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[en] Notwithstanding the considerable skepticism that prevailed at the beginning of nineties of the last century to the possible clinical significance of inhibitors of tyrosine kinase (TK), Druker et al. (1998) had developed a compound that inhibited the enzymatic activity of Abl protein and, consequently, increased activity of Bcr-Abl oncoprotein, whose presence is characteristic of chronic myeloid leukemia (CML). The TK inhibitor, imatinib mesylate (Glivec) has become the standard first-line therapy for all patients with newly diagnosed CML. Despite its high efficiency, part of patients is not responding to treatment with this preparation or is losing an already achieved response. In this case second-generation or third-generation tyrosine kinase inhibitors (TKIs) could be applied.. The paper presents an overview of treatment options for CML, focusing on biological therapy with TKIs. (author)
[en] Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the t(9;22) translocation. As in most cancers, short telomeres are one of the features of CML cells, and telomere shortening accentuates as the disease progresses from the chronic phase to the blastic phase. Although most individual telomeres are short, some of them are lengthened, and long individual telomeres occur non-randomly and might be associated with clonal selection. Telomerase is the main mechanism used to maintain telomere lengths, and its activity increases when CML evolves toward advanced stages. ALT might be another mechanism employed by CML cells to sustain the homeostasis of their telomere lengths and this mechanism seems predominant at the early stage of leukemogenesis. Also, telomerase and ALT might jointly act to maintain telomere lengths at the chronic phase, and as CML progresses, telomerase becomes the major mechanism. Finally, CML cells display an altered nuclear organization of their telomeres which is characterized by the presence of high number of telomeric aggregates, a feature of genomic instability, and differential positioning of telomeres. CML represents a good model to study mechanisms responsible for dynamic changes of individual telomere lengths and the remodeling of telomeric nuclear organization throughout cancer progression
[en] Treatment options for myelofibrosis as a myeloproliferative neoplasms are limited. Allogeneic hematopoietic stem cell transplant (HSCT) is the only one potentially curative option for MF. Conventional therapies are palliative, therefore there is an urgent need for new treatment strategies to be developed. The discovery of deregulation JAK/STAT pathway as main characteristics BCR-ABL-negative MPNs has led to a resurgence of medical interest in JAK-STAT targeted treatment modalities. First of JAK inhibitors ruxolitinib represents another example of an increasing trend in oncology where a detailed understanding of mechanisms of a disease allows the drug to be directed towards specific molecular pathways. Ruxolitinib is the most promising agent in the experimental treatment of MF. The risk adapted treatment and the right timing improved quality of life of patient and ultimately prolongs survival with MF. (author)
[en] Acute myeloid leukemia (AML) is an aggressive stem cell malignancy that is difficult to treat. There are limitations to the current treatment regimes especially after disease relapse, and therefore new therapeutic agents are urgently required which can overcome drug resistance whilst avoiding unnecessary toxicity. Among newer targeted agents, both tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and proteasome inhibitors show particular promise. In this report we show that a combination of the proteasome inhibitor bortezomib and TRAIL is effective against AML cell lines, in particular, AML cell lines displaying myelomonocytic/monocytic phenotype (M4/M5 AML based on FAB classification), which account for 20-30% of AML cases. We show that the underlying mechanism of sensitization is at least in part due to bortezomib mediated downregulation of c-FLIP and XIAP, which is likely to be regulated by NF-κB. Blockage of NF-κB activation with BMS-345541 equally sensitized myelomonocytic AML cell lines and primary AML blasts to TRAIL
[en] Metabolic reprogramming is an essential hallmark of neoplasia. Therefore, targeting cancer metabolism, including lipid synthesis, has attracted much interest in recent years. Serine palmitoyltransferase (SPT) plays a key role in the initial and rate-limiting step of de novo sphingolipid biosynthesis, and inhibiting SPT activity prevents the proliferation of certain cancer cells. Here, we identified a novel and orally available SPT inhibitor, compound-2. Compound-2 showed an anti-proliferative effect in several cancer cell models, reducing the levels of the sphingolipids ceramide and sphingomyelin. In the presence of compound-2, exogenously added S1P partially compensated the intracellular sphingolipid levels through the salvage pathway by partially rescuing compound-2-induced cytotoxicity. This suggested that the mechanism underlying the anti-proliferative effect of compound-2 involved the reduction of sphingolipid levels. Indeed, compound-2 promoted multinuclear formation with reduced endogenous sphingomyelin levels specifically in a compound-2-sensitive cell line, indicating that the effect was induced by sphingolipid reduction. Furthermore, compound-2 showed potent antitumor activity without causing significant body weight loss in the PL-21 acute myeloid leukemia mouse xenograft model. Therefore, SPT may be an attractive therapeutic anti-cancer drug target for which compound-2 may be a promising new drug. - Highlights: • We discovered compound-2, a novel and orally available SPT inhibitor. • Compound-2 was cytotoxic against PL-21 acute myeloid leukemia cells. • Compound-2 showed antitumor activity in the PL-21 mouse xenograft model.
