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

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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.