Posted by rob on November 17, 2010 under Uncategorized | 
Optimizing outcomes in patients with chronic myeloid leukemia in chronic phase: comparative safety profiles of newer agents.
Leuk Lymphoma. 2010 Aug;51(8):1399-413
Authors: Kelly K, Swords R, Mahalingam D, Giles FJ
Imatinib is broadly used in the frontline treatment of chronic myeloid leukemia (CML). Although long-term safety and efficacy have been established, some patients will not respond to imatinib. Nilotinib and dasatinib successfully recapture responses for most patients with imatinib-refractory or -intolerant disease. These drugs have different safety profiles, which are likely associated with their divergent inhibitory targets. The presence of Bcr-Abl mutations and safety profiles of available therapies in relation to patient history should be considered when choosing a second-line agent. This review evaluates the safety and tolerability of agents approved for CML treatment and briefly discusses newer third-line agents.
PMID: 20528247 [PubMed - indexed for MEDLINE]
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Posted by rob on November 16, 2010 under Uncategorized |
Down-regulation of MicroRNAs 222/221 in Acute Myelogenous Leukemia with Deranged Core-Binding Factor Subunits.
Neoplasia. 2010 Nov;12(11):866-76
Authors: Brioschi M, Fischer J, Cairoli R, Rossetti S, Pezzetti L, Nichelatti M, Turrini M, Corlazzoli F, Scarpati B, Morra E, Sacchi N, Beghini A
Core-binding factor leukemia (CBFL) is a subgroup of acutemyeloid leukemia (AML) characterized by genetic mutations involving the subunits of the core-binding factor (CBF). The leukemogenesis model for CBFL posits that one, or more, gene mutations inducing increased cell proliferation and/or inhibition of apoptosis cooperate with CBF mutations for leukemia development. One of the most commonmutations associated with CBF mutations involves the KIT receptor. A high expression of KIT is a hallmark of a high proportion of CBFL. Previous studies indicate that microRNA (MIR) 222/221 targets the 3′ untranslated region of the KIT messenger RNA and our observation that AML1 can bind the MIR-222/221 promoter, we hypothesized that MIR-222/221 represents the link between CBF and KIT. Here, we show that MIR-222/221 expression is upregulated after myeloid differentiation of normal bone marrow AC133(+) stem progenitor cells. CBFL blasts with either t(8;21) or inv(16) CBF rearrangements with high expression levels of KIT (CD117) display a significantly lower level of MIR-222/221 expression than non-CBFL blasts. Consistently, we found that the t(8;21) AML1-MTG8 fusion protein binds the MIR-222/221 promoter and induces transcriptional repression of a MIR-222/221-LUC reporter. Because of the highly conserved sequence homology, we demonstrated concomitant MIR-222/221 down-regulation and KIT up-regulation in the 32D/WT1 mouse cell model carrying the AML1-MTG16 fusion protein. This study provides the first hint that CBFL-associated fusion proteins may lead to up-regulation of the KIT receptor by down-regulating MIR-222/221, thus explaining the concomitant occurrence of CBF genetic rearrangements and overexpression of wild type or mutant KIT in AML.
PMID: 21076613 [PubMed - in process]
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Imatinib treatment in chronic myelogenous leukemia: What have we learned so far?
Cancer Lett. 2010 Nov 11;
Authors: Breccia M, Efficace F, Alimena G
Imatinib mesylate is currently the standard therapy for chronic myelogenous leukemia patients. Despite the remarkable results achieved with imatinib, the emergence of resistance to this drug has become a significant problem. Actually, two other second-generation tyrosine kinase inhibitors have been used for resistant/intolerant patients to imatinib. With the availability of oral tyrosine kinase inhibitors for the treatment of chronic myelogenous leukemia, questions relating to adherence to prescribed therapy have become an important issue. It has been demonstrated that the effectiveness of the treatment with imatinib requires high compliance to the prescribed dose of the drug for an indefinite period of time, whereas reduced adherence to therapy has been associated with delay in achieving cytogenetic or molecular response and/or possible development of resistance. The aim of this review is to discuss the importance of adherence, and the possible tools that we have to measure it, to improve our knowledge on possible underlying causes of non-adherence and the impact of non-adherence on hospitalization risk and healthcare cost through a systematic review of the data published to date.
