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Human guinea pigs lend their courage to a golden era of cancer research

January 31, 2012


Powered by Guardian.co.ukThis article titled “Human guinea pigs lend their courage to a golden era of cancer research” was written by Sarah Boseley, for The Guardian on Monday 22nd August 2011 17.06 UTC

David Cox is a human guinea pig. He is also a man with a cancer for whom there are no more conventional options and who reasonably believes that, at 56, it is too early to call it a day. So Cox is only too happy to be one of the first people to try out a new drug, fresh from the laboratory. It could come with a load of unpleasant and unexpected side-effects. But it just might save his life.

Cox was diagnosed with mesothelioma three years ago – the result of working as an engineer in a boiler room full of asbestos, he believes. It’s a cancer that doesn’t usually have a good outcome. Like many people with advanced cancers, he has been on one trial after another. The last was a phase 2 – the trial of a drug that has been shown to be safe and have some effect in some people already. It seemed to work for six months, he said, and then it stopped.

“I went for the results of some scans on the Tuesday,” he said. “They told me the results and the options I had. Within three days they’d got me on this trial.” This is a phase 1 trial – a drug that has never been tested in humans before.

Cox didn’t think twice about it. “I had nothing to lose,” he said. When he was warned about possible side-effects, he remarked that the side-effects of not trying another drug were death. “You can’t get much worse than that,” he told his doctor.

Both his trials were run by the Royal Marsden, the world-renowned cancer hospital. The first was at its Chelsea site in west London. The latest is taking place at the other site in Sutton, south London, where the Marsden’s cancer doctors work in close collaboration with scientists at the cutting edge of drug discovery and genomics in the adjoining building belonging to the Institute of Cancer Research.

When Harpal Kumar, chief executive of Cancer Research UK talks of a “golden era” of cancer research, these are some of the scientists and clinicians who are making it happen.

The Marsden uniquely has a drug development unit integrated into the hospital, allowing patients who have run out of options on conventional drugs to join trials where they can get the latest experimental medicines. Where those drugs were once aimed at a single cancer – breast or prostate or lung – these days they are targeted at particular mutations in the cancer. The old drugs worked in only up to a third of patients because each cancer is different. The new drugs aim to have a higher success rate – in a much smaller group of patients tested for the particular mutation.

Sarah Stapleton who runs the unit, said: “The patients have exhausted standard therapies and they are offered the option of a voluntary trial of targeted therapy.”

For the volunteers with advanced cancers, these experimental drugs are their last chance, but Stapleton and the doctors have to be careful what they say to them. “We have to be very honest about what we’re offering to our patients here. There are lots of ethical considerations for a patient entering a trial. These drugs are at a very early stage. They might not help and there is a fairly low chance of helping and they could cause them more problems in terms of side-effects than they are experiencing at the moment.

“The key is explaining it is not a miracle drug. Sometimes that is what people can expect, but it is not what we have got.”

A trial will last two or three years. Patients have to stay in hospital usually for the first month – though they go home at weekends. “It is a huge time commitment because they have to come every week. We are going to take some time that they may not get back,” said Stapleton. But many are philosophical and altruistic. They join the trial in the hope that it may help others, even if not themselves.

The exciting times are when they see particularly good and sometimes even dramatic results. It happened with a drug to prevent cancer returning in women with the BRCA genes that predispose them to breast and ovarian cancer. “We saw very good response rates from that,” said Stapleton.

If Kumar from Cancer Research is right, the unit could be seeing more and more good outcomes. The Marsden is involved in the tumour testing trial that is about to start – supplying patients and also one of the three labs that will design and interpret panels of genetic tests. Somehow, they have to do it within a tight budget – the plan is to find a relatively cheap and feasible way to offer these molecular diagnostic tests across the whole of the NHS.

Dr David Gonzalez de Castro, head of the Marsden’s molecular diagnostics laboratory, said the first two years, involving 9,000 tumour samples from patients in seven hospitals, was a bid to find out whether it was possible. “The question is can the NHS provide molecular diagnosis for all cancer types routinely and can this be linked not only to patient outcome but also research?” he said.

Each genetic test for lung, colorectal or breast cancer costs around £150 to £200. Cancer Research’s plan is to carry out a panel of five or six tests for each cancer type for maybe £300. Gonzalez de Castro shakes his head in a sort of wonder. “It’s a challenge,” he says with a laugh. If all goes well, after two years the tests will begin to be offered in a further 10 to 20 centres. Then before long, the testing will be available throughout the NHS. The government is behind the scheme – it committed to developing and funding a national testing structure in the last cancer plan in January.

The testing is essential even now to find out whether, for instance, a woman with breast cancer is HER2 positive and needs Herceptin or a man with bowel cancer has a K-RAS gene mutation and should be given another cancer drug called cetuximab. Yet, according to a recent study by the Royal College of Pathologists, not everybody who needs a test is getting one.

