Posted by rob on July 27, 2009 under Uncategorized | 
Nilotinib therapy in chronic myelogenous leukemia: the strength of high selectivity on BCR/ABL.
Curr Drug Targets. 2009 Jun;10(6):530-6
Authors: Breccia M, Alimena G
Imatinib mesylate is currently the standard therapy for chronic myeloid leukemia (CML) patients. Despite the remarkable results achieved with imatinib, the emergence of resistance to this drug has become a significant problem. Several strategies have been developed to overcome imatinib resistance, including dose escalation of the drug, combination treatments or novel targeted agents. Nilotinib is a second-generation tyrosine kinase inhibitor 30-50 fold more potent than imatinib with high affinity and selectivity on BCR/ABL, active against a wide range of mutant clones, except T315I mutation. Phase II trials of nilotinib showed high activity in imatinib-resistant or intolerant CML patients; front-line treatment of chronic phase Ph+ CML demonstrated rapid and stable cytogenetic responses and increasing molecular responses. We here review the development of nilotinib and the efficacy data in phase II and front-line trials.
PMID: 19519355 [PubMed - in process]
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Chronic myelogenous leukemia in a great horned owl (Bubo virginianus).
J Avian Med Surg. 2009 Mar;23(1):36-43
Authors: Wiley JL, Whittington JK, Wilmes CM, Messick JB
A free-ranging adult female great horned owl (Bubo virginianus) was presented to the Wildlife Medical Clinic at the University of Illinois after being observed with anorexia and decreased activity. A severe leukocytosis (212 400 cells/microl), primarily comprised of mature heterophils, was found at presentation. Results of various diagnostic tests including radiographs, Chlamydophila serologic testing, measurement of Aspergillus antibody and antigen titers, plasma protein electrophoresis, fecal culture and acid-fast staining, coelioscopy, endoscopy, tracheoscopy, exploratory coelomotomy, nuclear scintigraphy, tissue cultures, bone marrow biopsy, and histopathology revealed no underlying cause for the persistent leukocytosis. No response to treatment with antibiotics or antifungal agents was observed, although a transient, significant decrease in the leukocyte count (6200 cells/microl) was observed after treatment with fenbendazole. A presumptive diagnosis of chronic myelogenous leukemia was made based on 3 factors: disease duration of greater than 3 months, a lack of identifiable foci of inflammation, and a lack of response to conventional therapy. The diagnosis was confirmed based on postmortem examination and testing 177 days after initial presentation.
PMID: 19530405 [PubMed - indexed for MEDLINE]
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Acquired acute myelogenous leukemia after therapy for acute promyelocytic leukemia with t(15;17): a case report and review of the literature.
P R Health Sci J. 2009 Jun;28(2):146-50
Authors: Betancourt-García RD, Castro J, Fernández AC, López-Enríquez A, Fradera J, Pacheco E
Therapy-related myelodysplastic syndrome (t-MDS) and therapy-related acute myelogenous leukemia (t-AML) in patients with acute promyelocytic leukemia (APL) are rare events. The cumulative exposure to chemotherapy with alkylating agents and topoisomerase II inhibitors is associated with t-AML that may develop any time after the completion of the treatment. We report the case of an acquired AML who previously received therapy for APL, after two years of being diagnosed. The diagnosis was established by morphologic findings, membrane markers, cytogenetic studies, and fluorescence in situ hybridization (FISH). To our knowledge this is the first documented case in Puerto Rico of a patient with APL that developed a t-AML without the characteristic chromosomal and morphologic findings of APL.
PMID: 19530558 [PubMed - indexed for MEDLINE]
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Synthetic tumor-specific breakpoint peptide vaccine in patients with chronic myeloid leukemia and minimal residual disease: a Phase 2 Trial.
Cancer. 2009 Jun 17;
Authors: Jain N, Reuben JM, Kantarjian H, Li C, Gao H, Lee BN, Cohen EN, Ebarb T, Scheinberg DA, Cortes J
BACKGROUND:: Imatinib is the current standard frontline therapy for chronic myelogenous leukemia (CML). In the majority of patients, imatinib induces a complete cytogenetic response (CCyR); however, complete molecular responses are infrequent. The Bcr-Abl fusion creates a unique sequence of amino acids that could constitute a target for immunomodulation. METHODS:: A mixture of heteroclitic and native peptides derived from both b3a2 and b2a2 sequences was used to vaccinate patients with CML in CCyR who were receiving imatinib therapy and who had stable Bcr-Abl transcript levels. RESULTS:: Ten patients were enrolled, all with b2a2 transcripts (including 2 patients who had coexpression of b2a2 and b3a2). Patients had received imatinib for a median of 62 months. Three of 10 patients achieved 1-log reduction in Bcr-Abl transcript levels, including the 2 patients who had received previous interferon therapy, and 3 other patients achieved a major molecular response. The vaccine was tolerated well, and there were no grade >/=3 adverse events. Vaccination did not affect the leukocyte profiles in peripheral blood except for regulatory T cells, which were down-regulated briefly during the late stage of vaccination in patients who achieved approximately 1-log reduction in Bcr-Abl transcript levels. CONCLUSIONS:: The current data suggested that vaccination-related transient disruption of immune tolerance may contribute to the reduction in Bcr-Abl transcripts. Clinically, this Bcr-Abl peptide vaccine may transiently improve the molecular response in a subset of patients with CML. Cancer 2009. (c) 2009 American Cancer Society.
PMID: 19536894 [PubMed - as supplied by publisher]
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Tyrosine Kinase Inhibitors for the Treatment of Chronic Myeloid Leukemia.
Anticancer Agents Med Chem. 2009 Sep 1;
Authors: Tolomeo M, Dieli F, Gebbia N, Simoni D
Imatinib mesylate (Gleevec) is a drug unique for the treatment of certain forms of cancer. It works by targeting, and turning off, specific tyrosine kinase proteins that cause the uncontrolled cell growth and the inhibition of apoptosis in cancer cells. Imatinib was designed on the basis of the structure of the ATP binding site of the Abl protein kinase with the aim to stabilizes the inactive form of Bcr-Abl, an oncoprotein involved in malignant transformation in chronic myelogenous leukemia (CML). However, imatinib can also target other tyrosine kinase proteins different from Bcr-Abl such as Kit, that is the suspected cause of gastrointestinal stromal tumor (GIST). Despite successful clinical results observed in the last years, the long-term effects of imatinib and its ability to completely eradicate CML are still unknown. Moreover, similar to many other anti-cancer drugs, clinical resistance to imatinib has emerged. In this review we will discuss the in vitro and in vivo results obtained with the novel tyrosine kinase inhibitors developed to overcome imatinib resistance in Bcr-Abl expressing hematologiocal disorders.
PMID: 19538165 [PubMed - as supplied by publisher]
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Natural killer cells in allogeneic transplantation: effect on engraftment, graft- versus-tumor, and graft-versus-host responses.
Biol Blood Marrow Transplant. 2009 Jul;15(7):765-76
Authors: Gill S, Olson JA, Negrin RS
Natural killer (NK) cells are effectors of the innate immune system and recognize cells transformed by viruses or neoplasia. Their response to “missing self” signals was described 3 decades ago, but the recent discovery of a panoply of activating receptors has made it clear that NK cell reactivity arises from a combination of inhibitory and activating signals. Successful clinical exploitation of NK cell reactivity was demonstrated in allogeneic transplantation for acute myelogenous leukemia from HLA-haploidentical donors when matched donors were not available. Multiple clinical studies have since attempted to use NK reactivity in the setting of both HLA-matched and -mismatched transplantation, with varying results. This review summarizes the heterogeneous clinical results and explains them based on a succinct description of NK cell biology.
PMID: 19539207 [PubMed - in process]
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Late mortality and relapse following BuCy2 and HLA-identical sibling marrow transplantation for chronic myelogenous leukemia.
