There are microscopic communities living inside all of us.
These communities are made up of bacteria that happily live on or inside our bodies. Each community is called a ‘microbiome’, and they orchestrate a carefully balanced two-way relationship. We give them a place to live, and they help keep certain tissues healthy.
But last week, a team of US scientists offered a solution to one situation where these microbes aren’t so helpful.
But, most importantly, there’s also a potential way to limit these side-effects, using drugs that are already in development. And their findings reveal the targets of these drugs in unprecedented detail.
The study focuses on a chemotherapy drug called irinotecan (Campto), which is used to treat bowel cancer.
Sadly, as with any treatment, it has side-effects. And diarrhoea is a common one, affecting more than 1 in every 10 people.
For some this can be severe, meaning they may need additional treatment to combat it. So finding new ways to prevent these side-effects is really important, especially in cases where the diarrhoea may make the chemotherapy less effective.
“Controlling treatment-related side-effects is a real challenge,” explains Dr Miguel Ferreira, whose research at the Institute of Cancer Research in London focuses on understanding the side-effects caused by radiotherapy.
“Side-effects can limit the success of cancer treatment, whether this is chemotherapy, radiotherapy or surgery,” he says. “And side-effects from chemotherapy and radiotherapy are commonly seen in the bowel as these treatments target rapidly-growing cells, of which the bowel has many.”
And according to Miguel, the bacteria in the bowel have become the focus of a lot of research into how they might contribute to these side-effects.
So where does the latest study come in?
Processing the evidence
A key player in this story is our liver, an organ capable of carrying out a huge array of reactions to break down chemicals or render them easier to excrete from the body.
How does irinotecan work?
The drug switches off an enzyme called topoisomerase I found inside cells.
Cells needs this enzyme to divide and grow into two new cells. If this enzyme is blocked by irinotecan, then the cell’s DNA gets tangled up and the cancer cells can’t divide and grow.
Read more about irinotecan on our website.
Irinotecan gets chemically modified in our liver before being sent to our intestines, where it leaves the body in our faeces. During this modification process the liver attaches a sugar molecule – called glucuronic acid – to irinotecan, which inactivates it and makes it safe for removal from the body.
But the bacteria in our guts can produce specialised proteins called enzymes that scavenge for this sugar molecule so the bacteria can use it as an energy source.
In the case of irinotecan, these bacterial enzymes clip the inactivating sugar molecule off again, producing a new toxic form of the drug.
And it’s this toxic by-product that causes diarrhoea.
The US team’s previous research – led by Professor Matthew Redinbo – has pinpointed the bacterial enzymes involved, called β-glucuronidases. And this discovery has led to some experimental drugs able to prevent irinotecan-induced diarrhoea in mice.
But there are lots of different bacteria that call the gut home, each producing their own form of β-glucuronidase. And the drugs in the team’s previous research were developed to target the enzyme of just one type of bacteria, which aren’t particularly common in the human gut.
The new study takes things a step closer to human trials. The US team turned their focus to several, more common bacteria. And through a series of careful experiments, they have revealed some important new findings.
First they carefully reconstructed the shapes of the enzymes using a technique called X-ray crystallography.
Then, once they had an idea of what the proteins look like, they were able to ask how the experimental drugs might stick to the enzymes and switch them off. And according to Miguel, this is where the team uncovered some important new information.
This is very important for the design of future trials and the potential use of these drugs in the clinic for reducing these side-effects
– Dr Miguel Ferreira
“They found that the drugs stick to some of the enzymes better than others,” he says. “And this means that the different bacteria will react to the drugs in different ways.”
This is an important discovery, and should help the researchers fine-tune the drugs to make them as effective as possible.
Crucially, the team also went on to test how different versions of the experimental drugs might affect irinotecan and its side-effects in mice.
They found that while the β-glucuronidase blockers successfully reduced diarrhoea in mice treated with irinotecan, the drugs didn’t change the levels of active irinotecan in the bloodstream. This is a crucial early indicator that targeting these bacteria wouldn’t affect the effectiveness of irinotecan in targeting cancer. And the findings could lead to the next stage of testing these drugs in clinical trials.
“This is very important for the design of future trials and the potential use of these drugs in the clinic for reducing these side-effects,” says Miguel.
“It’s early days, but this really is a brilliant piece of science.”
More than just treatments
Studies like this are a great example of how scientists across the globe are doing more than just designing the next generation of treatments.
We know that side-effects are a big deal for patients and their doctors. And regardless of whether we’re talking about futuristic experimental treatments or long-standing chemotherapy drugs, understanding the potential side-effects – and finding ways to manage them – forms a crucial part of research.
Much like the bacteria that help us stay healthy, the experience of cancer treatment is one that is shared by the patient, their family and the people who treat them.
By viewing this as one working organism, we are in the best place to ensure cancer treatments are as safe and effective as patients need them to be.
Wallace, B., et al. (2015). Structure and Inhibition of Microbiome β-Glucuronidases Essential to the Alleviation of Cancer Drug Toxicity Chemistry & Biology DOI: 10.1016/j.chembiol.2015.08.005