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.