RADIOBIOLOGY OF LETHALITY, MUTATION, AND TRANSFORMATION

与DNA相互作用的电离辐射、阳光和化学物质 通常具有细胞毒性、诱变性和致癌性。细胞杀戮，是一种 癌症治疗中的终末效应。毒气的致命影响 辐射在诱变和肿瘤中也很重要 转化，因为这些端点需要细胞活性才能 被表达出来。在人体内，辐射已被确定为一种诱变剂 和致癌剂；一些化学品，包括光敏剂 像多环芳烃(PAH)这样的细胞，是 被认为具有相似性质的。出于这些原因，一项关于 辐射和遗传毒性化学物质的生物效应两者都相关 涉及公共健康和癌症治疗的问题。 该提案的每个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，它们背后的一个原因是 修复和细胞动力学在上述终点中的作用。例如, 在突变过程中，我们试图理解为什么突变的产量 随着剂量率的降低而减少；如果这种减少伴随着质量 产生的基因类型的转变；以及什么角色修复 能力在这样的转变中发挥着作用。与化学制剂有关的 可能与辐射一起存在于环境中，我们有 已确定一种多环芳烃会降低另一种多环芳烃的有效性。这个 这一观察结果的含义将首先得到跟进，因为 修复刺激的多环芳烃作用本身是重要的，其次 因为确定环境中的辐射和多环芳烃 互动要求理解每一个人的行为。 观察到G2/M期细胞对药物敏感性的增强。 杀戮、突变和转变将被大力推进，因为 有丝分裂在癌症生物学中的作用，因为这个细胞周期 敏感度窗口导致了对 低剂量、长时间的辐射。

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.