But the new trial has a second and equally important and exciting purpose beyond securing equal access to tumour testing. All the patients who join will be asked if their results can be stored, along with details of their treatment and the outcomes. Cancer Research will be working with the cancer registries who already collect anonymised data on patients, said James Peach, its director of stratified medicine who is in charge of the project.

It is exciting, says Peach, because researchers will be able to find out what works, not just in terms of drugs but also surgery and radiotherapy, for people with cancers caused by specific genetic mutations. It opens the way to much better, more accurate treatment. “We will find out which drugs we should not be using and discover combinations we did not know about,” he said. There will also be significant benefits in surgery and radiotherapy, because scientists may discover which sorts of tumours are likely to be more aggressive than others.

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Asbestos Fibre Shape and Their Role in Mesothelioma

January 17, 2010

 

Biological toxicity relates to the shape of asbestos fibres. The mesothelial cell appears to be a predominant target of the asbestos fibre – consequently leading to the disease ‘mesothelioma’. Understanding how the shape, chemical composition, and surface structure interact to result in a harmful biological agent is paramount to the study of prospective harmful fibrous materials in the future.

 

Amphibole needle-like fibres

Amphibole needle-like fibres

 

The long thin shape of an asbestos fibre may enhance its entry deep into the lung. Following inhalation, fibres of several micrometres in length can enter the respiratory airways, whereas other particles larger than 5 micrometres could not penetrate. Once in the lung – the long fibres may not be cleared by the bodies natural defence mechanism such as ‘macrophage clearance’ macrophages generally mop up foreign bodies, but scientists have discovered that certain stubborn asbestos fibres (such as needle-like shape) cannot be cleared by macrophages. These fibres may more easily migrate along tissue planes, lymphatic channels and make their way into the pleural space.


 Animal studies show certain asbestos shapes induce mesothelioma

Asbestos shape has been considered to be a primary characteristic determining asbestos toxicity, i.e. ‘Stanton et al’ 1977, recognised size and shape as a major factor in inducing mesothelioma in animal studies. For instance – other materials with the same shape but different chemical composition share the ability to produce mesothelioma. Also – studies of asbestos fibres with a long thin shape were shown to be able to induce chromosomal abnormalities.

 Studies of human epidemiological trials and lung mineral toxicity conclude that ‘amphibole’ asbestos fibres (crocidolite and amosite) are more predominantly associated with mesothelioma than chrysotile fibres. Amphibole fibres contain more iron; possess a higher aspect ratio, and their needle-like shape is more brittle.

 Conclusion

Asbestos shapes have chemical differences. Physical properties are important in determining the toxicity of the fibre, predominantly – the fibres shape, surface reactivity and chemical composition.

Asbestos and Mesothelioma

May 1, 2009

Approximately 9 out of 10 patients diagnosed with mesothelioma have a history of exposure to asbestos.

What is asbestos?

Asbestos is a natural rock mineral, mined or quarried and used commercially since the 18th century. It was discovered for its excellent fire retardant and insulation properties. It consists of strong pliable fibres that can be separated into thread like strands and spun or woven to produce several types of bonded material for many uses, predominantly in the building and construction industries between 1900’s – mid 1970’s.

asbestos-blue

 

 

 

 

 

 

 

 

 

 How  mesothelioma develops

As a rule most fibres and irritants that are inhaled are cleared through the natural body’s defence mechanism of coughing which forces them back up to the throat in a layer of mucus, the mucus is then either spat out, or swallowed, and makes it way out of the body naturally.

The theory is though – is that some inhaled asbestos fibres (particularly smaller strands) are not cleared from the lungs and have the ability to translocate to the lungs into other tissues such the alveolar sacs the tiny pockets where the fibres may remain indefinitely. Asbestos fibres that enter the alveoli can undergo a series of fates. I.e. some of the fibres may penetrate the alveolar wall and enter into the interstitial fluid thus posing of risk of them being cleared by the natural process of the lymphatic system and deposited in the perihilar lymph nodes. Other fibres particularly amphiboles (blue and brown asbestos fibres) may penetrate the lung parenchyma and enter the pleural or peritoneal space.

Amphibole fibres are considered to be more of a health hazard as they are less degradable than other asbestos fibres such as chrysotile fibres (white asbestos) and can stay in the lungs for much longer. Studies have concluded that smaller quantities of chrysotile fibres have been found in lung tissue than amphibole fibres and amphibole fibres cannot easily be degraded by macrophages (white blood cells that engulf and destroy foreign material). However – fibre size is believed to play a crucial role in determining the risk of a particular asbestos-related disease, and the health safety issues surrounding white asbestos still poses as a threat as medical evidence proves its significance in the development of mesothelioma.

Biopsy below shows a strand of asbestos fibre in a human lung.

asbestos-4

 

 

 

 

 

 

 

 

 

Asbestos particles are capable of stimulating chronic inflammatory responses in the pleura, inducing an array of cellular responses, i.e. interfering with mesothelial cells, damaging DNA that controls cell division, thus promoting malignant cell division – resulting in asbestos-induced tumours – mesothelioma.

 120_150_lung_mesothelioma1