ABSTRACT
BACKGROUND: Management of beta-thalassemia major (TM) requires life-long hemotransfusions leading to iron overload. Iron elimination is enhanced by the use of modern chelators. AIM: To assess the effect of modern chelation therapy by dynamics of serum ferritin concentration and liver MRI T2*. PATIENTS AND METHODS: Forty-six patients with TM (male to female ratio =1:1, mean age 33.2±10.9 years) were prospectively studied between 2011 and 2014. Twenty-one patients (45.7%) were treated with deferasirox, 17 (37%) - with deferiprone, and 8 (17.3%) - with deferiprone in combination with deferoxamine. Ferritin was measured by ELISA. MRI T2* was assessed by Siemens Magnetom Avanto 1.5T. The patients were allocated into 3 groups based on their initial ferritin level and liver MRI T2*. Statistical analysis was performed using SPSS v. 18 for Windows. Data were analysed by descriptive analysis, analysis of variance and correlative analysis, means were compared using t-test and one-way ANOVA. RESULTS: In 2011, 9 (19.5%) patients had normal liver MRI T2*; in 2014 they were 17 (37%). The patients with mild grade liver siderosis were 12 (26%) in 2011, and in 2014 they were 14 (30.4%). In 2011, the patients with moderate liver siderosis were 14 (30.4%), and in 2014 - 12 (26.0%). Eleven patients (23.9%) had severe liver siderosis in 2011 and only two patients (4.0%) were diagnosed with the condition in 2014. CONCLUSION: A reduction of iron overload was found in all studied groups. This positive effect is attributed to the use of modern chelators and the ease of access to accurate monitoring.
Subject(s)
Blood Transfusion , Ferritins/blood , Iron Overload/drug therapy , Liver/diagnostic imaging , Transfusion Reaction , beta-Thalassemia/therapy , Adult , Deferasirox/therapeutic use , Deferiprone/therapeutic use , Deferoxamine/therapeutic use , Female , Humans , Iron Overload/blood , Iron Overload/diagnostic imaging , Iron Overload/etiology , Magnetic Resonance Imaging , Male , Treatment Outcome , Young AdultABSTRACT
Chronic myeloid leukemia (CML) arises from the fusion of the BCR and the ABL1 genes. The BCR gene (chromosome 22q11.2) and the ABL1 gene (chromosome 9q34) fuse together due to reciprocal chromosome translocation forming the Philadelphia chromosome (Ph). This fusion gene codes tyrosine kinase which accelerates the cell division and reduces DNA repair. Imatinib mesylate is a selective inhibitor of this tyrosine kinase. It is the first-line treatment for CML-patients. However, it became clear that Philadelphia-positive (Ph+) cells could evolve to elude inhibition due to point mutations within the BCR-ABL kinase domain. To date more than 40 mutations have been identified and their early detection is important for clinical treatment. With the development of the new tyrosine kinase inhibitors (TKIs), associated with these mutations, the resistance problem seems to diminish, as some of the new drugs are less prone to resistance. The aim of this review is to focus on the diff erent mutations leading to resistance.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm/genetics , Fusion Proteins, bcr-abl/genetics , Imatinib Mesylate/pharmacology , Point Mutation , Amino Acid Substitution , Fusion Proteins, bcr-abl/chemistry , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Models, Molecular , Protein Domains , Protein Kinase Inhibitors/pharmacologyABSTRACT
Proteasome inhibitors are emerging as a promising class of anti-cancer therapeutic agents. The first of this new class of drugs with a clinical significance, bortezomib (PS 341, Velcade), is a modified dipeptidyl boronic acid. Bortezomib reduces the NF-kappaB translocation / transcription and blocks the drug-related signalling pathways critical to basic vital functions of myeloma cells. Bortezomib induces apoptosis by releasing cytochrome C from mitochondria and by activating caspase-9 and Jun-kinases (JNK) and the Fas-caspase-8-dependent apoptotic pathway. Bortezomib has been reported to down-regulate cytokine-induced expression of VCAM-1, a major ligand on bone marrow stromal cells for VLA-4; it inhibits the heterotypic adherence between the myeloma cells and stromal cells and blocks the signalling pathways of resistance to apoptosis. The drug has been shown experimentally to inhibit the IL-6-induced proliferation of myeloma cells; it demonstrates synergy with dexamethasone and inhibits angiogenesis. Phase II/ III clinical studies with Velcade have shown an overall therapeutic response rate of 35% in refractory, relapsed myeloma patients (Bladé criteria). These surprisingly good results, the drug's good tolerance and controllable side effects provide a solid base for further studies on bortezomib, including studies on the drug used as front line therapy.
