Drug to combat stubborn leukaemia

US scientists have made a drug that kills cancer cells which have escaped attack by the powerful leukaemia drug Glivec.

Up to a fifth of people with chronic myeloid leukaemia – a blood cell cancer – who take Glivec (imatinib) become resistant to it and relapse. Dr Charles Sawyers and colleagues at the University of California hope their treatment will help such people. The drug’s safety still needs to be tested, they reported in Science. Glivec, or Gleevec in the US, works by homing in on the faulty enzyme that allows leukaemia cells to multiply out of control. Dodging death Cancer cells become resistant to Glivec by mutating to change the structure of this enzyme so the drug can no longer fit its target. Tests on mice showed an experimental drug BMS-354825 sidestepped this problem. It does not hold the target to such tight structural constraints as Glivec. This “sloppiness” means it can kill the cancer cells when Glivec cannot. Dr Sawyers said: “We realised if we want to develop drugs that inhibit the mutants they need to be a little sloppier, less demanding in their binding rules.” Laboratory tests on human bone marrow cells showed the drug stopped cancer cells growing that were resistant to Glivec. Some cells were resistant to both Glivec and BMS-354825, however. Fellow researcher Dr Neil Shah said: “In the future we may be combining therapies that can, amongst them, override all the resistance mechanisms that allow cancer to evade individual therapies. “Cancer may be treated similarly to HIV, with a cocktail of drugs,” he said. The researchers are conducting further tests to make sure the drug is safe in humans. A spokesman for Leukaemia Research Fund said: “This is obviously welcome news. It’s a significant development. Glivec resistance is something that has been worrying doctors because it’s the drug of choice. It is very effective.” But he said the authors of the report had indicated that safety of the new drug had not yet been demonstrated, although current trials are addressing this issue. Safety “When they were first developing Glivec people were concerned that it might kill all the healthy cells as well as the cancer cells. Thankfully, this did not happen because Glivec is very targeted towards the cancer cells. “The new drug is less selective. It is sloppier and binds more readily to target molecules within the cell than Glivec. “If you use a drug that is less exactly targeted there’s a theoretical risk that it will cause damage to other cells. You have to demonstrate that you can use this drug safely,” he said. He said studies have shown when some people who are resistant to Glivec stop the treatment for a few months the resistant cells become sensitive to Glivec again. “If that’s the case, it may be that when Glivec resistance develops you only need to switch to something else for a couple of months and then switch back to Glivec later when they are sensitive to it again,” he said. Professor Junia Melo, professor of molecular haematology at Imperial College’s Hammersmith Hospital London, has been doing similar research. She said: “It’s a very good piece of work. It’s good news for people with chronic myeloid leukaemia. “We have been experimenting with a number of compounds similar to the BMS drug. “The beauty of this one [BMS-354825] is, like Glivec, it’s a very soluble compound so you can think about an oral formulation,” she said. Paul Travers, deputy head of research at the Anthony Nolan Trust, said: “It’s very interesting and attractive research which promised to help a lot of patients in the future. “However, it’s some way to go for that promise to be realised and even if it does fulfil that promise, there will still be some patients that it will not treat. “In some cases, for example in very young children, the preference may be to have a bone marrow transplant,” he said. (Source: