Selective inhibition of tyrosine kinases - a new therapeutic principle in oncology

Tyrosine kinases are enzymes that regulate mitosis, differentiation, migrat ion, neovascularization, and apoptosis. Their spectrum and association with specific malignancies offer multiple targets for therapeutic intervention. Chronic myelogenous leukemia (CIVIL) represents an ideal target for a ther apy using a selective inhibitor of the BCR-ABL tyrosine kinase. The 2-pheny lpyrimidine derivative ST1571 was rationally designed to inhibit ABL and BC R-ABL tyrosine kinase activities through competitive ATP-binding pocket int eractions. Phase II data demonstrate hematologic and cytogenetic responses in interferon refractory chronic-phase, accelerated-phase and blast crisis patients. However, long-term observation is needed to confirm that response data result in prolongation of survival. ST1571 is being studied in other malignancies, including leukemias characterized by expression of alternate molecular forms of BCR-ABL and those expressing protein tyrosine kinases wi th ATP-binding pockets structurally similar to ABL, e.g. c-kit and PDGF-R. Gastrointestinal stromal tumor (GIST) cells overexpress the stem cell facto r receptor CD117, the product of the proto-oncogene c-kit. Inhibition of c- kit in vivo results in an immediate metabolic change of the tumor cells, de tectable by positron emission tomography. Since c-kit overexpression is inh ibited in small-cell lung cancer cell lines, a study with STI571 as second- line therapy of c-kit-positive small-cell lung cancer is in progress. Clini cal studies are ongoing in malignancies associated with an enhanced activit y of the PDGF-R, such as high-grade glioma, prostate cancer and leukemias w ith rearrangements of PDGF-R. The development of selective tyrosine kinase inhibitors is considered a promising approach for the design of new drugs. Clinical responses to STI571 in various malignancies may stimulate greater interest in the clinical use of tyrosine kinase inhibitors.