Imatinib

Abstract

Imatinib (Gleevec, Glivec) is a synthetic tyrosine kinase inhibitor used in the treatment of chronic myeloid leukaemia (CML). It is specifically designed to inhibit the breakpoint cluster region (BCR)-Abelson (ABL) fusion protein that results from the chromosomal abnormality known as the Philadelphia chromosome. CML is characterised by this abnormality, which leads to abnormalities of the peripheral blood and bone marrow including an increase in the number of granular leukocytes. Imatinib is approved in numerous countries worldwide for the treatment of newly diagnosed Philadelphia chromosome-positive (Ph+) chronic-phase CML, Ph+ accelerated-phase or blast-crisis CML, and in patients with Ph+ chronic-phase CML who have failed to respond to interferon-alpha therapy. It is also indicated in paediatric patients with newly diagnosed Ph+ chronic-phase CML, in accelerated-phase or blast-crisis CML, or in chronic-phase CML after failure of interferon-alpha therapy or when the disease has recurred after haematopoietic stem cell transplantation (HSCT). Approved indications, however, may vary by country. Imatinib is effective and generally well tolerated in patients with Ph+ CML. In patients with newly diagnosed chronic-phase CML, imatinib was more effective than interferon-alpha plus cytarabine in preventing progression of the disease and in achieving haematological and cytogenetic responses. Overall survival rates remain high after 5 years of follow-up, and historical comparisons with other treatments demonstrate improved overall survival with imatinib in the long term. Patients with accelerated-phase or blast-crisis CML, or those who have not responded to prior interferon-alpha therapy also benefit from imatinib treatment. Some patients become resistant or intolerant to imatinib therapy; management strategies to overcome these problems include dosage adjustment, other treatments, or combination therapy with imatinib and other agents. Allogeneic HSCT is currently the only potentially curative treatment, but it is associated with high rates of morbidity and mortality and is not suitable for all patients. The introduction of imatinib has had a marked impact on outcomes in patients with CML. It remains a valuable treatment for all stages of the disease, especially initial treatment of newly diagnosed Ph+ chronic-phase CML, and is endorsed by European and US treatment guidelines as a first-line option.

Inhibition of Eukaryotic Translation by the Antitumor Natural Product Agelastatin A

“…Among the compounds identified as PTC inhibitors, homoharringtonine has already been approved for use as a treatment for CML patients resistant to tyrosine kinase inhibitors such as imatinib (Moen et al, 2007), providing support for inhibition of eukaryotic translation as a viable strategy to treat certain forms of cancer. The elucidation of A site of the 80S ribosome as the target for AglA and the new structural insights into its interaction with the ribosome through the X-ray crystal structure of the AglA-80S ribosome complex are likely to facilitate the development of new derivatives with greater potency and improved pharmacological activity as new anticancer drugs.…”

Targeting Catalase but Not Peroxiredoxins Enhances Arsenic Trioxide-Induced Apoptosis in K562 Cells

“…Interestingly, As 2 O 3 can also induce the degradation of BCR/ABL [15]–[16], the pivotal oncogenic fusion protein in CML, which arises from the t(9;22) chromosome translocation [17]. Targeting inhibition of BCR/ABL kinase activity by Gleevec induces cell death in CML cells and remission in CML patients [18]. Despite of this, APL cells are more sensitive to As 2 O 3 -induced cell death than CML cells, indicating that other factors, beyond these two oncoproteins, may responsible for their sensitivity to As 2 O 3 .…”

Sínteses e propriedades de fármacos inibidores da tirosina quinase BCR-ABL, utilizados no tratamento da Leucemia Mieloide Crônica

“…Além disso, espera-se a eliminação dos sintomas da doença como, por exemplo a esplenomegalia. 41 Embora o tratamento da LMC com imatinibe tenha alcançado resultados fantásticos, aproximadamente 20 a 30% dos pacientes têm apresentado resistência. 42 A resistência pode ser primária, quando desde o início o paciente não apresenta resposta alguma, ou pode ser resistência secundária, quando o paciente diminui ou não alcança mais resultados ao longo do tratamento.…”