Watanabe K H, Travis C C
Department of Environmental Health Sciences, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana 70112-2699, USA.
Toxicol Appl Pharmacol. 1997 Dec;147(2):419-30. doi: 10.1006/taap.1997.8286.
Published data from SENCAR mice were analyzed to elucidate mechanisms underlying the formation of chemically induced skin papillomas. The experimental data followed a two-step protocol using 7,12-dimethylbenz[a]anthracene (DMBA) for initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA) for promotion. The two-mutation model of Ellwein and Cohen was used to simulate the data. In this model, probabilities of stem cell birth and death along with initiation and increased cell division are allowed to vary in time. We incorporated a pulse dose with exponential decay to represent the effect of DMBA on the probability of initiation over time, and a summation of pulse doses to represent the repeated topical applications of TPA and its effect on cell division and cell death. We fitted the model to the papilloma and carcinoma data sequentially, and indirectly determined the dependence of model parameters on the administered dose of DMBA and TPA. The occurrence of chemically induced epidermal hyperplasia is a fundamental assumption in our fits of the papilloma data. We found a delay in the onset of normal and initiated cell death relative to the enhancement of cell division rates. In addition, the model parameters display a nonlinear dependence on the dose of DMBA or TPA administered.
分析了来自SENCAR小鼠的已发表数据，以阐明化学诱导皮肤乳头瘤形成的潜在机制。实验数据遵循两步方案，使用7,12-二甲基苯并[a]蒽（DMBA）进行启动，使用12-O-十四烷酰佛波醇-13-乙酸酯（TPA）进行促进。采用Ellwein和Cohen的双突变模型对数据进行模拟。在该模型中，干细胞产生和死亡的概率以及启动和细胞分裂增加的概率随时间变化。我们纳入了具有指数衰减的脉冲剂量来表示DMBA随时间对启动概率的影响，并纳入了脉冲剂量的总和来表示TPA的重复局部应用及其对细胞分裂和细胞死亡的影响。我们将模型依次拟合到乳头瘤和癌的数据上，并间接确定模型参数对DMBA和TPA给药剂量的依赖性。化学诱导的表皮增生的发生是我们对乳头瘤数据拟合的一个基本假设。我们发现正常细胞和启动细胞死亡的开始相对于细胞分裂率的提高存在延迟。此外，模型参数对所施用的DMBA或TPA剂量呈非线性依赖。
