Posted by rob on September 29, 2009 under Uncategorized | 
Arsenic trioxide downregulates the expression of annexin II in bone marrow cells from patients with acute myelogenous leukemia.
Chin Med J (Engl). 2009 Sep 5;122(17):1969-73
Authors: Zhang XH, Hu Y, Bao L, Jiang Q, Yang LH, Lu XJ, Hong M, Xia LH, Guo T, Shen GX, Zhu HH, Zhao T, Song SJ
BACKGROUND: Most patients with acute myelogenous leukemia (AML) suffer from disordered hemostasis. We have previously shown that annexin II (Ann II), a high-affinity co-receptor for plasminogen/tissue plasminogen activator, plays a central role in primary hyperfibrinolysis in patients with acute promyelocytic leukemia (APL). The expression of Ann II in cells from patients with major subtypes of AML and the effect of arsenic trioxide (As2O3) on Ann II expression in AML cells were investigated to determine whether As2O3-mediated downregulation of Ann II could restore hemostatic stability. METHODS: A total of 103 patients (48 females and 55 males; age, 19 – 58 years) were included. Plasma samples were collected before and after treatment as well as after complete remission. Ann II and plasminogen activation were measured in leukemic cells during treatment with 1 micromol/L As2O3. RESULTS: Before As2O3 treatment, Ann II mRNA expression (real-time PCR) was the highest in M3 cells (P < 0.05), higher in M5 cells than that in M1, M2, M4, and M6 cells (P < 0.001), and positively correlated with Ann II protein expression (flow cytometry) (r = 0.752, P < 0.01). Exposure for up to 120 hours to As2O3 (1 micromol/L) had no significant effect on Ann II protein in M1 and M2 leukemic cells, but decreased Ann II protein expression twofold within 48 hours of exposure in M3 cells (P < 0.05) and twofold within 96 hours in M5 cells (P < 0.05). The rate of plasmin generation was higher in APL, M5, and M4 cells than in M1, M2, and M6 cells. CONCLUSIONS: As2O3 may reduce hyperfibrinolysis in AML by downregulation of Ann II. Furthermore, As2O3 affects more than one form of AML (APL, M4 and M5), suggesting its potential role in their management.
PMID: 19781379 [PubMed - in process]
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Neratinib: an oral, irreversible dual EGFR/HER2 inhibitor for breast and non-small cell lung cancer.
Expert Opin Investig Drugs. 2009 Sep 28;
Authors: Bose P, Ozer H
Background: The revolutionary success of imatinib, a specific inhibitor of the BCR-ABL tyrosine kinase (TK) in the treatment of chronic myelogenous leukemia ushered in the era of targeted therapies in cancer. The erythroblastic leukemia viral oncogene homolog family of receptor TKs, to which EGFR (HER1) and human epidermal growth factor receptor 2 (HER2)/neu TKs belong, has been implicated in a variety of cancers, and several agents that inhibit these TKs are in clinical use, with many more in various stages of development. Objectives: To summarize current knowledge about neratinib (HKI-272), an oral, irreversible dual inhibitor of EGFR and HER2 and to define its future clinical role, especially in the context of related agents that are either available or in the pipeline. Methods: A Medline search using Pubmed was conducted using the keywords neratinib, HKI-272, EGFR, HER2, lapatinib, trastuzumab, erlotinib, gefitinib, cetuximab and panitumumab. Relevant abstracts presented at the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium meetings were also reviewed. Conclusions: Both preclinical and human studies have shown that neratinib has promising activity in both advanced breast cancer and NSCLC with an acceptable safety profile. The data support its continued clinical development.
PMID: 19780706 [PubMed - as supplied by publisher]
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Clinical relevance of a pharmacogenetic approach using multiple candidate genes to predict response and resistance to imatinib therapy in chronic myeloid leukemia.
Clin Cancer Res. 2009 Jul 15;15(14):4750-8
Authors: Kim DH, Sriharsha L, Xu W, Kamel-Reid S, Liu X, Siminovitch K, Messner HA, Lipton JH
PURPOSE: Imatinib resistance is major cause of imatinib mesylate (IM) treatment failure in chronic myeloid leukemia (CML) patients. Several cellular and genetic mechanisms of imatinib resistance have been proposed, including amplification and overexpression of the BCR/ABL gene, the tyrosine kinase domain point mutations, and MDR1 gene overexpression. EXPERIMENTAL DESIGN: We investigated the impact of 16 single nucleotide polymorphisms (SNP) in five genes potentially associated with pharmacogenetics of IM, namely ABCB1, multidrug resistance 1; ABCG2, breast-cancer resistance protein; CYP3A5, cytochrome P450-3A5; SLC22A1, human organic cation transporter 1; and AGP, alpha1-acid glycoprotein. The DNAs from peripheral blood samples in 229 patients were genotyped. RESULTS: The GG genotype in ABCG2 (rs2231137), AA genotype in CYP3A5 (rs776746), and advanced stage were significantly associated with poor response to IM especially for major or complete cytogenetic response, whereas the GG genotype at SLC22A1 (rs683369) and advanced stage correlated with high rate of loss of response or treatment failure to IM therapy. CONCLUSIONS: We showed that the treatment outcomes of imatinib therapy could be predicted using a novel, multiple candidate gene approach based on the pharmacogenetics of IM.
