CYCLE-DEPENDENT MECHANISMS OF CHEMICAL CARCINOGENESIS

有证据表明恶性转化与细胞有关 增殖，并特别依赖于DNA复制。 因此，对遗传物质造成的结构破坏 化学致癌物是必要的，但不足以引发 化学致癌化学致癌的过程仅适用于后续的 DNA复制的发生，那些尚未消除的改变 通过无错误的修复可以转化为实际的转换 损伤。单元格被转换为 化学致癌物不仅与DNA的频率有关 特定的损伤(受致癌物剂量和DNA修复的调节) DNA序列(原癌基因？)，但也是分子 结构改变的DNA的复制机制。我们的一个人 主要前提是肿瘤转化的过程是 基因决定并分享重要的机制 特征与基因突变的过程。这可能会 S相变突变相依关系的解释 在许多系统中观察到的。对恶性疾病的易感性更高 胃肠道晚期或早期处理细胞时观察到的转化 S期与细胞周期中的其他时点相比，可能是 由于特定细胞基因在或接近该时间的损伤 它们的复制。或者，更低的维修率在 S阶段也会增加注视一个人的概率 基因改变，与复制的时间无关 受损的DNA序列。在本计划项目中，我们将汇集我们的 获得坚实的实验证据的个人专业知识 支持或驳斥这些假说。我们提出了这个计划 将所述目标和努力结合在一起的项目赠款 以上为三个主要研究领域的个人拨款： 1)恶变的现象学特征 在三个不同的模型系统中，即C3H10T1/2和人类 体外成纤维细胞和体内肝细胞；2)机制 DNA复制和修复的研究；3)表征 转化和突变的遗传和分子机制。 在这些领域中的每一个领域，主要的重点将是细胞周期 上述不同终点的变化。

There is evidence that malignant transformation is related to cell proliferation and is specifically dependent on DNA replication. Thus, the structural damage inflicted upon the genetic material by chemical carcinogens is necessary but not sufficient to initiate the process of chemical carcinogenesis. Only with the subsequent occurrence of DNA replication, those alterations not yet eliminated by error-free repair could be converted into actual transforming lesions. The probability that a cell will be transformed by a chemical carcinogen is related not only to the frequency of DNA damage (modulated by carcinogen dose and DNA repair) in specific DNA sequences (proto-oncogenes?), but also, to the molecular mechanisms of replication of structurally altered DNA. One of our main premises is that the process of neoplastic transformation is genetically determined and shares important mechanistic characteristics with the process of gene mutation. This could explain the S phase dependence of transformation and mutation observed in many systems. The higher susceptibility to malignant transformation observed when cells are treated in late GI or early S phase, as compared to other points in the cell cycle, is probably due to damage to specific cellular genes at or close to the time of their replication. Alternatively, a lower rate of repair during the S phase would also increase the probability of fixation of a genetic alteration, independently of the timing of replication of the damaged DNA sequence. In this Program Project we will pool our individual expertise to obtain solid experimental evidence to support or refute these hypotheses. We propose this Program Project Grant to bring together the goals and efforts described above for the individual grants into three major research areas: 1) phenomenological characterization of malignant transformation in three distinct model systems, i.e., C3H 10T1/2 and human fibroblasts in vitro and liver cells in vivo; 2) mechanistic studies of DNA replication and repair; 3) characterization of genetic and molecular mechanisms for transformation and mutations. In each of these areas the main emphasis will be on the cell-cycle variations of the different end-points mentioned above.