Benfield J R, Hammond W G, Paladugu R R, Pak H Y, Azumi N, Teplitz R L
J Thorac Cardiovasc Surg. 1986 Nov;92(5):880-9.
A canine model of squamous cell lung cancer has been developed through studies with 110 dogs exposed by 11 focal endobronchial regimens to chemical carcinogens: benzo(a)pyrene, nitrosomethylurea, methylcholanthrene, and dimethylbenzanthracene. A combination of nitrosomethylurea and benzo(a)pyrene caused the first invasive cancer after 5.5 years. Toxic side-effects resulted from either nitrosomethylurea or high-dose dimethylbenzanthracene given by bronchial submucosal injection and from adjuvant immunosuppression with azathioprine and corticosteroids. Four regimens in 58 dogs caused 31 cancers, including five T1-2 N0 M0 cancers, 17 metastasizing carcinomas, and nine carcinomas of lesser stages. The following regimens caused cancers: sequential benzo(a)pyrene, nitrosomethylurea, and yttrium 91; benzo(a)pyrene and topical nitrosomethylurea; low-dose dimethylbenzanthracene; high-dose methylcholanthrene. The most suitable regimen to date has been 30 mg of methylcholanthrene given by submucosal injection every 2 to 3 weeks; this produced cancers at preselected sites within 2 years of first exposure in eight of 10 dogs. The neoplastic continuum has followed a predictable, reproducible sequence that regularly began with epithelial hyperplasia. Squamous metaplasia occurred in 6 to 18 weeks; it was followed by progressive squamous atypia. The interval until invasive cancer developed varied with the regimen employed; it was about 20 months with methylcholanthrene. Serial cytologic specimens, studied by image analysis, revealed progressive increase in mean total cellular deoxyribonucleic acid content from diploid in normal cells to greater than tetraploid in cancer cells (p less than 0.01). We have recently been successful with serial passage of four canine lung cancers from four to twelve transplant generations in nude mice. There is now a predictable large animal model of squamous cell lung carcinoma at preselected site(s) that closely resembles human lung cancer. The preneoplastic period is short enough to be fiscally defensible, but long enough to permit study of the biologic changes during endobronchial carcinogenesis.
通过对110只狗进行11种局灶性支气管内给药方案，使其接触化学致癌物（苯并(a)芘、亚硝基甲基脲、甲基胆蒽和二甲基苯并蒽）的研究，已建立了一种犬鳞状细胞肺癌模型。亚硝基甲基脲和苯并(a)芘的联合使用在5.5年后导致了首例浸润性癌症。毒性副作用源于支气管黏膜下注射亚硝基甲基脲或高剂量二甲基苯并蒽，以及使用硫唑嘌呤和皮质类固醇进行辅助免疫抑制。58只狗采用的4种给药方案导致了31例癌症，包括5例T1-2 N0 M0癌症、17例转移性癌和9例较早期癌症。以下给药方案导致了癌症：依次给予苯并(a)芘、亚硝基甲基脲和钇91；苯并(a)芘和局部应用亚硝基甲基脲；低剂量二甲基苯并蒽；高剂量甲基胆蒽。迄今为止最合适的给药方案是每2至3周通过黏膜下注射给予30毫克甲基胆蒽；这使得10只狗中有8只在首次接触后的2年内，在预先选定的部位发生了癌症。肿瘤形成的连续过程遵循可预测、可重复的顺序，通常始于上皮增生。鳞状化生在6至18周出现；随后是进行性鳞状细胞异型增生。直到浸润性癌症发生的间隔时间因所采用的给药方案而异；使用甲基胆蒽时约为20个月。通过图像分析研究的系列细胞学标本显示，平均总细胞脱氧核糖核酸含量从正常细胞的二倍体逐渐增加到癌细胞的四倍体以上（p<0.01）。我们最近成功地将4例犬肺癌在裸鼠中进行了从4代到12代的连续传代。现在有了一种在预先选定部位的可预测的大型动物鳞状细胞肺癌模型，它与人类肺癌非常相似。肿瘤前期足够短，在经济上是可行的，但又足够长，能够允许研究支气管内致癌过程中的生物学变化。