Biol Blood Marrow Transplant. 2009 Jul;15(7):851-5
Authors: Copelan EA, Crilley PA, Szer J, Dodds AJ, Stevenson D, Phillips G, Elder P, Nivison-Smith I, Avalos BR, Penza S, Topolsky D, Sobecks R, Kalaycio M, Bolwell BJ
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only known curative therapy for chronic myelogenous leukemia (CML). Failure, because of relapse or nonrelapse mortality (NRM), generally occurs within 3 years of transplantation, but large studies with long-term follow-up are limited. We present mature results in 335 patients with CML who underwent allogeneic bone marrow transplantation (BMT) from HLA-identical siblings following busulfan and cyclophosphamide (BU/Cy2). Two hundred twenty-nine were in chronic phase (CP) and 106 in accelerated or blastic phase at transplantation. Median follow-up exceeded 14 years. The estimated probability of 18-year leukemia-free survival (LFS) for CP patients was 55.6% and for those beyond CP, 10.5%. Of 182 patients who survived leukemia-free at 3 years, the estimated probability of LFS at 18 years was 61.9%. Late relapse (P = .039) and late NRM (P = .008) occurred at higher rates in patients beyond CP at transplantation. There was no plateau in LFS.
PMID: 19539217 [PubMed - in process]
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Occupational exposure to benzene at the ExxonMobil refinery at Baton Rouge, Louisiana (1977-2005).
J Occup Environ Hyg. 2009 Sep;6(9):517-29
Authors: Panko JM, Gaffney SH, Burns AM, Unice KM, Kreider ML, Booher LE, Gelatt RH, Marshall JR, Paustenbach DJ
Because crude oil contains up to 3% benzene and there is an association between high chronic exposure to appreciable concentrations of benzene and acute myelogenous leukemia, exposure of refinery workers has been studied for many years. To date, no extensive industrial hygiene exposure analyses for historical benzene exposure have been performed, and none have focused on the airborne concentrations in the workplace at specific refineries or for specific tasks. In this study, the authors evaluated the airborne concentrations of benzene and their variability over time at the ExxonMobil refinery in Baton Rouge between 1977 and 2005. Refinery workers were categorized into 117 worker groups using company job descriptions. These 117 groups were further collapsed into 25 job categories based on similarity of measured exposure results. Results of 5289 personal air samples are included in this analysis; 3403 were considered nontask (>or= 180 min) personal samples, and 830 were considered task-related (< 180 min) personal samples; the remainder did not fit in either category. In general, nontask personal air samples indicated that exposures of the past 30 years were generally below the occupational exposure limit of 1 ppm, but there was only a small, decreasing temporal trend in the concentrations. The job sampled most frequently during routine operations was process technician and, as broken down by area, resulted in the following mean benzene concentrations: analyzers (mean = 0.12 ppm), coker (mean = 0.013 ppm), hydrofiner (mean = 0.0054 ppm), lube blending and storage (mean = 0.010 ppm), waste treatment (mean = 0.092 ppm), and all other areas (mean = 0.055 ppm). Task-based samples indicated that the highest exposures resulted from the sampling tasks, specifically from those performed on process materials; in general, though, even these tasks had concentrations well below the STEL of 5 ppm. The most frequently sampled task was gauging (mean = 0.12 ppm). Task-related exposures were also similar across job categories for a given task, with a few exceptions. This study thus provides a task-focused analysis for occupational exposure to benzene during refinery operations, which can be insightful for understanding exposures at this refinery and perhaps others operated since about 1975.
PMID: 19544135 [PubMed - indexed for MEDLINE]
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Inhibition of MEK signaling enhances the ability of cytarabine to induce growth arrest and apoptosis of acute myelogenous leukemia cells.
Apoptosis. 2009 Jun 23;
Authors: Nishioka C, Ikezoe T, Yang J, Yokoyama A
The mitogen-activated protein kinase/ERK kinase (MEK)/ERK pathway was shown to be constitutively activated in a large number of acute myelogenous leukemia (AML) cells, suggesting the important roles of this pro-survival signaling in leukemogenesis and proliferation of AML cells. This study explored the impact of the MEK inhibitor AZD6244 on the effect of cytarabien (AraC), one of the most commonly used anti-leukemia agents, to induce growth arrest and apoptosis of AML cells. AZD6244 effectively blocked AraC-induced MEK/ERK activation and enhanced its ability to induce growth arrest and apoptosis of NB4 and HL60 cells in parallel with induction of DNA damage as measured by detection of gamma-H2AX by Western Blot analysis, resulting in enhanced expression of p21( waf1 ) and downregulation of c-Myc and Bcl-xl in these cells. Enhanced induction of apoptosis mediated by combination of AZD6244 and AraC was also shown in freshly isolated AML cells (n = 3). Taken together, concomitant administration of AraC and the inhibitor of MEK/ERK signaling may be useful for treatment of individuals with AML.
