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​Improving the effects of radiotherapy using anti-malaria drugs









Radiotherapy – what is it?
Radiotherapy means using radiation to treat cancer. Radiation works by damaging DNA in cells which causes cells to die and therefore, over time radiation can be used to kill cancer cells and lead to the shrinking of tumours (1). Radiation is a local treatment because it is aimed at a certain area of the body that contains the tumour- therefore it is thought to have reduced side effects but it also means it is not useful for treating cancer that has spread to many distant areas of the body. Radiotherapy is used to shrink tumours, or make them disappear completely – both alone and in combination with chemotherapy. It can also be used before surgery to shrink the tumour and after surgery to prevent reoccurance of the tumour (1). It is a widely used treatment in cancer patients but like many other treatments it needs to be optimized to make it a more successful treatment against cancer. 

The problems with radiotherapy
Radiotherapy is a common treatment for cancer tumours however, often tumours can become ‘radioresistant’. This term refers to tumours that are less sensitive to radiation therefore some cells in the tumour may not be killed by the radiotherapy. This can lead to the more resistant cells being left behind and so the tumour will not be completely removed and continue to grow back. This is clearly a limiting factor in how effective radiotherapy can be and so research into making tumours more radiosensitive is important (2). Oxygen is also thought to reduce the ability of cancer cells to repair themselves after radiotherapy, so cancer cells with low levels of oxygen can also repair themselves more easily after radiation – adding to the resistance (3).

How does radiotherapy work?
Radiotherapy often works by using oxygen, it can either create free radicals out of oxygen to react with and damage DNA or the radiotherapy can directly change the DNA in cells itself and make things called ‘radiation induced DNA radicals’ (2). Radiation does this by removing electrons from atoms to leave behind ions that are highly reactive (1). In both mechanisms, the DNA becomes damaged causing the tumour cells to die. However, in tumours there are often areas of hypoxia. Hypoxia is a word used to describe areas of low oxygen, and this can be caused by a number of reasons. It may simply be because the tumour is so large that inside the centre of the tumour there is less blood supply and therefore less oxygen. But it can also be caused by things like anaemia and smoking (2). 
 






Hypoxic cells are thought to limit the sensitivity of tumours to radiation, and only the well oxygenated cells are killed, leaving the resistant cells behind. After radiation, it is thought the proportion of hypoxic cells will return back to normal as the cells are re-oxygenated (2). However, hypoxia still aids the resistance and growth of the tumour whilst using radiotherapy. 
So in the illustration above, the light orange region would not be killed by radiation as it is hypoxic. After the radiation kills the beige, oxygenated, region the light orange region would begin to grow again with access to more oxygen. Alongside this, the dark orange region would also gain more access to oxygen, allowing this area of the tumour to recover and also start to grow again. 


Using anti-malaria drugs to sensitize cells to radiotherapy 
A study was carried out by the cancer research UK radiation centre to look at the effect of a drug called atovaquone on tumours that have low oxygen levels. This study showed that this anti-malaria drug, atovaquone, slows down the rate that cancer cells use oxygen by targeting mitochondria. Mitochondria are small organelles in cells that use oxygen to make energy – slowing down this process allows more oxygen to be available in cells. So essentially this drug reverses the low-oxygen levels in tumours by slowing down the use of oxygen (3).
The drug was shown to work in a range of cancers including lung, bowel, brain, head and neck cancer. Therefore this is an exciting avenue of research. The use of this drug could be promising to increase the sensitivity of hypoxic cells to radiation and it is also fairly cheap to buy (3). 


Other methods to sensitize tumours to radiation
Aside from this recent finding, many other methods are being researched to try and increase the sensitivity of tumours to radiotherapy. One of these methods is called hyperbaric oxygen therapy – this is a procedure where you breathe pure oxygen in a sealed chamber which helps to increase the sensitivity of cells to radiation by increasing the levels of oxygen in your body. Radiosensitizers are also being researched – similar to the use of atovaquone however, preferably ones that will only target tumour cells to try and reduce the side effects of radiotherapy (1). 

So what does this all mean?
Essentially this is an exciting prospect in terms of improving the effectiveness of current cancer treatments. A big problem with current cancer treatments is both the resistance of cancer tumours to these treatments and the lack of targetted treatments. So for us, this is a step in the right direction to making radiotherapy a more successful treatment against hard to treat tumours. However, this study was only completed in mice (3) and therefore there is a long way to go until we know if this will be safe and effective for use in humans. 

Jemma Campbell 
Co-Founder and Secretary of Jills Fundraising Journey​

References:
1 – American cancer society, 2014. The Science Behind Radiation Therapy [Online]. Available from: http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/radiation/radiationtherapyprinciples/ [Accessed: 26/07/2016]
2 – Willers, H., Azzoli, C.G., Santivasi, W.L., Xia, F., 2013. Basic mechanisms of therapeutic resistance to radiation and chemotherapy in lung cancer, Cancer journal. 19(3), 200-207.
3 – Cancer Research UK, 2016. Anti-malaria drug could make tumours easier to treat [Online]. Available from: http://www.cancerresearchuk.org/about-us/cancer-news/press-release/2016-07-25-anti-malaria-drug-could-make-tumours-easier-to-treat [Accessed 26/07/16]

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