PMID: 19584153 [PubMed - indexed for MEDLINE]
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Partially matched related donor transplantation can achieve outcomes comparable with unrelated donor transplantation for patients with hematologic malignancies.
Clin Cancer Res. 2009 Jul 15;15(14):4777-83
Authors: Xiao-Jun H, Lan-Ping X, Kai-Yan L, Dai-Hong L, Yu W, Huan C, Yu-Hong C, Wei H, Jing-Zhi W, Yao C, Xiao-Hui Z, Hong-Xia S, Feng-Rong W, Fei-Fei T
PURPOSE: The study aimed to compare the outcomes of patients undergoing hematopoietic stem cell transplantation (HSCT) from partially matched related donors (PMRD) and unrelated donors (URD) for hematologic malignancies without the use of in vitro T cell depletion. EXPERIMENTAL DESIGN: HSCT was done on 297 consecutive patients from URDs (n = 78) and PMRDs (n = 219) during the same time period. Incidences of graft-versus-host disease (GVHD), relapse, nonrelapse mortality, overall survival, and leukemia-free survival between the PMRD and URD groups were compared. RESULTS: All patients achieved full engraftment. The cumct65ulative incidences of grades II to IV acute GVHD in the PMRD and URD cohorts were 47% [95% confidence interval (95% CI), 33-62%] versus 31% (CI, 20-42%; P = 0.033), with a relative risk of 1.72 (95% CI, 1.01-2.94; P = 0.046). The incidence of chronic GVHD did not differ significantly between the two cohorts (P = 0.17). The 2-year incidences of nonrelapse mortality and relapse were 20% (CI, 15-26%) versus 18% (CI, 10-27%), with P = 0.98, and 12% (CI, 8-16%) versus 18% (CI, 10-27%), with P = 0.12, for the PMRD versus the URD cohort, respectively. The 4-year overall survival and leukemia-free survival were 74% (CI, 67-80%) versus 74% (CI, 62-85%), with P = 0.98, and 67% (CI, 59-75%) versus 61% (CI, 47-74%), with P = 0.74, respectively. CONCLUSIONS: Our comparisons show that every major end point, including relapse, nonrelapse mortality, overall survival, and leukemia-free survival, was comparable between the PMRD and the URD groups.
PMID: 19584148 [PubMed - indexed for MEDLINE]
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Deletion of the der(9q) in chronic myeloid leukemia: the controversy continues.
Leuk Lymphoma. 2009 Jun;50(6):871-2
Authors: Godley LA
PMID: 19479615 [PubMed - indexed for MEDLINE]
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Previous best responses can be re-achieved by resumption after imatinib discontinuation in patients with chronic myeloid leukemia: implication for intermittent imatinib therapy.
Leuk Lymphoma. 2009 Jun;50(6):944-51
Authors: Goh HG, Kim YJ, Kim DW, Kim HJ, Kim SH, Jang SE, Lee J, Kim D, Kim WS, Park SH, Kweon IY
Although imatinib is considered as a front line therapy in patients with chronic myeloid leukemia (CML), it is still unclear whether transient imatinib discontinuation may adversely affect the outcome. This study was conducted to investigate long-term outcome after discontinuation and resumption of imatinib, and to determine whether intermittent imatinib therapy can be employed in patients with CML. Twenty six Philadelphia chromosome positive (Ph+) patients with CML discontinued imatinib when they achieved complete cytogenetic response (CCyR) or complete molecular response (CMR), and they were retreated with imatinib in case of hematologic, cytogenetic or molecular relapse. Except one patient who progressed and two patients who are in persistent molecular remission without imatinib resumption, all of 23 patients are maintaining the best response achieved after imatinib resumption with a median follow-up of 44 months. This study shows that although imatinib cannot be discontinued completely, intermittent therapy can be considered for the treatment of patients with CML in particular situations.
PMID: 19479613 [PubMed - indexed for MEDLINE]
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Karyotype changes during long-term targeted therapy of chronic myeloid leukemia with imatinib.
Leuk Lymphoma. 2009 Jun;50(6):952-65
Authors: Pieńkowska-Grela B, Rygier J, Woroniecka R, Grygalewicz B, Pastwińska A, Krawczyk P, Ceglerek B, Seferyńska I, Sikorska A, Konopka L
The main risk factors during imatinib therapy of chronic myeloid leukemia are still subject to discussion. A group of 39 patients was cytogenetically examined and monitored before and during long-term treatment with imatinib. The cytogenetic response was investigated using karyotype analysis and fluorescence in situ hybridisation method. Different therapy effects were shown for three subgroups distinguished before the start of treatment: patients with the sole translocation t(9;22) with a typical pattern of BCR/ABL fusion vs. patients with submicroscopic deletion in the fusion region ABL/BCR of the sole t(9;22) vs. patients with aberrations additional to t(9;22) and without submicroscopic deletion. Of the two group with sole t(9;22) the group with deletion in the ABL/BCL region suffered a poorer treatment outcome than the group without deletion. The risk of progression of cytogenetic changes in group with deletion was more than nine times higher than in patients with sole t(9;22) without deletion (statistically significant).
PMID: 19479611 [PubMed - indexed for MEDLINE]
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Discontinuing imatinib in chronic myeloid leukemia: don’t try this at home.
Leuk Lymphoma. 2009 Jun;50(6):868-70
Authors: Mattison R, Larson RA
PMID: 19455466 [PubMed - indexed for MEDLINE]
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