PMID: 21074936 [PubMed - as supplied by publisher]
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Involvement of oxidative stress in taxol-induced apoptosis in chronic myelogenous leukemia K562 cells.
Exp Toxicol Pathol. 2010 Nov 10;
Authors: Meshkini A, Yazdanparast R
It is now well accepted that taxol exhibits cytotoxicity and antitumor activity in many human tumors through microtubule stabilization and induction of G2/M cell cycle arrest with final extensive cell apoptosis. Since many anti-cancer agents exert their cytotoxic effects through reactive oxygen species (ROS), we were interested to evaluate whether oxidative stress is involved in taxol-induced cytotoxicity among human leukemia K562 cells. Our results showed that induction of apoptosis was associated with generation of ROS and glutathione (GSH) depletion. The increase in ROS production and apoptosis were both suppressed by antioxidant N-acetyl-l-cysteine (NAC). Moreover, taxol caused an increase in c-Jun NH(2)-terminal kinase (JNK) and p38 activities, two of the well known mediators of the stress activation pathways. Attenuation of JNK expression in the presence of NAC might indicate the modulation of the level of JNK activity by ROS. Furthermore, our data indicated that Bcl-2? was down-regulated in taxol-treated cells and its expression was modulated by ROS and JNK activity. The activities of caspase-9 and -3 were also increased upon treatment with taxol; however, pre-treatment of cells with NAC or JNK inhibitor (SP600125) impeded taxol-mediated caspase activation and apoptosis in K562 cells, suggesting that JNK acts upstream of the caspases. Taken together, these results indicate that taxol induces apoptosis in chronic myelogenous leukemia cells by inducing intracellular oxidative stress and JNK activation pathway.
PMID: 21074392 [PubMed - as supplied by publisher]
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A novel FRET-based biosensor for the measurement of BCR-ABL activity and its response to drugs in living cells.
Clin Cancer Res. 2010 Aug 1;16(15):3964-75
Authors: Mizutani T, Kondo T, Darmanin S, Tsuda M, Tanaka S, Tobiume M, Asaka M, Ohba Y
PURPOSE: To develop a novel diagnostic method for the assessment of drug efficacy in chronic myeloid leukemia (CML) patients individually, we generated a biosensor that enables the evaluation of BCR-ABL kinase activity in living cells using the principle of fluorescence resonance energy transfer (FRET). EXPERIMENTAL DESIGN: To develop FRET-based biosensors, we used CrkL, the most characteristic substrate of BCR-ABL, and designed a protein in which CrkL is sandwiched between Venus, a variant of YFP, and enhanced cyan fluorescent protein, so that CrkL intramolecular binding of the SH2 domain to phosphorylated tyrosine (Y207) increases FRET efficiency. After evaluation of the properties of this biosensor by comparison with established methods including Western blotting and flow cytometry, BCR-ABL activity and its response to drugs were examined in CML patient cells. RESULTS: After optimization, we obtained a biosensor that possesses higher sensitivity than that of established techniques with respect to measuring BCR-ABL activity and its suppression by imatinib. Thanks to its high sensitivity, this biosensor accurately gauges BCR-ABL activity in relatively small cell numbers and can also detect <1% minor drug-resistant populations within heterogeneous ones. We also noticed that this method enabled us to predict future onset of drug resistance as well as to monitor the disease status during imatinib therapy, using patient cells. CONCLUSION: In consideration of its quick and practical nature, this method is potentially a promising tool for the prediction of both current and future therapeutic responses in individual CML patients, which will be surely beneficial for both patients and clinicians.
PMID: 20670950 [PubMed - indexed for MEDLINE]
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Cytogenomics of cancers: from chromosome to sequence.
