Tyrosine kinase inhibitor imatinib (STI571) as an anticancer agent for solid tumours

Imatinib mesylate, also known as ST1571 or CGP57148, is a competitive inhib itor of a few tyrosine kinases, including BCR-ABL, ABL, KIT, and the plate let-derived growth factor receptors (PDGF-R). It binds to the ATP-binding s ite of the target kinase and prevents the transfer of phosphate from ATP to the tyrosine residues of various substrates. At oral doses of 300 mg or gr eater, the vast majority of patients with chronic myeloid leukaemia achieve a haematological response and this is usually associated with limited toxi city. Imatinib also has substantial activity in Philadelphia chromosome-pos itive acute lymphoblastic leukaemia expressing the BCR-ABL fusion protein. Gastrointestinal stromal tumours (GISTs) have also been evaluated for clini cal activity of imatinib. About 90% of malignant GISTs harbour a mutation i n c-kit leading to KIT receptor autophosphorylation and ligand-independent activation. According to initial clinical studies, more than 50% of GISTs r espond to therapy within a few months, and only about 10-15% progress. The potential for cure and the optimal length of treatment are currently not kn own. Several other human cancers may over-express KIT or PDGF-R, and clinic al trials to evaluate the role of imatinib in the treatment of such cancers are currently ongoing. Imatinib is an example of a specifically designed, highly targeted cancer therapy, which poses novel requirements for both pat hology laboratories and clinicians in terms of identifying the major molecu lar mechanisms involved in tumour growth.