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Colchicum autumnale

The autumn crocus, Colchicum autumnale, source of colchicine

Today’s headlines bring us news of a ‘cancer chemotherapy breakthrough’ using a chemical derived from colchicine, found in crocuses.

According to the news coverage, this ‘new drug’ could ‘bring hope to millions’, ‘dramatically reduce side-effects’, and ‘kill tumours in one treatment’, because it acts as a ‘smart-bomb’ and only affects tumour cells. This sounds tremendously exciting, but the truth is that this is a long way from being a drug that could be used to treat patients.

So far, the chemical has only been tested in mice, and there are many more tests that need to be done before it makes it to clinical trials.

Let’s unpick the science behind the story, find out where it came from, and see where it sits in the broader context of cancer research.

Where did the story come from?

The headlines come from a talk due to be given today at the 2011 British Science Festival, which is this year in Bradford. The festival is a scientific outreach event organised by the British Science Association. The talk, by researchers from the Universityof Bradford, appears to be based on peer-reviewed work they published in July 2010.

The talk was press released by the University of Bradford press office in advance of the talk.

As far as we’re aware, the team haven’t published any new results since their 2010 paper.

What is colchicine?

Colchicine is found in crocuses and is used to treat gout, but is extremely poisonous. It has also been investigated as an anti-cancer agent.

The Bradford researchers, led by Professor Laurence Patterson, have been trying to tweak the colchicine molecule to make it less toxic, thus making it more suitable to investigate as an anti-cancer drug.

How could colchicine kill cancer cells?

Colchicine severely damages a cell’s internal scaffolding by blocking the action of a protein called tubulin. Because tubulin plays a vital role in helping cells divide in two, colchicine effectively stops cell division in its tracks – an important trait for any potential cancer drug.

Unfortunately, colchicine doesn’t just attack cancer cells – it will stop healthy cells from dividing too. As a result, colchicine is regarded as a poison, with similar effects on the body to arsenic.

One way round this problem, as Professor Patterson and his team have been investigating, would be to deliver colchicine directly to a tumour, and prevent it escaping around the rest of the body.

Targeting colchicine to cancer cells

In order to target colchicine directly to tumours, the researchers enlisted the help of a family of proteins called matrix metalloproteases, which are often produced in large amounts by many cancers.

MMPs are powerful enzymes that can dissolve the gelatinous gloop that surrounds our cells, known as the extracellular matrix. Cancer cells use it to clear a path for new blood vessels to grow towards them (during a process called angiogenesis), providing essential oxygen and nutrients.

To exploit this, the researchers used some clever chemistry to attach long molecular ‘tails’ to individual colchicine molecules. They found that this modified colchicine, called ICT2588, was less toxic to healthy cells, but if the ‘tail’ was hacked off by MMP enzymes then it was activated into the potent cell-killing form of the drug.

The idea is that in healthy tissues (which don’t have much MMP), the modified colchicine molecule is essentially harmless. But when it arrives in areas with lots of MMP – namely tumours – the tail is cut off and the drug is activated.

In turn, this activated colchicine would then poison anything in the vicinity, including any new-growing blood vessels. The overall effect would be to stop the cancer cells from growing, and starve the tumour of blood and oxygen.

That’s the theory. So far the researchers have tested their modified colchicine in mice carrying a variety of human tumours, including bowel, breast and lung cancers, and say they’ve cured about half the mice they’ve studied, in trials lasting around 2 months each.

But let’s be clear – this is a long way from curing human cancers.

How important is this research?

The researchers’ results so far are impressive, but they’re just one of several hundreds of similar intricate approaches taken to tackle cancer by researchers around the globe, which are generally referred to as ‘enzyme-prodrug therapy’, and involve activating a harmless form of a drug near or in a tumour.

For example, scientists we’ve funded have worked on more complex variations of the technique, where rather than relying on an inherent property of tumour cells (in this case, matrix metalloproteases), the cancer cells are artificially engineered to activate the prodrug – you can see press releases from our archives herehere, and here.

