BioEd Online

Cancer treatment's 'magic bullet' has had a makeover. Researchers have developed and tested a second-generation version of the leukaemia drug, Gleevec. It is hoped that the newcomer will offer relief to those who have developed resistance to the original drug.

Gleevec was the first cancer drug of its kind - designed specifically to target the molecules that cause chronic myeloid leukaemia (CML), a deadly form of cancer that affects 1 in 100,000 people. Since its approval by the US Food and Drug Administration in 2001, it has become the front-line therapy for CML. But around 20% of patients become resistant to the drug in the early stages of the disease, so other treatments are needed.

The new drug, called BMS-354825, shrinks tumours and prolongs life in mice with a Gleevec-resistant form of CML, researchers report in Science¹. Around 80% of treated rodents were still alive one month after their cancer started to develop. Without treatment, all animals died within two weeks.

BMS-354825 also slows the proliferation of cultured bone marrow cells taken from CML patients, regardless of whether they have developed resistance to Gleevec or not.

In theory this means that the drug could work against both drug-resistant and Gleevec-treatable forms of human CML, says Neil Shah from the University of California, Los Angeles, who co-authored the study. But the best treatment regime may involve prescribing Gleevec and BMS-354825 together, he says.

Designer drugs

Gleevec, also known as imatinib, works by binding to and blocking an enzyme that drives the growth of leukaemia cells. Because it targets only the cancer cells, it leaves neighbouring healthy cells unharmed.

The problem is that sometimes genetic mutations occur that cause the enzyme to change shape and prevent the drug from latching on. BMS-354825 is less selective about how it binds to the enzyme, so it can attach even to mutated forms of the protein.

Up to now, 17 resistance-causing mutations have been spotted. The new drug works against 14 of the 15 tested so far. "We're optimistic that the other untested mutations will also be sensitive to the compound," says Shah.

At present, when Gleevec fails, patients hold out for a bone-marrow transplant. But less than a third of patients are eligible, discounted by their age and a lack of tissue-matched donors. Without treatment, the cancer is invariably fatal.

So BMS-354825 is a welcome addition to the CML armoury. Last November, the first human patient began taking the drug as part of a phase I clinical trial. Around 30 CML patients are taking the drug to help assess its safety.

"It's good news for the CML community," says Junia Melo who studies haematology at London's Hammersmith Hospital. But she says it is disappointing that one of the tested mutations is immune. The mutation, known as T315I, is responsible for around one fifth of all drug-resistant CML cases.