PMID: 19548087 [PubMed - as supplied by publisher]
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The antiproliferation effect of berbamine on k562 resistant cells by inhibiting NF-kappaB pathway.
Anat Rec (Hoboken). 2009 Jul;292(7):945-50
Authors: Wei YL, Liang Y, Xu L, Zhao XY
Imatinib mesylate is effective against Ph chromosome-positive leukemia; however, resistance has been reported. High expression of bcr-abl in mRNA and protein levels, and other alterations were found in patients who experienced imatinib treatment failures and thus it is important to design alternative treatment strategies. The aim of this study was to evaluate the in vitro effect of berbamine, on imatinib-resistant chronic myelogenous leukemia (CML) K562 (K562-r) cells, and explore the mechanisms. The growth of K562-r cells was examined using the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Morphological analysis and DNA agarose electrophoresis were used to detect apoptosis in K562-r cells, and the extent of the cells in the sub-G1 cell cycle phase was measured using flow cytometry. The expression levels of BCR-ABL, phospho-BCR-ABL, and nuclear factor kappaB (NF-kappaB), IkappaBalpha, phospho-IkappaBalpha, IkappaB kinases alpha(IKKalpha), and Survivin were determined by Western blot. bcr-abl mRNA expression was determined by RT-PCR. MTT assays indicated that berbamine significantly inhibited the proliferation of K562-r cells. Cells with characteristics of apoptosis were confirmed by morphology examination and DNA agarose electrophoresis and percentage of apoptosis were increased after treatment with berbamine. The results also showed that berbamine was able to down-regulate BCR-ABL and phospho-BCR-ABL proteins by affecting bcr-abl mRNA expression and decrease expression of nuclear NF-kappaB, phospho-IkappaBalpha, IKKalpha, and Survivin. Collectively, berbamine could inhibit the proliferation of K562-r cells and induce apoptosis. The mechanisms may be related at least in part, to inhibit BCR-ABL and its downstream NF-kappaB signaling. Berbamine may provide an alternative candidate for the treatment of patients with CML resistant to imatinib therapy.
PMID: 19548306 [PubMed - in process]
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Inhibitory effect of wild-type p53 gene on excessive replication of centrosomes in leukemia cell line K562.
Chin J Cancer. 2009 Feb;28(2):122-6
Authors: Tian WJ, Feng WL, Wang HB, Huang SF, Cao WX, Huang ZG
BACKGROUND AND OBJECTIVE: Mutation and deletion of the p53 gene in tumor cells is one of the major reasons for aneuploid development and genomic instability. Abnormal centrosomes exist in chronic myelogenous leukemia patients at different stages; furthermore, the degree of abnormality is associated with the clinical stage and more severe in the blast crisis stage. This study was to establish the leukemia cell line K562 with the exogenous wild-type p53 (wt-p53) gene, and to explore the effect of the p53 gene on centrosomes in K562 cells. METHODS: The recombinant adenoviruses carrying the wt-p53 gene (Ad5wtp53), the mutant p53 gene (Ad5mtp53) and the green fluorescent protein gene (Ad5GFP) were amplified respectively in HEK293 cells, and co-infected with cation polybrene into K562 cells respectively; uninfected K562 cells were used as blank control. The infection efficiency was analyzed by flow cytometry. P53 expression was detected by Western blot. Centrosomes were counted under the laser confocal microscope after indirect immunofluorescence staining. The expression of Gadd45a (growth arrest and DNA damage), BubR1 (Bub 1 related) and Aurora A was detected by western blot. RESULTS: K562 cell line with exogenous wt-p53 gene was established. The infection efficiencies of three groups were over 60%, and P53 sustained expression for 72 h. The percentage of cells with amplified centrosomes (more than 2/cell) in Ad5wtp53 group was decreased to (0.38 +/- 0.02)%, lower than that of blank control group (p < 0.05). Meanwhile, the protein levels of Gadd45a and BubR1 in Ad5wtp53 group were upregulated by 93% and 88% of blank control (p < 0.05), respectively, and the protein level of Aurora A was downregulated by 56% of blank control (p < 0.05). CONCLUSIONS: P53 protein is sustained to express in K562 cells after being infected by Ad5wtp53. wt-p53 can suppress excessive replication of centrosomes that may contribute to the upregulation of Gadd45a and BubR1 protein expression as well as the downregulation of Aurora A protein expression.
