Cancer and immune drug insights suggest new uses

11 July 2012

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A new study of existing drugs has found out more about exactly how they work. It also suggests new ways they could be used to treat patients.

The drugs, known as thiopurines, have been prescribed for 50 years to treat cancer. They are also used as immunosuppressants to treat autoimmune diseases and to prevent rejection in organ transplant recipients. Their effectiveness depends on their ability to target and kill cancer cells or activated immune cells without damaging the patient's other cells. Exactly how they do this wasn't completely understood, however. 

There are three thiopurine drugs - azathioprine, 6-mercaptothiopurine and 6-thioguanine (6-TG). The first two have been extensively prescribed, mostly to treat leukaemia and inflammatory bowel disease. The third, 6-TG, has been less widely used, and there is controversy over its possible toxic effects on the liver. 

Peter Karran and Reto Brem of Cancer Research UK's London Research Institute (now part of the Francis Crick Institute) used molecular and cell biology methods to examine what happens inside cells when patients are treated with 6-TG. 

The effects of the drug are two-fold. It accumulates in the cells' DNA and it also depletes the cells' defences against the toxic forms of oxygen - which are generated naturally as a by-product of energy production. Toxic oxygen reacts with the 6-TG in DNA to cause damage that, if not repaired, ultimately triggers cell death. 

The researchers discovered that normal cells can repair these DNA lesions by a molecular pathway that is known to be inactive in some cancers. Based on their finding, they suggest that the drug might be particularly effective for patients whose cancer cells lack this particular DNA repair pathway because of an inherited gene mutation. 

Dr Karran explained: "The new research also suggests that the side effects of treatment might be alleviated if patients are given a second drug, allopurinol, along with 6-TG. Allopurinol can counteract the formation of toxic oxygen. These findings suggest that clinical trials with this new drug combination might reveal significant benefit to patients." 

He added: "Our research provides support for the possible clinical effectiveness of combined 6-TG and allopurinol in certain patient groups, such as people with inflammatory bowel disease who don't respond to azathioprine or 6-mercaptothiopurine. It seems appropriate to test the combination in patients." 

The paper, Oxidation-mediated DNA crosslinking contributes to the toxicity of 6-thioguanine in human cells, is published in Cancer Research.

  • A new study of thiopurines - drugs used to treat cancer and as immunosuppressants - has uncovered more about how they work and suggested possible new ways they could be used.
  • New insights into their mechanism suggest they may be particularly effective in certain cancer patients. They also indicate how previously encountered side-effects might be overcome.
  • The study was carried out by Peter Karran and Reto Brem of Cancer Research UK's London Research Institute.