Cheap malaria drug could treat colorectal cancer effectively too, say experts

Artemisinin is isolated from the plant Artemisia annua also known as sweet wormwood. Credit: Image courtesy of University of St George's London

Medical experts say a common malaria drug could have a significant impact on colorectal cancer providing a cheap adjunct to current expensive chemotherapy.

A pilot study by researchers at St George's, University of London, has found the drug artesunate, which is a widely used anti-malaria medicine, had a promising effect on reducing the multiplication of tumour cells in colorectal cancer patients who were already going to have their cancer surgically removed.

Colorectal cancer (CRC) makes up about 10 percent of the annual 746,000 global cancer cases in men and 614,000 cases in women.

In the UK, 110 new cases are diagnosed daily, with older patients particularly at risk of death. Prognosis even with the best available treatments does not increase disease free or overall survival beyond 60 percent, five years after diagnosis.

Professor Sanjeev Krishna, an infectious disease expert at St George's who jointly-led the study, said: "There is therefore a continuing and urgent need to develop new, cheap, orally effective and safe colorectal cancer treatments.

"Our approach in this study was to take a close look at an existing drug that already had some anticancer properties in experimental settings, and to assess its safety and efficacy in patients.

"The results have been more than encouraging and can offer hopes of finding effective treatment options that are cheaper in the future."

"Larger clinical studies with artesunate that aim to provide well tolerated and convenient anticancer regimens should be implemented with urgency, and may provide an intervention where none is currently available, as well as synergistic benefits with current treatment regimens," added Professor Devinder Kumar, a leading expert in colorectal cancer at St George's and joint-lead of this study.

For most patients globally, access to advanced treatments is difficult as they are too expensive to be widely available, or associated with significant morbidity thereby further compromising their survival.

"In the St George's study, patients were examined and then were given either the anti-malaria drug artesunate or a placebo. After 42 months following surgery, there were six recurrences of cancer in the placebo group (of 12 patients) and one recurrence in an artesunate recipient (of 10 patients).The survival beyond two years in the artesunate group was estimated at 91% whilst surviving the first recurrence of cancer in the placebo group was only 57%.

This is the first randomized, double blind study to test the anti-CRC properties of oral artesunate. The anticancer properties of artemisinins have been seen in the laboratory previously but this is the first time their effect has been seen in patients in a rigorously designed study.

Source: University of St George's London

New approach aims to silence cancer 'survival genes'

Silencing the SIRT1 gene: Cancer cells before and after treatment in vitro. Non-cancerous cells (not shown) are unaffected. Credit: Image courtesy of University of York

Scientists at the University of York are working on a promising new approach for tackling colorectal cancer, the second most common cause of cancer-related death.

The new method works by silencing cancer 'survival genes' and could potentially combat cancer through the selective killing of colorectal cancer cells without adverse effects on normal, non-cancer cells.

Funded by York's Centre for Chronic Diseases and Disorders (C2D2), the project led by Professor Jo Milner from York's Department of Biology involved preliminary studies to establish the suitability of an ex vivo model for the future development of anti-cancer therapies for colorectal cancer using a technique called RNA interference.

The new approach builds on ground-breaking research by Professor Milner and her team at York more than a decade ago. This early work, funded by Yorkshire Cancer Research (YCR), used the newly-developed technique of RNA interference to successfully kill human cervical cancer cells grown in culture without causing damage to healthy cells.

Professor Milner explained: "When a mammalian cell elects to die it does so with great precision and without harming its neighbours. This process of 'programmed cell death' enables the continuous replacement of aging cells and also the sculpting of tissues and neuronal pathways.

"However, when this normal process of programmed cell death fails the continued abnormal growth of affected cells can lead to cancer. Some cancers develop following infection with a virus, such as human papilloma virus which causes human cervical cancer. Here the virus expresses specific viral genes that disrupt normal cellular control mechanisms resulting in abnormal cell proliferation and survival.

"Using RNA interference (RNAi) we first identified the viral gene responsible for the continued survival of cervical cancer cells. Then we established the feasibility of RNAi-based therapeutics for the selective killing of human cervical cancer cells growing in vitro."

Professor Milner and her team next studied cells from other cancer types, including colorectal cancer and breast cancer. Such cancers develop when the cell's internal control system fails due to damage to one or more of the regulatory genes.

Professor Milner said "We discovered that other genes, belonging to a group called stress-response genes, acquire a new pro-survival function during the process of cancerous transformation. Importantly, this acquired cancer-specific survival function operates under normal, physiological conditions. Silencing these cancer-specific survival genes by RNA interference causes the cancer cells to die while the survival of non-cancerous cells appears normal. This is in contrast to treating cancer by radiotherapy and/or genotoxic drugs -- these agents cause genotoxic stress and damage both cancer and normal cells and tissues in the body, resulting in unwanted adverse side effects for the patient."