Mol Oncol. 2010 Aug;4(4):309-22
Authors: Bernheim A
The role of acquired chromosomal rearrangements in oncogenesis (cytogenomics) and tumor progression is now well established. These alterations are multiple and diverse and the products of these rearranged genes play an essential role in the transformation and growth of cancer cells. The validity of this assumption is demonstrated by the development of specific inhibitors or antibodies that eliminate tumoral cells by targeting some of these changes. Imatinib, an inhibitor of the tyrosine kinase ABL, the prototype of these targeting drugs, is yielding complete remissions in most CML patients. Knowledge of chromosomal abnormalities is becoming an essential contribution to the diagnosis and prognosis of cancers but also for monitoring minimal residual disease or relapse. The concept of the “cytogenetic uniqueness” of each cancer has resulted in personalized treatment. This investigation will expound upon, besides the recurrent genomic alterations, the numerous products of perverted Darwinian selection at the cellular level.
PMID: 20599448 [PubMed - indexed for MEDLINE]
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Conclusions Histopathologic analysis is not useful as a routine diagnostic tool in EM because no morphological changes are specific to EM. The capillary proliferation and vasculopathy are assumed to be a consequence of intermittent skin hypoxia (vascular hypothesis of pathogenesis). Whether the proliferation is a consequence of EM or a pathogenic factor in the development of the disease is uncertain. (Source: Archives of Dermatology)
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In this study, we queried whether miR-107 and paralogs regulated GRN in human cancers. In cultured cells, anti-argonaute RNA coimmunoprecipitation with downstream microarray analyses indicates that GRN mRNA is directly targeted by numerous miR-15/107 miRNAs. We further tested this association in human tumors. MiR-15 and miR-16 are known to be downregulated in chronic lymphocytic leukemia (CLL). Using pre-existing microarray datasets, we found that GRN expression is higher in CLL relative to nonneoplastic lymphocytes (P < 0.00001). By contrast, other prospective miR-15/miR-16 targets in the dataset (BCL-2 and cyclin D1) were not upregulated in CLL. Unlike in CLL, GRN was not upregulated in chronic myelogenous leukemia (CML) where miR-107 paralogs are not known to be dysregulated. Prior s…
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Posted by rob on November 15, 2010 under Uncategorized |
Acute Myelogenous Leukemia Patients Are at Low Risk for Invasive Fungal Infections after High-Dose Cytarabine Consolidations and Thus Do Not Require Prophylaxis.
Acta Haematol. 2010 Nov 12;124(4):206-213
Authors: Lewis G, Hall P, Eisa N, Deremer D, Dobbins R, El-Geneidy M, Jillella A, Ustun C
We evaluated the frequency of invasive fungal infections (IFI), the frequency of empirical antifungal use (EAFU), and the efficacy of fluconazole prophylaxis on IFI and EAFU after high-dose cytarabine (HiDAC) consolidations. Twenty-seven acute myelogenous leukemia patients in their first complete remission received 76 cycles of HiDAC (median cycle: n = 3). Fluconazole prophylaxis was administered following 44 cycles (fluconazole group) and not given in 32 cycles (control group). IFI (2 episodes) + EAFU (11 episodes) was observed in 13 of 76 cycles (17%); there was no difference between the fluconazole group and the control group (p = 0.469). Neutropenia duration was <13 days in 89% of the 76 cycles and was similar in the fluconazole and control groups (p = 0.845). Neutropenic fever was observed in 34 of the 76 cycles (45%) and was similar in the fluconazole group and the control group (p = 0.43). Although HiDAC cycle 1 was associated with a shorter neutropenia duration, there was no association between HiDAC cycle numbers and neutropenic fever or IFI + EAFU. HiDAC consolidations resulted in a high rate of neutropenic fever, the lack of an appreciable benefit from EAFU, and rare IFI. Most likely because of the low incidence of IFI, use of fluconazole or another antifungal is not warranted in this setting.
PMID: 21071929 [PubMed - as supplied by publisher]
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Targeting AML through DR4 with a novel variant of rhTRAIL.
J Cell Mol Med. 2010 Nov 10;
Authors: Szegezdi E, Reis CR, Van Der Sloot A, Natoni A, O’Reilly A, Reeve J, Cool RH, O’Dwyer M, Knapper S, Serrano L, Quax WJ, Samali A
Despite progress in the treatment of acute myelogenous leukemia (AML) the outcome often remains poor. TNF-Related Apoptosis-Inducing Ligand (TRAIL) is a promising therapeutic agent in many different types of tumors, but AML cells are relatively insensitive to TRAIL-induced apoptosis. Here we show that TRAIL-induced apoptosis in AML cells is predominantly mediated by death receptor 4 (DR4) and not death receptor 5 (DR5). Therefore, we constructed a variant of TRAIL (rhTRAIL-C3) that is a strong inducer of DR4-mediated apoptosis. TRAIL-C3 demonstrated much stronger pro-apoptotic activity than wild type (WT) TRAIL in a panel of AML cell lines as well as in primary AML blasts. The higher pro-apoptotic potential was further enhanced when the TRAIL mutant was used in combination with BMS-345541, a selective inhibitor of Inhibitor-?B kinases. It illustrates that combination of this TRAIL variant with chemotherapeutics or other targeted agents can kill AML with high efficacy. This may represent a major advantage over the currently used therapies that have serious toxic side effects. The high efficacy of rhTRAIL-C3 containing therapies may enable the use of lower drug doses to reduce the toxic side effects and improve patient outcome. Our findings suggest that the rational design of TRAIL variants that target DR4 potentiate the death-inducing activity of TRAIL and offer a novel therapeutic strategy for the treatment of AML.
PMID: 21070598 [PubMed - as supplied by publisher]
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Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR.
Leukemia. 2010 Oct;24(10):1719-24
Authors: Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Bartley PA, Slader C, Field C, Dang P, Filshie RJ, Mills AK, Grigg AP, Melo JV, Hughes TP
Around 40-50% of patients with chronic myeloid leukemia (CML) who achieve a stable complete molecular response (CMR; undetectable breakpoint cluster region-Abelson leukemia gene human homolog 1 (BCR-ABL1) mRNA) on imatinib can stop therapy and remain in CMR, at least for several years. This raises the possibility that imatinib therapy may not need to be continued indefinitely in some CML patients. Two possible explanations for this observation are (1) CML has been eradicated or (2) residual leukemic cells fail to proliferate despite the absence of ongoing kinase inhibition. We used a highly sensitive patient-specific nested quantitative PCR to look for evidence of genomic BCR-ABL1 DNA in patients who sustained CMR after stopping imatinib therapy. Seven of eight patients who sustained CMR off therapy had BCR-ABL1 DNA detected at least once after stopping imatinib, but none has relapsed (follow-up 12-41 months). BCR-ABL1 DNA levels increased in all of the 10 patients who lost CMR soon after imatinib cessation, whereas serial testing of patients in sustained CMR showed a stable level of BCR-ABL1 DNA. This more sensitive assay for BCR-ABL1 provides evidence that even patients who maintain a CMR after stopping imatinib may harbor residual leukemia. A search for intrinsic or extrinsic (for example, immunological) causes for this drug-free leukemic suppression is now indicated.
PMID: 20811403 [PubMed - indexed for MEDLINE]
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Analysis of BCR-ABL1 tyrosine kinase domain mutational spectra in primitive chronic myeloid leukemia cells suggests a unique mutator phenotype.
Leukemia. 2010 Oct;24(10):1817-21
Authors: Grant H, Jiang X, Stebbing J, Foroni L, Craddock C, Griffiths M, Clark RE, O’Brien S, Khorashad JS, Gerrard G, Wang L, Irving JA, Wang M, Karran L, Dyer MJ, Forrest D, Page K, Eaves CJ, Woolfson A
PMID: 20739956 [PubMed - indexed for MEDLINE]
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HH-GV-678, a novel selective inhibitor of Bcr-Abl, outperforms imatinib and effectively overrides imatinib resistance.
Leukemia. 2010 Oct;24(10):1807-9
Authors: Luo H, Quan H, Xie C, Xu Y, Fu L, Lou L
PMID: 20703259 [PubMed - indexed for MEDLINE]
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The impact of HLA matching on long-term transplant outcome after allogeneic hematopoietic stem cell transplantation for CLL: a retrospective study from the EBMT registry.
Leukemia. 2010 Oct;24(10):1725-31
Authors: Michallet M, Sobh M, Milligan D, Morisset S, Niederwieser D, Koza V, Ruutu T, Russell NH, Verdonck L, Dhedin N, Vitek A, Boogaerts M, Vindelov L, Finke J, Dubois V, van Biezen A, Brand R, de Witte T, Dreger P,
We analyzed 368 chronic lymphocytic leukemia patients who underwent allogeneic hematopoietic stem cell transplantation reported to the EBMT registry between 1995 and 2007. There were 198 human leukocyte antigen (HLA)-identical siblings; among unrelated transplants, 31 were well matched in high resolution (‘well matched’ unrelated donor, WMUD), and 139 were mismatched (MM), including 30 matched in low resolution; 266 patients (72%) received reduced-intensity conditioning and 102 (28%) received standard. According to the EBMT risk score, 11% were in scores 1-3, 23% in score 4, 40% in score 5, 22% in score 6 and 4% in score 7. There was no difference in overall survival (OS) at 5 years between HLA-identical siblings (55% (48-64)) and WMUD (59% (41-84)), P=0.82. In contrast, OS was significantly worse for MM (37% (29-48) P=0.005) due to a significant excess of transplant-related mortality. Also OS worsened significantly when EBMT risk score increased. HLA matching had no significant impact on relapse (siblings: 24% (21-27); WMUD: 35% (26-44), P=0.11 and MM: 21% (18-24), P=0.81); alemtuzumab T-cell depletion and stem cell source (peripheral blood) were associated with an increased risk. Our findings support the use of WMUD as equivalent alternative to HLA-matched sibling donors for allogeneic HSCT in CLL, and justify the application of EBMT risk score in this disease.
PMID: 20703257 [PubMed - indexed for MEDLINE]
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Analysis of genomic breakpoints in p190 and p210 BCR-ABL indicate distinct mechanisms of formation.
Leukemia. 2010 Oct;24(10):1742-50
Authors: Score J, Calasanz MJ, Ottman O, Pane F, Yeh RF, Sobrinho-Simões MA, Kreil S, Ward D, Hidalgo-Curtis C, Melo JV, Wiemels J, Nadel B, Cross NC, Grand FH
We sought to understand the genesis of the t(9;22) by characterizing genomic breakpoints in chronic myeloid leukemia (CML) and BCR-ABL-positive acute lymphoblastic leukemia (ALL). BCR-ABL breakpoints were identified in p190 ALL (n=25), p210 ALL (n=25) and p210 CML (n=32); reciprocal breakpoints were identified in 54 cases. No evidence for significant clustering and no association with sequence motifs was found except for a breakpoint deficit in repeat regions within BCR for p210 cases. Comparison of reciprocal breakpoints, however, showed differences in the patterns of deletion/insertions between p190 and p210. To explore the possibility that recombinase-activating gene (RAG) activity might be involved in ALL, we performed extra-chromosomal recombination assays for cases with breakpoints close to potential cryptic recombination signal sequence (cRSS) sites. Of 13 ALL cases tested, 1/10 with p190 and 1/3 with p210 precisely recapitulated the forward BCR-ABL breakpoint and 1/10 with p190 precisely recapitulated the reciprocal breakpoint. In contrast, neither of the p210 CMLs tested showed functional cRSSs. Thus, although the t(9;22) does not arise from aberrant variable (V), joining (J) and diversity (D) (V(D)J) recombination, our data suggest that in a subset of ALL cases RAG might create one of the initiating double-strand breaks.
PMID: 20703256 [PubMed - indexed for MEDLINE]
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Inhibition of Grb2 expression demonstrates an important role in BCR–ABL-mediated MAPK activation and transformation of primary human hematopoietic cells
Leukemia advance online publication, November 12, 2010. doi:10.1038/leu.2010.257
Authors: H Modi, L Li, S Chu, J Rossi, J-K Yee
& R Bhatia (Source: Leukemia)
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Posted by rob on November 12, 2010 under Uncategorized |
Total Body Irradiation (TBI) in Pediatric Patients : A Single-center Experience after 30 Years of Low-dose Rate Irradiation.
