Abstract:
:Targeting the tyrosine kinase activity of Bcr-Abl is an attractive therapeutic strategy in chronic myeloid leukemia (CML) and in Bcr-Abl-positive acute lymphoblastic leukemia. Whereas imatinib, a selective inhibitor of Bcr-Abl tyrosine kinase, is now used in frontline therapy for CML, second-generation inhibitors of Bcr-Abl tyrosine kinase such as nilotinib or dasatinib have been developed for the treatment of imatinib-resistant or imatinib-intolerant disease. In the current study, we generated nilotinib-resistant cell lines and investigated their mechanism of resistance. Overexpression of BCR-ABL and multidrug resistance gene (MDR-1) were found among the investigated mechanisms. We showed that nilotinib is a substrate of the multidrug resistance gene product, P-glycoprotein, using verapamil or PSC833 to block binding. Up-regulated expression of p53/56 Lyn kinase, both at the mRNA and protein level, was found in one of the resistant cell lines and Lyn silencing by small interfering RNA restored sensitivity to nilotinib. Moreover, failure of nilotinib treatment was accompanied by an increase of Lyn mRNA expression in patients with resistant CML. Two Src kinase inhibitors (PP1 and PP2) partially removed resistance but did not significantly inhibit Bcr-Abl tyrosine kinase activity. In contrast, dasatinib, a dual Bcr-Abl and Src kinase inhibitor, inhibited the phosphorylation of both BCR-ABL and Lyn, and induced apoptosis of the Bcr-Abl cell line overexpressing p53/56 Lyn. Such mechanisms of resistance are close to those observed in imatinib-resistant cell lines and emphasize the critical role of Lyn in nilotinib resistance.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Mahon FX,Hayette S,Lagarde V,Belloc F,Turcq B,Nicolini F,Belanger C,Manley PW,Leroy C,Etienne G,Roche S,Pasquet JMdoi
10.1158/0008-5472.CAN-08-1008subject
Has Abstractpub_date
2008-12-01 00:00:00pages
9809-16issue
23eissn
0008-5472issn
1538-7445pii
68/23/9809journal_volume
68pub_type
杂志文章相关文献
CANCER RESEARCH文献大全abstract::A high-affinity localization of [2H]methylcholanthrene and/or its metabolites to a specific nuclear fraction (Fraction l) between 4 and 72 hr of exposure is described. Other carcinogenic hydrocarbons, such as benzo(a)pyrene and dibenz(a,h)anthracene, demonstrate a similar markded localization in Fraction l after 24 hr...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1977-05-01 00:00:00
abstract::5-lodo-2'-deoxyuridine (lUdR) significantly increases the total number of spleen cells on the fourth day after administration of 100 mg/kg in normal C3HeB/FeJ male mice. The number of splenic B-cells [cells sensitive to the cytotoxic activity of a rabbit antiserum to mouse F(ab)2, plus complement] increases on the sam...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1976-01-01 00:00:00
abstract::Phosphorylation of histone H3 at Ser-10 is required for maintenance of properchromosome dynamics during mitosis. AIM-1, a mammalian Ipl1/aurora kinase involved in H3 phosphorylation, is transcriptionally overexpressed in many tumor cell lines. Increased expression of the AIM-1 gene has been observed in human colorecta...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2002-09-15 00:00:00
abstract::We have investigated the antiproliferative and cytotoxic effects of selected enediynes against three Kaposi's sarcoma (KS) cell lines. The enediynes tested were found to be very potent in inhibiting the growth of KS cells. Treatment with concentrations of 10(-10) M or less were capable of producing 50% inhibition of g...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1994-08-15 00:00:00
abstract::Antigenic stimulation of athymic mice on the BALB/c background by infection with the pinworms Aspiculuris tetraptera and Syphacia obvelata or by xenografts of human tumors induced a proliferation of T- and B-lymphocytes in spleen and lymph nodes and occasional germinal center formation. The proliferating T-lymphocytes...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1981-06-01 00:00:00
abstract::Von Hippel-Lindau (VHL) tumor suppressor protein is expressed in neurons of the central nervous system and plays an important role during the neuronal differentiation of central nervous system progenitor cells. To elucidate the neuronal differentiating potential of VHL protein in neuroblastoma cells, we overexpressed ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2002-12-01 00:00:00
abstract::Adrenocortical carcinoma (ACC) is a rare disease with an overall poor but heterogeneous prognosis. This heterogeneity could reflect different mechanisms of tumor development. Gene expression profiling by transcriptome analysis led to ACC being divided into two groups of tumors with very different outcomes. Somatic ina...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-10-2014
更新日期:2010-11-01 00:00:00
abstract::The majority of BRCA1-associated breast cancers are basal cell-like, which is associated with a poor outcome. Using a spontaneous mouse mammary tumor model, we show that platinum compounds, which generate DNA breaks during the repair process, are more effective than doxorubicin in Brca1/p53-mutated tumors. At 0.5 mg/k...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-07-5480
更新日期:2008-05-01 00:00:00
abstract::We searched for potential suppressors of tumor metastasis by identifying the genes that are frequently down-regulated in hepatocellular carcinomas (HCC) while being negatively correlated with clinical parameters relevant to tumor metastasis, and we report here on the identification of N-myc downstream regulated gene 2...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-07-5040
更新日期:2008-06-01 00:00:00
abstract::The epidermal growth factor (EGF) receptor in two colon carcinoma lines and in one vulval carcinoma line tested contains carbohydrate determinants that are recognized by monoclonal antibodies to tumor-associated antigens. These antibodies are directed to sialylated Lea and to difucosylated structures of the Y type. Ce...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1987-05-15 00:00:00
abstract::Phase I evaluation of spiromustine was performed using an every-3-week schedule and a weekly X 3 schedule. Neurotoxicity was the dose-limiting toxicity presenting as alterations in cortical integrative functions (orientation, language, coordination), leading to a decrease in the level of consciousness. Traditional cri...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1987-08-01 00:00:00
abstract::The effects of transforming growth factor-beta (TGF beta) on a human colon carcinoma cell line (MOSER) were investigated. TGF beta, at low concentrations (between 0.1 and 1.0 ng/ml), inhibited the proliferation of MOSER cells both in monolayer culture and soft agarose, in a dose-dependent manner. MOSER cells adapted t...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1987-06-01 00:00:00
abstract::Immunologic targeting of the oncoprotein HER2/neu with monoclonal antibodies is an important component of current therapeutic strategies for patients with locally and systemically advanced breast cancer. Engineered antibodies targeting HER2 may have agonist or antagonist effects on HER2, but little is known about whet...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2005-01-15 00:00:00
abstract::Accurate normalization is an absolute prerequisite for correct measurement of gene expression. For quantitative real-time reverse transcription-PCR (RT-PCR), the most commonly used normalization strategy involves standardization to a single constitutively expressed control gene. However, in recent years, it has become...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-04-0496
更新日期:2004-08-01 00:00:00
abstract::Gene targeting studies in mice have shown that the transcription factor Ikaros plays an essential role in lymphoid development and as a tumor suppressor in T cells, whereas the related gene Aiolos functions as a tumor suppressor in B cells. We analyzed the expression levels of the Ikaros gene family, Ikaros and Aiolos...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2000-08-01 00:00:00
abstract::Although regulatory T cells (Tregs) have been detected in clinically apparent and experimentally induced tumors, the significance of their presence is obscured because past studies examined late-stage tumors that had formed in immunocompetent hosts and thus had evolved mechanisms to escape immunologic recognition and/...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-06-0556
更新日期:2006-07-15 00:00:00
abstract::Immunotherapy based on adoptive transfer of tumor antigen-specific CD8(+) T cell (TC) is generally limited by poor in vivo expansion and tumor infiltration. In this study, we report that activated STAT5 transcription factors (STAT5CA) confer high efficiency on CD8(+) effector T cells (eTC) for host colonization after ...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-11-2187
更新日期:2012-01-01 00:00:00