PMID: 19550118 [PubMed - in process]
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Mental status changes after hematopoietic stem cell transplantation.
Cancer. 2009 Jun 23;
Authors: Chang G, Meadows ME, Orav EJ, Antin JH
BACKGROUND:: The growing numbers of survivors of innovative cancer treatments, such as hematopoietic stem cell transplantation (HSCT), often report subsequent cognitive difficulties. The objective of this study was to evaluate and compare neurocognitive changes in patients with chronic myelogenous leukemia (CML) or primary myelodysplastic syndrome (MDS) after allogeneic HSCT or other therapies. METHODS:: In this prospective cohort study, serial evaluations of attention, concentration, memory, mood, and quality of life were used in a consecutive sample of 106 eligible patients who had CML (n = 91) or MDS (n = 15) at enrollment and then 12 months and 18 months after HSCT or other therapy. RESULTS:: The 3 evaluations at enrollment, 12 months, and 18 months were completed by 98%, 95%, and 89% of surviving participants, respectively. Among all patients, there was significant improvement in memory over 18 months. For example, the 45 patients who underwent HSCT (42 patients with CML and 3 patients with MDS) compared favorably with the patients who received other treatment on most measures of neuropsychological function, except they had improved mental health (P = .034), worse physical function (P = .049), and more difficulty with coordination and fine motor speed bilaterally (dominant hand, P = .005; nondominant hand, P = .0019). Patients with CML overall had improved phonemic fluency (P = .014). CONCLUSIONS:: The current study indicated that time and diagnosis may be important factors when assessing neurocognitive and other changes. Complaints regarding “chemobrain” after HSCT merit further study, because deficits actually may predate the initiation of treatment and subsequently may improve. The study results could reassure prospective HSCT recipients, because HSCT compared favorably with other treatments when mental status side effects were considered. Cancer 2009. (c) 2009 American Cancer Society.
PMID: 19551887 [PubMed - as supplied by publisher]
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Overexpression of nucleolin in engrafted acute myelogenous leukemia cells.
Am J Hematol. 2009 May 27;
Authors: Gattoni-Celli S, Buckner CL, Lazarchick J, Stuart RK, Fernandes DJ
PMID: 19554553 [PubMed - as supplied by publisher]
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Anti-tumor activity of noble indirubin derivatives in human solid tumor models in vitro.
Arch Pharm Res. 2009 Jun;32(6):915-22
Authors: Kim SH, Choi SJ, Kim YC, Kuh HJ
Indirubin has been identified as a component of a traditional Chinese medicine, Danggui Longhui Wan, which is used for the treatment of chronic myelogenous leukemia. Indirubin inhibits cyclin-dependent kinases (CDKs) and induces cell cycle arrest and apoptosis in cancer cells. Many indirubin derivatives have been studied for their potential anti-solid tumor activity. We have synthesized and evaluated many indirubin derivatives. In order to compare and confirm the potential of our major derivatives as anti-solid tumor agents, we examined their anti-proliferative activity in monolayers, as well as in multicellular spheroids (MCS) cultures of human colorectal cancer cells, DLD-1 and HT-29. The MCS model is an in vitro solid tumor model that is increasingly used for the evaluation of anti-solid tumor activity. 5-nitro-indirubin-3′-oxime (4c) and 5′-bromo-5-nitro-indirubin-3′-oxime (4l), compared to 5-trimethylacetamido-indirubin-3′-oxime (11) and 5-diphenylacetamido-indirubin-3′-oxime (33) showed greater anti-proliferative effects in monolayers, but lower anti-proliferative effects in MCS. Overall, our data suggest that compounds 11 and 33 may exert a significant anti-solid tumor activity via a mechanism other than CDK inhibition, different from that of 4c and 4l. These compounds are worth further investigation with respect to their anti-solid tumor activity and their mechanism of action in various solid tumor models.
