[Bcr-Abl inhibition as molecular therapy approach in chronic myeloid leukemia]

Bcr-Abl, a constitutively activated tyrosine kinase, is a product of the Philadelphia chromosome (Ph) translocation t(9;22), present in nearly all cases of chronic myeloid leukemia (CML) and in about 20% of cases with acute lymphoblastic leukemia. CML, a myeloproliferative disorder, progresses through three phases--chronic phase, accelerated phase and blast crisis. Current therapies include drug regimens such as interferon alpha, hydroxyurea, busulfan or allogeneic bone marrow transplantation, the only curative treatment for CML, which is, however, limited to younger patients with a suitable donor. INHIBITION OF BCR-ABL AS EFFECTIVE AND SELECTIVE TREATMENT IN CML: In vitro studies and studies in animal models have shown, that Bcr-Abl is the molecular cause CML. Therefore inhibition of the Bcr-Abl tyrosine kinase is expected to be an effective and selective treatment modality for CML. STI571 was shown to be a competitive inhibitor at the ATP-binding site of the Bcr-Abl tyrosine kinase, the platelet-derived growth factor receptor and c-kit tyrosine kinases. It shows effects on proliferation and survival of Bcr-Abl-expressing cells without affecting normal cells or Ph-negative leukemic cells. DRUG RESISTANCE TO STI571: Several mechanisms of resistance have been identified from in vitro studies with Bcr-Abl-positive cell lines. Mechanisms include amplification or overexpression of Bcr-Abl or an increased expression of P-gly-coprotein. In a mouse model the binding of STI571 to acidic alpha 1 glycoprotein (AAG) has been proposed to be involved in the development of STI571 resistance. Recent studies with clinical samples from resistant patients have shown that point mutations in the kinase domain of Bcr-Abl play a role in the development of resistance to STI571.

STI571 is a promising example of a moleculary targeted therapy directed towards the molecular cause of CML. To maximize the therapeutic value and to avoid the induction of resistance, a combination of the drug with other chemotherapies should be considered. According to its pharmacological profile, STI571 could also be useful in the treatment of tumors with deregulated PDGF receptor or c-kit signaling, e.g., in chronic myelomonocytic leukemia with a t(5;12) chromosomal translocation or in cases with gastrointestinal stromal tumors (GIST). STI571 shows a new paradigm in the development of new targeted therapies for the treatment of malignant diseases.