60-year-old drug shows new promise for inherited cancer

Cancer Research UK

CANCER RESEARCH UK-funded scientists have shown that an early chemotherapy drug invented in the 1940s has the potential to work against a genetic fault called HNPCC which is linked to bowel and other cancers. The results are published in EMBO Molecular Medicine* today, (Thursday).

HNPCC is a hereditary condition involved in around five per cent of all bowel cancer cases. As well as bowel cancer, it puts people at increased risk of developing stomach, womb, ovarian, kidney and other cancers. Almost 40 per cent of people with HNPCC have a faulty MSH2 gene.

Scientists at the Breakthrough Breast Cancer Research Centre at The Institute of Cancer Research (ICR) in London sought to improve treatments for people with cancer caused by HNPCC by finding drugs which selectively kill cells containing the damaged MSH2 gene. In this study, the scientists tested a range of drugs on cells with the faulty MSH2 gene. They found that a drug called methotrexate worked particularly well in destroying these cells.

This study suggests that methotrexate could help to treat people whose cancer is driven by the MSH2 genetic fault, potentially opening the door to a more targeted treatment option. A new clinical trial has begun at The Royal Marsden NHS Foundation Trust to see how well methotrexate treats patents with advanced bowel cancer following this study.

Methotrexate is similar to a normal molecule called folinic acid, which is required for copying DNA. The drug prevents cells from making and repairing DNA - a process needed for cancer growth. It was one of the first chemotherapy drugs to be invented in the 1940s and is still used to treat a number of cancers today. But until now, it has not commonly been used to treat people with HNPCC.

Professor Alan Ashworth, who led this Cancer Research UK-funded study at the ICR, said: "The MSH2 gene plays a vital role in repairing DNA damage but if it is faulty, mistakes accumulate in cells and increase the risk of cancer developing.

"What's exciting about methotrexate is that it selectively destroys the cells lacking the MSH2 function. This indicates that it may make an excellent treatment for patients with the genetic alteration. With our colleagues at The Royal Marsden Hospital, we have set up clinical trials to test this."

Dr Lesley Walker, director of cancer information at Cancer Research UK said: "In the past, many treatments were developed which indiscriminately kill dividing cells. With improved scientific understanding, we are starting to be able to offer targeted therapies that are selective for the genetic faults in cancer. It's really fascinating that our scientists have discovered that an old- fashioned drug of this type shows new promise for this very specific group of patients.

"This is the first time scientists have identified a drug that targets cells lacking functional MSH2 genes. The chemotherapy drug methotrexate has already shown benefit for patients with breast, bladder and bone cancer as well as some types of leukaemia. We now need to find out if it is effective in patients with MSH2 gene defects."

ENDS

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*Methotrexate induces oxidative DNA damage and is selectively lethal to tumour cells with defects in the DNA mismatch repair gene MSH2. EMBO Molecular Medicine. Martin et al. August 2009.