For the work on colorectal cancer therapies to progress towards the clinic, the team has had to meet the challenge of modifying the agent siRNA. siRNA is the synthetic RNA molecule which is designed to silence a chosen gene by inducing RNA interference and selectively suppressing expression of that gene. However, siRNA is very unstable and is rapidly degraded when in contact with human tissues.

As reported in the journal Molecular Therapy, the team has now successfully met this challenge and converted the unstable siRNA molecule into a stable form without losing its ability and very high efficacy for targeted gene silencing. A novel siRNA/DNA has been shown to be resistant to degradation while retaining high efficacy and selectivity for target gene silencing when tested on human cancer cells grown in culture.

The next step will involve testing this novel therapeutic agent for cancer-specific cell killing using human tissue maintained ex vivo, using an experimental model which was validated in the course of the C2D2-funded research.

Professor Paul Kaye, Director of C2D2, said: "Professor Milner's team has now shown that ex vivo cultures of colorectal tumour material, derived from human patients, maintain cancer-related biochemistry over several days, and of sufficient time known to produce a killing effect with the novel siRNA/DNA in vitro. It is marvelous that C2D2 has been able to support this ground breaking research that has validated an ex vivo model that can be used to progress this novel therapeutic towards the clinic, and without the need for animal research."

Source: University of York

High milk intake linked with higher fractures and mortality, research suggests

Women who drank more than three glasses of milk a day had a higher risk of death than women who drank less than one glass of milk a day. Credit: © Africa Studio / Fotolia

A high milk intake in women and men is not accompanied by a lower risk of fracture and instead may be associated with a higher rate of death, suggests observational research published in The BMJ this week.

This may be explained by the high levels of lactose and galactose (types of sugar) in milk, that have been shown to increase oxidative stress and chronic inflammation in animal studies, say the researchers.

However, they point out that their study can only show an association and cannot prove cause and effect. They say the results "should be interpreted cautiously" and further studies are needed before any firm conclusions or dietary recommendations can be made.

A diet rich in milk products is promoted to reduce the likelihood of osteoporotic fractures, but previous research looking at the importance of milk for the prevention of fractures and the influence on mortality rates show conflicting results.

So a research team in Sweden, led by Professor Karl Michaëlsson, set out to examine whether high milk intake may increase oxidative stress, which, in turn, affects the risk of mortality and fracture.

Two large groups of 61,433 women (aged 39-74 years in 1987-1990) and 45,339 men (aged 45-79 years in 1997) in Sweden completed food frequency questionnaires for 96 common foods including milk, yoghurt and cheese.

Lifestyle information, weight and height were collated and factors such as education level and marital status were also taken into account. National registers were used to track fracture and mortality rates.

Women were tracked for an average of 20 years, during which time 15,541 died and 17,252 had a fracture, of whom 4,259 had a hip fracture.

In women, no reduction in fracture risk with higher milk consumption was observed. Furthermore, women who drank more than three glasses of milk a day (average 680 ml) had a higher risk of death than women who drank less than one glass of milk a day (average 60 ml).

Men were tracked for an average of 11 years, during which time 10,112 died and 5,066 had a fracture, with 1,166 hip fracture cases. Men also had a higher risk of death with higher milk consumption, although this was less pronounced than in women.

Further analysis showed a positive association between milk intake and biomarkers of oxidative stress and inflammation.

In contrast, a high intake of fermented milk products with a low lactose content (including yoghurt and cheese) was associated with reduced rates of mortality and fracture, particularly in women.

They conclude that a higher consumption of milk in women and men is not accompanied by a lower risk of fracture and instead may be associated with a higher rate of death. 

Consequently, there may be a link between the lactose and galactose content of milk and risk, although causality needs be tested.

"Our results may question the validity of recommendations to consume high amounts of milk to prevent fragility fractures," they write. "The results should, however, be interpreted cautiously given the observational design of our study. The findings merit independent replication before they can be used for dietary recommendations."

Michaëlsson and colleagues raise a fascinating possibility about the potential harms of milk, says Professor Mary Schooling at City University of New York in an accompanying editorial. However, she stresses that diet is difficult to assess precisely and she reinforces the message that these findings should be interpreted cautiously.

"As milk consumption may rise globally with economic development and increasing consumption of animal source foods, the role of milk and mortality needs to be established definitively now," she concludes.

Source: BMJ-British Medical Journal