RADIOBIOLOGY OF LETHALITY, MUTATION, AND TRANSFORMATION

电离辐射、阳光和与DNA相互作用的化学物质， 通常具有细胞毒性、致突变性和致癌性。 细胞杀伤，是一种 在癌症治疗中的重要终末效应。 的致死效应 辐射在诱变和肿瘤中也很重要 因为这些终点需要细胞活力， 表达出来。 在人类中，辐射已被确定为诱变剂 和致癌剂;一些化学品，包括光敏剂 像多环芳烃（PAH）的细胞， 被认为具有相似的属性。 由于这些原因， 辐射和遗传毒性化学品的生物效应与 公共卫生和癌症治疗的问题。 本提案的每一部分都针对基本的放射生物学和 哺乳动物细胞中的分子过程。 尽管如此，一个潜在的问题是， 修复和细胞动力学在上述终点中的作用。 比如说， 在诱变中，我们试图理解为什么突变的产量 随剂量率降低;如果这种降低伴随着定性 产生的基因型的变化;以及修复的作用 能力在这种转变中发挥作用。 与化学制剂有关， 可能与辐射一起沿着存在于环境中， 确定一种PAH可以降低另一种PAH的有效性。 的 将首先跟踪这一观察结果的影响，因为 修复刺激的PAH作用本身就很重要，其次 因为确定环境中的辐射和多环芳烃 相互作用要求理解每一方的行动。 最后，观察到G2-/M-期细胞对 杀戮、变异和转化将被大力追求， 有丝分裂在癌症生物学中的作用， 灵敏度窗口导致重要的预测的影响 低剂量的长期辐射

Ionizing radiation, sunlight, and chemicals that interact with DNA are generally cytotoxic, mutagenic, and oncogenic. Cell killing, is an essential end effect in the therapy of cancer. The lethal effects of radiation are radiation are also important in mutagenesis and neoplastic transformation because cell viability is required for these endpoints to be expressed. In people, radiation has been established as a mutagenic and oncogenic agent; a number of chemicals, including photosensitizers of cells like the polycyclic aromatic hydrocarbons (PAH's), are recognized to have similar properties. For these reasons, a study of the biological effects of radiation and genotoxic chemicals is relevant both to issues of public health and the treatment of cancer. Each part of this proposal is directed at basic radiobiological and molecular processes in mammalian cells. Still, an underlying them is the roles of repair and cell kinetics in the endpoints above. For example, in mutagenesis, we seek to understand why the yield of mutations decreases with dose rate; if this decrease is accompanied by qualitative shifts in the genotypes that are produced; and what role repair competence plays in such shifts. In connection with chemical agents that may be present in the environment along with radiation, we have determined that one PAH can reduce the effectiveness of another. The implications of this observation will be followed up first because repair-stimulated PAH action is important in its own right, and second because a determination of how radiation and PAH's in the environment interact requires that the action of each should be understood. Lastly, the observation of enhanced sensitivity of G2-/M-phase cells to killing, mutation, and transformation will be vigorously pursued because of the role of mitosis in cancer biology, and because this cell-cycle window of sensitivity leads to important predictions of the effects of low, protracted doses of radiation.