Strahlenther Onkol. 2010 Nov 8;
Authors: Linsenmeier C, Thoennessen D, Negretti L, Bourquin JP, Streller T, Lütolf UM, Oertel S
PURPOSE: : To retrospectively analyze patient characteristics, treatment, and treatment outcome of pediatric patients with hematologic diseases treated with total body irradiation (TBI) between 1978 and 2006. PATIENTS AND METHODS: : 32 pediatric patients were referred to the Department of Radiation-Oncology at the University of Zurich for TBI. Records of regular follow-up of 28 patients were available for review. Patient characteristics as well as treatment outcome regarding local control and overall survival were assessed. A total of 18 patients suffered from acute lymphoblastic leukemia (ALL), 5 from acute and 2 from chronic myelogenous leukemia, 1 from non-Hodgkin lymphoma, and 2 from anaplastic anemia. The cohort consisted of 15 patients referred after first remission and 13 patients with relapsed leukemia. Mean follow-up was 34 months (2-196 months) with 15 patients alive at the time of last follow-up. Eight patients died of recurrent disease, 1 of graft vs. host reaction, 2 of sepsis, and 2 patients died of a secondary malignancy. RESULTS: : The 5-year overall survival rate (OS) was 60%. Overall survival was significantly inferior in patients treated after relapse compared to those treated for newly diagnosed leukemia (24% versus 74%; p=0.004). At the time of last follow-up, 11 patients survived for more than 36 months following TBI. Late effects (RTOG ?3) were pneumonitis in 1 patient, chronic bronchitis in 1 patient, cardiomyopathy in 2 patients, severe cataractogenesis in 1 patient (48 months after TBI with 10 Gy in a single dose) and secondary malignancies in 2 patients (36 and 190 months after TBI). Growth disturbances were observed in all patients treated prepubertally. In 2 patients with identical twins treated at ages 2 and 7, a loss of 8% in final height of the treated twin was observed. CONCLUSION: : As severe late sequelae after TBI, we observed 2 secondary malignancies in 11 patients who survived in excess of 36 months. However, long-term morbidity is moderate following treatment with the fractionated TBI at the low-dose rate that was generally used here. Conditioning for bone marrow transplantation without radiation is an attractive option, but is not sufficiently effective to completely replace TBI for the most common pediatric indications.
PMID: 21069270 [PubMed - as supplied by publisher]
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Posted by rob on November 11, 2010 under Uncategorized |
Targeting neuropilin-1 in human leukemia and lymphoma.
Blood. 2010 Nov 9;
Authors: Karjalainen K, Jaalouk DE, Bueso-Ramos CE, Zurita AJ, Kuniyasu A, Eckhardt BL, Marini FC, Lichtiger B, O’Brien S, Kantarjian HM, Cortes JE, Koivunen E, Arap W, Pasqualini R
ABSTRACTTargeted drug delivery offers an opportunity for the development of safer and more effective therapies for the treatment of cancer. In this study, we sought to identify short cell-internalizing peptide ligands that could serve as directive agents for specific drug delivery in hematological malignancies. By screening of human leukemia cells with a combinatorial phage display peptide library, we isolated a peptide motif, sequence F(F)/(Y)XLRS, which bound to different leukemia cell lines and to patient-derived bone marrow samples. The motif was internalized through a receptor-mediated pathway, and we next identified the corresponding receptor as the transmembrane glycoprotein neuropilin-1 (NRP-1). Moreover, we observed a potent anti-leukemia cell effect when the targeting motif was synthesized in tandem to the pro-apoptotic sequence (D)(KLAKLAK)(2). Finally, our results confirmed increased expression of NRP-1 in a representative human leukemia and lymphoma cell lines and in a panel of bone marrow specimens obtained from patients with acute lymphoblastic leukemia or acute myelogenous leukemia compared to normal bone marrow. Taken together, these results indicate that NRP-1 could, potentially, be used as a target for ligand-directed therapy in human leukemias and lymphomas and that the prototype CGFYWLRSC-GG-(D)(KLAKLAK)(2) is a promising drug candidate in this setting.
PMID: 21063027 [PubMed - as supplied by publisher]
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Adamantyl-Substituted Retinoid-Related Molecules Induce Apoptosis in Human Acute Myelogenous Leukemia Cells.