[en] p15INK4B, a cyclin-dependent kinase inhibitor, has been recognized as a tumor suppressor. Loss of or methylation of the p15INK4B gene in chronic myeloid leukemia (CML) cells enhances myeloid progenitor formation from common myeloid progenitors. Therefore, we examined the effects of overexpressed p15INK4B on proliferation and apoptosis of CML cells. Overexpression of p15INK4B inhibited the growth of K562 cells by downregulation of cyclin-dependent kinase 4 (CDK4) and cyclin D1 expression. Overexpression of p15INK4B also induced apoptosis of K562 cells by upregulating Bax expression and downregulating Bcl-2 expression. Overexpression of p15INK4B together with STI571 (imatinib) or BCR-ABL1 small interfering RNA (siRNA) also enhanced growth inhibition and apoptosis induction of K562 cells. The enhanced effect was also mediated by reduction of cyclin D1 and CDK4 and regulation of Bax and Bcl-2. In conclusion, our study may provide new insights into the role of p15INK4B in CML and a potential therapeutic target for overcoming tyrosine kinase inhibitor resistance in CML
[en] Most patients with multiple myeloma (MM) have even in the era new drugs an incurable disease. Deacetylase inhibitors (DACi) extend the possibilities in MM treatment. Effects in MM is through targeting of epigenetic and protein metabolism pathways. Panobinostat, pan DCAi, in combination with bortezomib and dexamethasone was approved for treatment in patients with relapsed or refractory MM. Results of clinical study a phase 3 showed improved progression free survival and overall response rate. Adverse events this combination included thrombocytopenia, diarrhoea, fatigue and peripheral neuropathy. Research how to maintain effect while improving tolerability is ongoing. (author)
[en] We report the case of an inflammatory abdominal aortic aneurysm incidentally detected clearly with diffusion-weighted magnetic resonance imaging (DW-MRI) during the examination of a patient with myelofibrosis with myeloid metaplasia that later converted to acute myeloid leukemia. DW-MRI revealed a hyperintense halo surrounding the abdominal aorta with aneurysmatic dilatation, establishing the diagnosis.
[en] Acute leukemia is a rare complication of long-term chemotherapy, immunosuppressive therapy and radiotherapy. With improved survival in cancer patients resulting from modern methods of investigations and treatment, more case of secondary leukemia have come to light. In this review, fifteen cases of secondary leukemia, its prognostic implications and methods to reduce the risk of its development are emphasised. Relevant literature is also reviewed. (author). 3 tabs., 24 refs
[en] There are considerable discrepancies between clinical symptoms and imaging diagnosis in the localization of the responsible rediculopathy. The purpose of this study are to analyze the dynamic alteration of contrast filling of the spinal nerve sleeves during positional changes and determine how the abnormalities of nerve sleeves on lateral bending A-P views correlate with sciatica. The criteria indicating the root abnormality in functional myelography were (1) bad filling of ipsolateral root to sciatica and (2) good filling of contralateral root compared with those in neutral A-P view. Of total 77 patients, 67 had radiculopathy and 10 had no radiculopathy. In 23 (34.3%) of 67 patients with radiculopathy and 6 (60%) of 10 patients with no radiculopathy, their clinical symptoms well correlated with conventional myelographic findings. However, in 35 (52.2%) of 67 patients with radiculopathy and 6 (60%) of 10 patients with no radiculopathy, their symptoms well correlated with functional myelographic findings. This study suggest that the functional myelography using both lateral bending A-P views can be used as a complementary tool in the evaluation of the radiculopathy