A major problem in the search for new cancer drug targets is that the drugs are often toxic to normal tissues and require high doses to kill tumor cells. Therefore cellular targets which appear to involve low dose responses to cancer therapy are especially interesting since they could selectively target normal tissues which are not targeted by the treatment and thus may be responsible for unpleasant side effects or may be amenable to exploitation in order to improve the therapeutic ratio. One such target, which is the subject of this review, is radiation-induced bystander effects [RIBE], which result in the observation of radiation like responses in cells which have not been irradiated. RIBE is a novel phenomenon which indicates that at low doses, cell signaling is more important than direct DNA damage. Historically, DNA has always been considered to be the target for radiation therapy. The growing realization that signaling is important opens up several important therapeutic strategies which will be discussed in this review. RIBE appears to be the result of a generalized stress response in tissues or cells which is expressed at the level of the tissue, organ or organism rather than at the level of the individual cell. The signals may be produced by all exposed cells, but the response may require a quorum of cells in order to be expressed. The major response involving low LET (x- or gamma-ray) radiation exposure discussed in the existing literature is a death response. This has many characteristics of apoptosis but may be detected in cell lines without p53 expression, although the death response is suppressed in many tumor cell lines. While a death response in unirradiated normal cells around a tumor might appear to be adverse, it can in fact be protective and remove damaged cells from the population. If harnessed correctly, it could lead to the development of new drugs aimed not at tissue destruction but at enabling homeostatic mechanisms to control tumor expansion. In this scenario, the level of harmful or beneficial response will be related to the background damage, carried by the cell population, and the genetic programme determining response to damage. This focus may be important when attempting to predict the consequences of mixed therapies involving radiation and other cytotoxic agents. In this review, our current knowledge of the mechanisms underlying the induction of bystander effects by ionizing radiation is reviewed, and the question of how bystander effects may be harnessed to produce a new generation of anti-cancer drugs aimed at stabilization of tissue homeostasis rather than tissue destruction is considered.

译文

:寻找新的癌症药物靶标的主要问题是该药物通常对正常组织有毒性,需要高剂量才能杀死肿瘤细胞。因此,细胞靶标似乎涉及对癌症治疗的低剂量反应,因此特别令人感兴趣,因为它们可以选择性地靶向未被治疗靶标的正常组织,因此可能引起令人不快的副作用,或者可能适合于剥削以改善治疗效果。治疗比率。辐射诱导的旁观者效应[RIBE]是本综述的主题之一,该效应导致在未辐射的细胞中观察到辐射样反应。 RIBE是一种新现象,表明在低剂量时,细胞信号传导比直接DNA损伤更为重要。从历史上看,DNA一直被认为是放射治疗的目标。人们日益认识到信号转导很重要,这开启了几种重要的治疗策略,本文将对此进行讨论。 RIBE似乎是组织或细胞中普遍的应激反应的结果,这种应激反应是在组织,器官或生物体的水平而不是单个细胞的水平表达的。信号可能由所有暴露的细胞产生,但响应可能需要一定数量的细胞才能表达。现有文献中讨论的涉及低LET(X射线或γ射线)辐射暴露的主要反应是死亡反应。这具有许多细胞凋亡特征,但尽管在许多肿瘤细胞系中死亡反应受到抑制,但在没有p53表达的细胞系中可能检测到。虽然在肿瘤周围未辐射的正常细胞中的死亡反应似乎是不利的,但实际上可以起到保护作用,并从群体中清除受损的细胞。如果利用得当,它可能会导致开发新药物,其目的不是破坏组织,而是使稳态机制能够控制肿瘤的扩展。在这种情况下,有害或有益反应的水平将与细胞群体所携带的背景损伤以及决定对损伤的反应的遗传程序有关。当试图预测涉及放射线和其他细胞毒剂的混合疗法的后果时,这一重点可能很重要。在这篇综述中,我们对电离辐射诱发旁观者效应的潜在机制的现有知识进行了综述,并探讨了如何利用旁观者效应来生产旨在稳定组织稳态而不是稳定组织的新一代抗癌药物的问题。考虑组织破坏。

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