Hammond W G, Yellin A, Gabriel A, Azumi N, Hill L R, Teplitz R L, Benfield J R
Department of Thoracic Surgery, City of Hope National Medical Center, Duarte, CA 91010.
Cancer Commun. 1990;2(4):135-44. doi: 10.3727/095535490820874506.
Sustained release implants (SRI) containing 10% benzo(a)pyrene (BP) were placed endobronchially into outbred and syngeneic (F1D) hamsters. Randomly selected OB and F1D hamsters also received 5-azacytidine (AZC), 5 mg/kg i.p., twice weekly until death (AZC-CONT); two more groups of F1D hamsters were given the same AZC dose either for the first 75 days of SRI implantation (AZC-EARLY) or from 80 days after SRI placement until death (AZC-LATE). OB Hamsters were sacrificed at regular intervals from 62 to 189 days of SRI exposure. F1D Hamsters were sacrificed in groups after 120, 150, 180, and 220 days of SRI exposure. The bronchial mucosa at the SRI site was examined cytologically and histologically, as were the tumors that developed. Mean quantitative total cellular DNA values (QDNA) were measured by image analysis. For both varieties of hamster given AZC, QDNA values were higher in early carcinogenesis (CG) and lower in the late stage of CG than in hamsters that did not get AZC (P less than 0.001). QDNA values were lower in epidermoid than in non-epidermoid cancers (P less than 0.001); for both types of cancer, QDNA was lower in AZC-treated hamsters (P less than 0.01). Cancers induced under the influence of AZC included more epidermoid cancers (P less than 0.01) and were of a higher degree of differentiation (P less than 0.01) than those induced by BP alone, especially when AZC was given early in CG. There was no consistent relationship between QDNA and degree of differentiation in tumors. These differential effects of AZC given early during CG suggest that 1) for epidermoid bronchial CG, some of the molecular alterations involved in hyperploidy and in differentiation occur early in the sequential progression of carcinogenesis; and 2) for both epidermoid and non-epidermoid bronchial CG, the necessary changes must occur in a fixed sequence instead of as random events, until all needed changes have occurred.
将含有10%苯并(a)芘（BP）的缓释植入物（SRI）经支气管内植入远交系和同基因（F1D）仓鼠体内。随机选取的远交系和F1D仓鼠还接受了5-氮杂胞苷（AZC），腹腔注射，剂量为5mg/kg，每周两次，直至死亡（AZC-CONT）；另外两组F1D仓鼠在SRI植入的前75天（AZC-EARLY）或SRI植入后80天直至死亡期间给予相同剂量的AZC（AZC-LATE）。在SRI暴露的62至189天期间，定期处死远交系仓鼠。在SRI暴露120、150、180和220天后，分批处死F1D仓鼠。对SRI部位的支气管黏膜进行细胞学和组织学检查，对所形成的肿瘤也进行同样检查。通过图像分析测量平均定量总细胞DNA值（QDNA）。对于给予AZC的两种仓鼠品种，在早期致癌过程（CG）中QDNA值较高，而在CG晚期则低于未接受AZC的仓鼠（P<0.001）。表皮样癌的QDNA值低于非表皮样癌（P<0.001）；对于这两种类型的癌症，接受AZC治疗的仓鼠的QDNA值较低（P<0.01）。在AZC影响下诱发的癌症包括更多的表皮样癌（P<0.01），并且与单独由BP诱发的癌症相比，分化程度更高（P<0.01），尤其是在CG早期给予AZC时。肿瘤中的QDNA与分化程度之间没有一致的关系。在CG早期给予AZC的这些差异效应表明：1）对于表皮样支气管CG，超倍体和分化过程中涉及的一些分子改变在致癌的连续进展过程中早期就会发生；2）对于表皮样和非表皮样支气管CG，必要的改变必须按固定顺序发生，而不是作为随机事件，直到所有所需改变都已发生。
