CYCLE-DEPENDENT MECHANISMS OF CHEMICAL CARCINOGENESIS

有证据表明，恶性转化与细胞 增殖，并特别依赖于DNA复制。 因此，遗传物质受到的结构性损伤， 化学致癌物是必要的，但不足以启动 化学致癌的过程。 只有与随后的 DNA复制的发生，这些改变尚未消除 通过无错修复可以转化为实际的变换 病变一个单元格被一个 化学致癌物不仅与DNA的频率有关， 损伤（由致癌物剂量和DNA修复调节）， DNA序列（原癌基因？），而且，对于分子 DNA结构改变的复制机制。 我们的一 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， 基因突变过程的特征。 这可能 解释了S相位依赖的转变和突变 在许多系统中观察到。 对恶性肿瘤的易感性更高 当在GI晚期或GI早期处理细胞时观察到转化 与细胞周期中的其他时间点相比，S期可能是 由于特定的细胞基因在或接近于 他们的复制。或者，在此期间较低的修复率 S期也会增加固定的可能性， 基因改变，独立于复制的时间， 受损的DNA序列在这个项目中，我们将汇集我们的 个人的专业知识，以获得坚实的实验证据， 支持或反驳这些假设。 我们提出这个方案 项目补助金，以汇集所述的目标和努力 上述个人赠款分为三个主要研究领域： 1)恶变的现象学表征 在三个不同的模型系统中，即，C3 H 10 T1/2和人 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。 在每一个领域的主要重点将是对细胞周期 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.