PMID: 19557370 [PubMed - in process]
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Laparoscopic management of an obstructing granulocytic sarcoma of the jejunum causing intussusception in a nonleukemic patient: report of a case.
Surg Today. 2009;39(7):606-9
Authors: Palanivelu C, Rangarajan M, Senthilkumar R, Annapoorni S
Granulocytic sarcoma is an extramedullary tumor of immature myeloid cells which is often a forerunner to the development of acute myelogenous leukemia. Granulocytic sarcoma of the gastrointestinal tract frequently involves the small intestine and often presents with abdominal pain and obstruction. Our patient presented with a proximal jejunal mass causing intussusception and obstruction. This type of manifestation has never before been reported. A laparoscopy-assisted resection of the affected portion of jejunum was performed for him. The initial pathological findings were high-grade non-Hodgkin’s lymphoma; immunohistochemistry confirmed a diagnosis of granulocytic sarcoma. After a follow-up of 14 months, there was no evidence of leukemia. This condition is often mistaken for lymphoma and confirmation is necessary by immunohistochemistry. Chemotherapy is the treatment of choice and surgery is indicated only in the event of complications, such as bowel obstruction, bleeding, or perforation. The prognosis of granulocytic sarcoma is similar to that of myeloid leukemia.
PMID: 19562450 [PubMed - in process]
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[Steroid-refractory graft-versus-host disease : Extracorporeal irradiation of leucocytes induces immunotolerance.]
Internist (Berl). 2009 Jun 21;
Authors: Schinwald N, Rank A, Tischer J, Kolb HJ
A 42 year-old woman develops steroid refractory graft-versus-host disease (GVHD) after second allogeneic stem cell transplantation for acute myelogenous leukemia with severe GVHD of her skin with blisters, severe GVHD of her gut with watery and bloody diarrhea and GVHD of her liver with cholestasis. In a further attempt to control GVHD extracorporeal photochemotherapy is administered. The treatment exposures peripheral mononuclear cells to photoactivated psoralen before they subsequently are given back to the patient. This approach apparently offers selective immune tolerance.
PMID: 19565209 [PubMed - as supplied by publisher]
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Prolonged chronic phase in chronic myelogenous leukemia after homoharringtonine therapy.
Chin Med J (Engl). 2009 Jun 20;122(12):1413-7
Authors: Li YF, Deng ZK, Xuan HB, Zhu JB, Ding BH, Liu XN, Chen BA
BACKGROUND: Homoharringtonine (HHT) is effective in treating late stage chronic myelogenous leukaemia (CML), but little is known about long term maintenance during complete cytogenetic response. Long term efficacy and toxicity profiles of low dose HHT were evaluated in this study. METHODS: One hundred and six patients with CML received 1.5 mg/m(2) of HHT alone by continuous daily infusion for seven to nine days every four weeks. Of 79 patients in the control group, 31 were treated with interferon alpha (IFN-alpha) and 48 with hydroxycarbamide. For 17 patients who failed to achieve cytogenetic response within 12 months’ treatment of IFN-alpha, HHT was administered. Quantitative RT-PCR was used to detect the BCR-ABL mRNA expression in 36 Philadelphia positive CML patients enrolled after 2007. Haematological and cytogenetic responses were evaluated in all patients at the 12th month of follow-up. Long term efficacy was assessed in a follow-up with a median time of 54 months (12 months-98 months). RESULTS: After 12 months of therapy, cytogenetic response rate of the HHT, IFN-alpha and hydroxycarbamide groups were 39/106, 14/31 and 3/48, and corresponding molecular cytogenetic response rates 6/18, 3/8 and 0. Of the 17 patients who received HHT as salvage treatment, 6 achieved cytogenetic response (3 major). At the 48 months’ follow-up, cytogenetic response was maintained in 32/39 patients treated with HHT. Patients who had cytogenetic response in HHT group or treated with IFN-alpha also showed longer median chronic durations, which were 45 months (12 months-98 months) and 49 months (12 months-92 months) respectively, indicating a longer survival time. CONCLUSIONS: Low dose HHT alone showed considerable short term and long term efficacy in the treatment of late stage CML. It may also be a good choice for patients who have failed imatinib, IFN-alpha treatment or haematopoietic stem cell transplantation or cannot afford these treatments.
