期人类用途给予氯喹时，是否会在大鼠中引起致癌反应。年轻的性成熟雌性大鼠每侧子宫角接受两次氯喹（或 1%甲基纤维素对照）给药，两次给药间隔约 21 天，并在第二次给药后观察 23 个月。剂量水平分别为 0/0、0/0、10/10、70/70 和 70/250-350mg/kg（第一次剂量/第二次剂量），这代表了子宫内局部剂量，约为人类用于女性非手术绝育（mg 氯喹/g 子宫重量）剂量的 1x、8x 和 40x。大鼠的生存能力、毒性的临床症状、体重和食物消耗的变化均在观察之列。解剖时，对选定的器官进行称重，记录大体观察结果，并收集、固定、处理和检查组织的显微镜病理发现。在给药期间，急性氯喹毒性明显，但并未影响长期生存。与对照组相比，治疗组的非肿瘤性发现更为常见，这证明了生物测定的适宜性。生殖道罕见肿瘤的发生率在 10/10mg/kg 剂量组与对照组相似，但随着剂量水平的增加而增加，且在≥70/70mg/kg 剂量组与对照组相比显著更高。我们的结论是，在年轻的性成熟大鼠的子宫内给予两次约 21 天间隔的氯喹给药，局部剂量约为人类用于非手术女性绝育的剂量的 8 倍，增加了生殖道肿瘤发生的终生风险。
