The Drosophila adult intestine as a model for radiation tolerance and resistance

放射治疗是癌症治疗中必不可少的工具。它的成本效益非常高，占40%的治愈率，其中化疗占11%，外科手术占49%。这种治疗有效的原因是，辐射对所有细胞都是有毒的，但肿瘤细胞通常对辐射更敏感。(总的来说，同样的原则也适用于化疗。)治疗的目的是在对患者的健康组织造成太大损害之前杀死肿瘤。因此，放射治疗可能会在治疗后不久和长期内产生严重的副作用。此外，一些肿瘤对放射治疗具有很强的抵抗力。肿瘤耐药性和患者毒性的结合是放射治疗成功应用的一个重要限制。为了克服这个限制，我们需要了解肿瘤耐药性和健康组织敏感性的原因是什么。例如，我们知道，开启某些基因的肿瘤是不受辐射影响的；人们可以设计一种药物，阻止其中一种基因发挥作用，从而提高这类肿瘤对放射治疗的敏感性。另一方面，我们需要了解辐射是如何导致健康组织功能失调的。例如，我们知道特定类型的细胞对辐射特别敏感；确定使它们敏感的因素可以帮助设计预防或纠正放射治疗副作用的治疗方法。这一领域的研究非常活跃，已被国家癌症研究所确定为英国的优先事项。这种类型的研究在某种程度上是使用培养皿中的细胞进行的。然而，在医学实践取得任何进展之前，对整个动物(主要是小鼠和大鼠)的研究是必要的，因为用培养细胞所做的观察并不总是与真实组织中发生的事情相关。为了取代小鼠和大鼠的使用，我们希望建立果蝇作为一种替代物种来研究整个动物的辐射敏感性。果蝇被用于生物学的许多领域的研究，因为它们很便宜，而且有很多实验工具可以用来与它们合作。此外，在肿瘤中提供对放射治疗的抵抗的基因在果蝇中也是相同的，因此在果蝇中获得的关于这些基因功能的知识可能适用于人类。我们将重点放在苍蝇肠道，因为许多癌症患者由于放射治疗而有长期的肠道副作用。为了测试苍蝇肠道是否可以成为一个有用的研究系统来改进放射治疗，以取代啮齿动物，我们将寻求建立：(1)人类放射治疗的副作用是否也反映在苍蝇肠道中，(2)我们是否可以识别出提高健康组织耐受性的基因和药物，以及(3)我们是否可以在苍蝇肠道内创建肿瘤样细胞，当它们启动肿瘤的放射抗性基因时，它们显示出更高的辐射抗性。如果我们成功地建立了这些观察，这将表明苍蝇肠道可以有效地用于替代小鼠和大鼠的放射治疗研究，我们将向从事这一领域的科学家宣传我们的发现，以鼓励这种替代。

Radiation therapy is an essential tool in the treatment of cancer. It is very cost effective, and responsible for 40% of cures, with chemotherapy contributing to 11% and surgery to 49% of cures. The reason why this treatment works is that radiation is toxic for all cells, but tumour cells are generally more sensitive to radiation. (Broadly speaking, the same principle applies to chemotherapy.) Treatment is applied with the aim of killing the tumour before causing too much damage in the healthy tissue of the patient. Therefore, radiotherapy can have serious side effects both shortly after treatment and in the longer term. Moreover, some tumours turn out to be very resistant to radiotherapy. The combination of this tumour resistance and the toxicity for the patient is an important limitation to the successful application of radiotherapy.To overcome this limitation, we need to understand what are the causes of resistance in the tumours and of sensitivity in the healthy tissue. For instance, we know that tumours that switch on certain genes are protected from radiation; one could design a drug that prevents one of these genes from functioning and so improve the sensitivity of that type of tumours to radiotherapy. On the other hand, we need to understand how radiation causes malfunctioning in the healthy tissue. For instance, we know that specific cell types are particularly sensitive to radiation; identifying the factors that make them sensitive could help to design preventive or corrective treatments for the side effects of radiotherapy.Research in this area is very active and has been identified as a priority for the UK by the National Cancer Research Institute. This type of research is conducted to some extent using cells in culture dishes. However, before any progress in medical practice takes place, research in whole animals (mostly mice and rats) is necessary, as it is not always the case that observations made with cultured cells are relevant to what happens in real tissues. With the aim of replacing the use of mice and rats, we want to establish the fruit fly as an alternative species where to study radiation sensitivity in whole animals.Fruit flies are used for research in many areas of biology, as they are cheap and there are many experimental tools available to work with them. Moreover, the genes that provide resistance to radiotherapy in tumours have an equivalent in flies, and therefore knowledge obtained in flies about the functioning of these genes could have applicability in humans. We will focus on the fly intestine because many cancer patients have long-term intestinal side effects due to radiotherapy.To test whether the fly intestine can be a useful research system to improve radiotherapy in substitution of rodents, we will seek to establish:(1) whether the side effects of radiotherapy in humans are also mirrored in the fly intestine,(2) whether we can identify genes and drugs that improve the tolerance of the healthy tissue, and(3) whether we can create tumour-like cells inside the fly intestine that show increased radio resistance when they switch on the tumour radio resistance genes.If we establish these observations successfully, this will indicate that the fly intestine can be used effectively in radiotherapy research in substitution of mice and rats, and we will advertise our findings to scientists working in this field, to encourage such replacement.