PMID: 19567163 [PubMed - in process]
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Gene expression profiling of imatinib and PD166326-resistant CML cell lines identifies Fyn as a gene associated with resistance to BCR-ABL inhibitors.
Mol Cancer Ther. 2009 Jul;8(7):1924-33
Authors: Grosso S, Puissant A, Dufies M, Colosetti P, Jacquel A, Lebrigand K, Barbry P, Deckert M, Cassuto JP, Mari B, Auberger P
Imatinib is used to treat chronic myelogenous leukemia (CML), but resistance develops in all phases of this disease. The purpose of the present study was to identify the mode of resistance of newly derived imatinib-resistant (IM-R) and PD166326-resistant (PD-R) CML cells. IM-R and PD-R clones exhibited an increase in viability and a decrease in caspase activation in response to various doses of imatinib and PD166326, respectively, as compared with parental K562 cells. Resistance involved neither mutations in BCR-ABL nor increased BCR-ABL, MDR1 or Lyn expression, all known modes of resistance. To gain insight into the resistance mechanisms, we used pangenomic microarrays and identified 281 genes modulated in parental versus IM-R and PD-R cells. The gene signature was similar for IM-R and PD-R cells, accordingly with the cross-sensitivity observed for both inhibitors. These genes were functionally associated with pathways linked to development, cell adhesion, cell growth, and the JAK-STAT cascade. Especially relevant were the increased expression of the tyrosine kinases AXL and Fyn as well as CD44 and HMGA2. Small interfering RNA experiments and pharmacologic approaches identified FYN as a candidate for resistance to imatinib. Our findings provide a comprehensive picture of the transcriptional events associated with imatinib and PD166326 resistance and identify Fyn as a new potential target for therapeutic intervention in CML.
PMID: 19567819 [PubMed - in process]
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ERK2, but not ERK1, mediates acquired and “de novo” resistance to imatinib mesylate: implication for CML therapy.
PLoS One. 2009;4(7):e6124
Authors: Aceves-Luquero CI, Agarwal A, Callejas-Valera JL, Arias-González L, Esparís-Ogando A, del Peso Ovalle L, Bellón-Echeverria I, de la Cruz-Morcillo MA, Galán Moya EM, Moreno Gimeno I, Gómez JC, Deininger MW, Pandiella A, Sánchez Prieto R
Resistance to Imatinib Mesylate (IM) is a major problem in Chronic Myelogenous Leukaemia management. Most of the studies about resistance have focused on point mutations on BCR/ABL. However, other types of resistance that do not imply mutations in BCR/ABL have been also described. In the present report we aim to study the role of several MAPK in IM resistance not associate to BCR/ABL mutations. Therefore we used an experimental system of resistant cell lines generated by co-culturing with IM (K562, Lama 84) as well as primary material from resistant and responder patient without BCR/ABL mutations. Here we demonstrate that Erk5 and p38MAPK signaling pathways are not implicated in the acquired resistance phenotype. However, Erk2, but not Erk1, is critical for the acquired resistance to IM. In fact, Bcr/Abl activates preferentially Erk2 in transient transfection in a dose dependent fashion through the c-Abl part of the chimeric protein. Finally, we present evidences demonstrating how constitutive activation of Erk2 is a de novo mechanism of resistance to IM. In summary our data support the use of therapeutic approaches based on Erk2 inhibition, which could be added to the therapeutic armamentarium to fight CML, especially when IM resistance develops secondary to Erk2 activation.
PMID: 19568437 [PubMed - in process]
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A novel aberrant form of e13a2 BCR-ABL1 transcript in chronic myelogenous leukemia undetectable with the standardized real-time quantitative polymerase chain reaction from the Europe Against Cancer Program.
Clin Chem Lab Med. 2009;47(7):885-7
Authors: Matsushita H, Yamamoto M, Tsuboi K, Masukawa A, Arakawa S, Asai S, Ogawa Y, Ando K, Miyachi H
PMID: 19575551 [PubMed - in process]