Mol Cancer Ther. 2010 Nov 9;
Authors: Farhana L, Dawson MI, Xia Z, Aboukameel A, Xu L, Liu G, Das JK, Hatfield J, Levi E, Mohammad R, Fontana JA
The adamantyl-substituted retinoid-related (ARR) compounds 3-Cl-AHPC and AHP3 induce apoptosis in vitro and in vivo in a newly established human acute myelogenous leukemia (AML) cell line, FFMA-AML, and in the established TF(v-SRC) AML cell line. FFMA-AML and TF(v-SRC) cells displayed resistance to apoptosis mediated by the standard retinoids (including trans-retinoic acid, 9-cis-retinoic acid, and the synthetic retinoid TTNPB) but showed sensitivity to apoptosis mediated by 3-Cl-AHPC- and AHP3 in vitro and in vivo as documented by poly(ADP-ribose) polymerase (PARP) cleavage and apoptosis terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling assay. 3-Cl-AHPC or AHP3 exposure in vitro resulted in decreased expression of the antiapoptotic proteins (cellular inhibitor of apoptosis 1, X-linked inhibitor of apoptosis protein) and phospho-Bad and activated the NF-?B canonical pathway. A significant prolongation of survival was observed both in nonobese diabetic severe combined immunodeficient mice carrying FFMA-AML cells and treated with either 3-Cl-AHPC or AHP3 and in severe combined immunodeficient mice carrying TF(v-SRC) cells and treated with AHP3. We have previously shown that ARRs bind to the orphan nuclear receptor small heterodimer partner (SHP) and that the expression of SHP is required for ARR-mediated apoptosis. Induced loss of SHP in these AML cells blocked 3-Cl-AHPC- and AHP3-mediated induction of apoptosis. These results support the further development of 3-Cl-AHPC and AHP3 as potential therapeutic agents in the treatment of AML patients. Mol Cancer Ther; 9(11); 2903-13. ©2010 AACR.
PMID: 21062916 [PubMed - as supplied by publisher]
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Hematopathologic and cytogenetic findings in imatinib mesylate treated chronic myelogenous leukemia patients: 2.5 years’ experience.
Vojnosanit Pregl. 2010 Oct;67(10):802-6
Authors: Cojbasi? I, Macukanovi?-Golubovi? L
BACKGROUND/AIM: Imatinib mesylate, a tyrosine kinase inhibitor with specific activity against the breakpoint cluster region–Abelson murine leukemia (BCR-ABL) tyrosine kinase has been developed for treatment of chronic myelogenous leukemia (CML). Its hematologic and cytogenetic effects have been evaluated in a series of clinical trials. The aim of this study was to report hematologic and cytogenetic response in CML patients during the treatment with imatinib mesylate. METHODS: A total of 21 patients were treated and observed from July 2006 to December 2008. The median time from CML diagnosis was no more than 12 months, so all the patients received previous treatment with hydroxyurea for which the median time was 3 months. The patients received imatinib mesylate in an effective oral dose of 400 to 800 mg daily, which was followed with peripheral blood counts, bone marrow examination, and cytogenetic studies at 6, 12, 18 and 24 months. RESULTS: Complete hematologic responses were reported for 19 (90.48%) of 21 patients studied. Among 19 patients who had a response, 16 (86%) did so within 3 months. The best cytogenetic response rate at any time during the study treatment with imatinib mesylate, among 14 patients in which cytogenetic response evaluated was: complete cytogenetic response in 7 (50%) patients, partial cytogenetic response in 6 (42.9%) patients and minor cytogenetic response in 1 (7.1%) patient. No patients had progressed to accelerated or blastic phase. The most frequent adverse effects that seemed to be related to treatment with imatinib mesylate were edema and musculoskeletal pain; overall, most were mild. Only one patient discontinued treatment because of hematologic toxic effects. CONCLUSION: The results obtained in this study confirm that imatinib mesylate induces a complete hematological and cytogenetic response in a high percentage of patients with chronic-phase CML.
PMID: 21061842 [PubMed - in process]
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