Rehman I, Lowry D T, Adams C, Abdel-Fattah R, Holly A, Yuspa S H, Hennings H
Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255, USA.
Mol Carcinog. 2000 Apr;27(4):298-307.
The skin tumor initiators N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and 7,12-dimethylbenz[a]anthracene (DMBA) differ in effectiveness when tumor formation is promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA). Even at high doses, MNNG is less effective, producing fewer benign and malignant tumors with a longer latent period. In DMBA-initiated skin, 10 wk of TPA promotion produced a maximal tumor response. With MNNG, 20 wk of TPA promotion was required, producing nearly four times as many papillomas as 10 wk of promotion. Promotion of MNNG-initiated skin with mezerein induced the appearance of very rapidly-growing papillomas within 5 wk, 3 wk earlier than the first TPA-promoted papillomas. Thus, MNNG may induce a novel mutation resulting in a population of initiated cells that respond especially well to mezerein. Since ras mutations are common in experimental tumors in many tissues, we determined the frequency of activating mutations in the Ha-ras, Ki-ras, and N-ras oncogenes. Activating Ha-ras mutations were present in essentially all DMBA-initiated tumors and about 70% of MNNG-initiated tumors. No N-ras mutations were found in tumors lacking other ras mutations. Surprisingly, 41% of the papillomas arising in the first 11 wk in MNNG-initiated, mezerein-promoted mice bore mutations in codon 12 of the Ki-ras oncogene. Activating Ki-ras mutations were also found in more than 60% of squamous cell carcinomas and 40% of keratoacanthomas. Although mutations in Ha-ras are frequently detected in mouse skin tumors, mutations in Ki-ras are rare. This is the first report of mutated Ki-ras in skin tumors from mice initiated by MNNG.
当用12-O-十四烷酰佛波醇-13-乙酸酯（TPA）促进肿瘤形成时，皮肤肿瘤引发剂N-甲基-N'-硝基-N-亚硝基胍（MNNG）和7,12-二甲基苯并[a]蒽（DMBA）的效果有所不同。即使在高剂量下，MNNG的效果也较差，产生的良性和恶性肿瘤较少，潜伏期更长。在DMBA引发的皮肤中，10周的TPA促进产生了最大的肿瘤反应。对于MNNG，则需要20周的TPA促进，产生的乳头状瘤数量几乎是10周促进的四倍。用芫花酯素促进MNNG引发的皮肤，在5周内就诱导出了生长非常迅速的乳头状瘤，比第一个TPA促进的乳头状瘤早3周。因此，MNNG可能诱导了一种新的突变，导致一群引发细胞对芫花酯素反应特别良好。由于ras突变在许多组织的实验性肿瘤中很常见，我们确定了Ha-ras、Ki-ras和N-ras癌基因中激活突变的频率。基本上所有DMBA引发的肿瘤和约70%的MNNG引发的肿瘤中都存在激活的Ha-ras突变。在没有其他ras突变的肿瘤中未发现N-ras突变。令人惊讶的是，在MNNG引发、芫花酯素促进的小鼠中，在最初11周内出现的乳头状瘤中有41%在Ki-ras癌基因的第12密码子处发生了突变。在超过60%的鳞状细胞癌和40%的角化棘皮瘤中也发现了激活的Ki-ras突变。虽然在小鼠皮肤肿瘤中经常检测到Ha-ras突变，但Ki-ras突变很少见。这是关于MNNG引发的小鼠皮肤肿瘤中Ki-ras突变的首次报道。
