Gleevec 19/4/03. By Richard Twyman Gleevec (known outside the USA as Glivec, and also by its generic name imatinib) is a small-molecule drug used to treat chronic myeloid leukaemia and certain other forms of cancer.

The disease

Chronic myeloid leukaemia (CML) is a rare form of cancer in which the bone marrow cells that give rise to certain white blood cells begin to divide and multiply much faster than normal. The disease affects 1 in 50 000 adults between the ages of 40 and 60, but may also strike earlier.

In contrast to acute forms of leukaemia, where large numbers of immature white blood cells are produced relatively quickly, the early chronic stage of CML (which may last several years) is characterised by the presence of large numbers of normal, mature white blood cells.

Some patients have no symptoms during this stage, while others may experience fatigue, appetite loss and fever.

Eventually, the disease progresses to the accelerated phase and then to blast crisis, where increasing numbers of immature white cells accumulate and fewer red cells and platelets are produced. This results in bruising, prolonged bleeding and enlargement of the spleen. The prognosis at this stage is poor, with a life expectancy of between two and 12 months.

The target

CML is associated with a particular type of chromosome abnormality, where chromosome 22 is much shorter than normal and the missing material is transferred to chromosome 9. The truncated chromosome 22, which is known as the Philadelphia chromosome after the place of its discovery, is used as a diagnostic marker for the disease.

The translocation event between chromosomes 9 and 22 results in the fusion of two broken genes, the BCR gene on chromosome 9 and the ABL gene on chromosome 22, to generate a new gene called BCR-ABL. The product of the ABL gene is a tyrosine kinase, an enzyme that, under normal circumstances, helps to convey signals between cells to control growth and division. The abnormal fusion protein retains the tyrosine kinase activity of ABL but the signals are not regulated in any way. The white blood cells therefore divide continuously, and massive numbers of cells are produced.

The discovery of the BCR-ABL fusion protein not only showed how CML was caused, but also revealed a potential drug target that was not present in unaffected people.

The drug and how it works

Gleevec is a small molecule drug belonging to a class of chemicals known as the phenylaminopyrimidines. These have been shown to interact with and inhibit tyrosine kinases. Gleevec itself is highly specific for the BCR-ABL tyrosine kinase, therefore blocking any growth signals the abnormal protein generates and preventing cell proliferation.

Gleevec also inhibits the normal version of ABL, but this does not seem to have any clinical side effects on normal cellular processes, probably because alternative signalling pathways can be used.

How Gleevec was developed

The development of Gleevec began in the late 1980s, when several pharmaceutical companies initiated screens to identify compounds that would interact with the BCR-ABL tyrosine kinase. By 1990, researchers at Ciba-Geigy (now part of Novartis) had discovered the inhibitory activity of phenylaminopyrimidines, but their initial lead compounds showed weak activity and poor specificity. Painstaking work was necessary to optimise the lead compounds, involving the trial-and-error testing of many variations on the basic molecular skeleton.

Eventually, the choice was whittled down to a small number of promising candidates, one of which was STI571, later to be known as Gleevec.

The next stage was preclinical testing, in which the candidate molecules were tested for their ability to inhibit BCR-ABL both in the test tube and in living cells. Gleevec stood out in both types of test, and was shown to inhibit the proliferation of cells containing the Philadelphia chromosome without affecting normal cells. The new drug was then submitted for clinical trials and showed a remarkable early success. In phase I trials involving 31 patients with advanced stage CML, all the participants showed a notable reduction in their white cell count and in ten of the patients the Philadelphia chromosome could not be detected at the end of the trial. The drug was approved in 2001.

The results of the phase III trial showed that Gleevec is four times more effective than standard therapy, with only 25 per cent of patients treated at the chronic stage progressing to blast crisis. Trials with other forms of cancer are in progress.