Mufti S I, Becker G, Sipes I G
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona Health Sciences Center, Tucson 85721.
Carcinogenesis. 1989 Feb;10(2):303-9. doi: 10.1093/carcin/10.2.303.
Preliminary dose finding studies showed that 22 mg/kg of N-nitrosomethylbenzylamine (NMBZA) delivered over 5 days did not induce esophageal lesions, but 18 mg/kg administered over a period of 2 or 3 weeks did induce these lesions. Based on these results, Sprague-Dawley rats were treated with 2.5 mg/kg NMBZA three times a week for 3 weeks to initiate esophageal carcinogenesis. The experimental animals were administered isocaloric ethanol diet either before and during NMBZA initiated carcinogenesis, or after initiation as a tumor promoter. The esophagi of rats that died or who were terminated at 18 months of age were examined for nodules and tumors. When ethanol was administered before and during initiation, the mean frequency of esophageal lesions was 8.04 +/- 3.04/rat with an average size of 1.44 +/- 0.27 mm versus 12.41 +/- 2.12/rat and 0.92 +/- 0.17 mm respectively for the controls. Only three out of 13 of the ethanol-fed rats had tumors (mainly squamous papillomas) versus 10 out of 26 of the control-fed animals. Ethanol consumption before and during initiation, therefore, decreased the incidence of esophageal nodules and tumors. With ethanol administered as a promoter, on the other hand, while incidence of the total lesions was not affected appreciably, the incidence of tumors was remarkably increased. With ethanol promotion the mean frequency of lesions was 8.75 +/- 1.07/rat with an average size of 1.02 +/- 0.09 mm versus 10.94 +/- 1.49/rat and 1.32 +/- 0.13 mm respectively for the controls. In this case, the ethanol-consuming rats had tumors in 14 out of 75 animals versus one small tumor in 32 of the controls. The results indicate that the occurrence of esophageal tumors is inhibited by simultaneous ethanol administration, but promoted when ethanol is administered post-initiation ostensibly by allowing extensive dysplastic proliferation of the carcinogen-induced lesions.
初步剂量探索研究表明，5天内给予22毫克/千克的N-亚硝基甲基苄胺（NMBZA）不会诱发食管病变，但在2或3周内给予18毫克/千克则会诱发这些病变。基于这些结果，将Sprague-Dawley大鼠每周三次给予2.5毫克/千克的NMBZA，持续3周以启动食管癌发生过程。实验动物在NMBZA启动致癌过程之前和期间，或在启动后作为肿瘤促进剂给予等热量乙醇饮食。对在18个月龄时死亡或被处死的大鼠的食管进行结节和肿瘤检查。当在启动之前和期间给予乙醇时，食管病变的平均频率为8.04±3.04个/大鼠，平均大小为1.44±0.27毫米，而对照组分别为12.41±2.12个/大鼠和0.92±0.17毫米。在给予乙醇饮食的13只大鼠中只有3只发生肿瘤（主要是鳞状乳头状瘤），而在给予对照饮食的26只动物中有10只发生肿瘤。因此，在启动之前和期间摄入乙醇会降低食管结节和肿瘤的发生率。另一方面，当乙醇作为促进剂给予时，虽然总病变的发生率没有受到明显影响，但肿瘤的发生率显著增加。在乙醇促进作用下，病变的平均频率为8.75±1.07个/大鼠，平均大小为1.02±0.09毫米，而对照组分别为10.94±1.49个/大鼠和1.32±0.13毫米。在这种情况下，摄入乙醇的大鼠在75只动物中有14只发生肿瘤，而对照组的32只动物中有1只发生小肿瘤。结果表明，同时给予乙醇可抑制食管肿瘤的发生，但在启动后给予乙醇时则会促进肿瘤发生，表面上是通过使致癌物诱导的病变广泛发育异常增殖来实现的。