Overall it’s fair to say that this kind of approach is still at a relatively early stage, although the Bradford results are certainly impressive, and their beauty is in their relative simplicity.

And so to the headlines

The media reporting of this story has, in general, failed to emphasise the early nature of this work. Many questions remain to be answered.

For example, only half the mice in the studies were cured. Why weren’t the other half? How would this scale up to studies in people?

Several newspapers talked of “side effect-free drugs” or “dramatically reduced side effects”, but no effective drug is truly side effect-free – not even the new generation of targeted therapies that are currently emerging from clinical trials. The early results from the Bradford team tell us little about any potential human side effects of the modified drug, or even whether it would be safe to give to patients.

Another report initially got the name of the molecule wrong, calling it ‘coltrazine’, and claimed that it was already used to treat cancer (although this has since been corrected).

Finally, a common feature was the judicious use of the word ‘could’ throughout many of the articles, particularly in the headlines, allowing reporters to make claims that undoubtedly raised hopes of many people currently undergoing treatment for cancer.

In summary, this research is a small – although intriguing – step forward in the laboratory, but there are many hurdles still to clear for the Bradford team before their findings can be used to help the cancer patients of the future.

Cancer survival rates are rising, thanks to improvements in cancer detection and treatment brought by research. But while scientists need to keep the public informed and engaged with the progress they’re making, we all need to take care not to raise expectation and hope unduly.

Henry


Reference:

Atkinson, J., Falconer, R., Edwards, D., Pennington, C., Siller, C., Shnyder, S., Bibby, M., Patterson, L., Loadman, P., & Gill, J. (2010). Development of a Novel Tumor-Targeted Vascular Disrupting Agent Activated by Membrane-Type Matrix Metalloproteinases Cancer Research, 70 (17), 6902-6912 DOI: 10.1158/0008-5472.CAN-10-1440

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Comments

Henry Scowcroft September 13, 2011

John – you’re absolutely right, we’ve mixed up our matrix metalloproteases. It seems that there are several mentions of MMP1 in the coverage of this story – The Press Association and the Guardian both mention it – but it’s nowhere in the press release and the paper from last year focuses on MT1-MMP as you mention. We can only suppose that the researchers talked about MMP-1 in a press conference prior to the stories’ publication, and this crept in while we were writing our piece. Either way we’ve amended our post. Thanks for pointing this out!

Henry
Cancer Research UK

john bradley September 13, 2011

Henry, your article mentions MMP1 yet the reference by Patterson actually deals with MT1-MMP which is also know as MMP14. Am I missing something?

Henry Scowcroft September 13, 2011

Harry – thanks for your comment. We’re certainly agree that the results from the lab are promising, and we look forward to seeing how the researchers progress. But we felt it was important to point out that much of the media coverage didn’t properly place this research in context or add enough caveats – essentially we’re talking about the difference between saying “researchers are working on an exciting new strategy that may lead to a cancer drug”, and saying “researchers have discovered a new cancer drug”. But just to stress again – we’re not trying to pour cold water on the research itself, and yes you’re right, we did help fund part of it.

It’s also worth mentioning that when stories like this appear in the media, we frequently receive calls and emails from patients asking where they can get this treatment, or offering to take part in trials. Telling them that there aren’t any trials, and that the ‘cancer drug’ reported in the media isn’t technically a drug yet, can be distressing for all concerned.

And we share your hope for the future – for this particular work, and for cancer research in general – it’s this hope that keeps us coming to work every day.

Henry
Cancer Research UK

Harry September 12, 2011

I was very excited about this research and so went and read the original paper. (Something Henry should have done before his blog!).
The data looked convincing in my eyes, and actually caused effects against all of the tumours (curing half the mice after a single dose).
I agree this is only in mice, but it is very promising and isn’t really that far away from humans. As in several of the press releases, this could be trialled within 2 years. So we should try and keep our hopes up for treatments like this! and not try and discredit them.

It is also worth mentioning that Cancer Research UK are acknowledged for supporting this project, so the science must be good!