abstract::Hollow organs lined by columnar epithelial cells normally secrete mucins and their proteolytic fragments vectorially into the lumen. These heterogeneously O-glycosylated molecules are known to aberrantly enter the bloodstream in the setting of epithelial carcinomas and possibly during injury or inflammation. We have r...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-05-3851
更新日期:2006-02-15 00:00:00
abstract::Polymeric interstitial chemotherapy increases survival of humans with recurrent gliomas and animals with transplanted tumors in the brain, but the relationship between rates of drug release from polymer implants and drug concentration in brain tissue is unknown. This work presents a pharmacokinetic framework for appli...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1998-02-15 00:00:00
abstract::The study of two major risk factors in the development of hepatocellular carcinoma, namely persistent hepatitis virus infection and exposure to dietary aflatoxins, has been hampered by lack of an experimental system. To this end we have used a Pekin duck model to examine the effect of congenital duck hepatitis B virus...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1990-04-01 00:00:00
abstract::To understand the involvement of allelic losses and inactivation of tumor suppressor genes for the development of endometrial carcinoma of the uterus (EC), 24 cases of EC were examined for loss of heterozygosity (LOH) using a total of 57 polymorphic DNA markers covering all 23 pairs of chromosomes. LOH was observed at...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1991-10-15 00:00:00
abstract::Prostate cancer (PCa) is the most common male cancer in the United States. A major challenge that remains is to predict the clinical outcome in managing PCa patients. The prolyl isomerase Pin1 has been shown to be overexpressed in some human cancer tissues and thought to be an important player in several oncogenic pat...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2003-10-01 00:00:00
abstract::One of the most promising new avenues for the development of more selective and efficacious cancer therapies relies on the antibody-mediated targeted delivery of bioactive agents (e.g., cytokines) to the tumor environment. The identification of quantitative differences in the expression of accessible vascular proteins...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-07-1436
更新日期:2007-11-15 00:00:00
abstract::We have shown previously that IgM from Ehrlich tumor (ET)-immunized mice, recognizing ET cell surface carbohydrates, protects control mice to a subsequent tumor challenge. The factors involved in such IgM-mediated protection were unknown, since it was independent of complement activation. Here, we have extended these ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1990-11-15 00:00:00
abstract::Acute lymphoblastic leukemia (ALL) with 11q23 translocations is usually associated with MLL gene rearrangement, but little is known about its leukemogenesis. We analyzed the gene expression profiles of pediatric ALL samples according to their translocations. Using oligonucleotide microarray analysis, we identified dis...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2003-08-15 00:00:00
abstract::We report that tumor necrosis factor (TNF) alpha induced a strong antitumor immune reaction when it was produced in arteries leading to tumors by gene transfer in vivo. We used a mouse model carrying a sarcoma-180 tumor in the right footpad and injected the fusogenic liposomes encapsulating the human TNF-alpha gene in...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1998-12-15 00:00:00
abstract::Whole-slide histology images contain information that is valuable for clinical and basic science investigations of cancer, but extracting quantitative measurements from these images is challenging for researchers who are not image analysis specialists. In this paper, we describe HistomicsML2, a software tool for learn...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-20-0668
更新日期:2020-12-21 00:00:00
abstract::The clinical utility of cisplatin to treat human malignancies is often limited by the development of drug resistance. We have previously shown that cisplatin-resistant human KB adenocarcinoma cells that are cross-resistant to methotrexate and heavy metals have altered endocytic recycling. In this work, we tracked lipi...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-05-3436
更新日期:2006-02-15 00:00:00
abstract::In humans and rabbits, differences in the rate of N-acetylation of aromatic amines are under polymorphic genetic control. Individuals are classified as either rapid or slow acetylators. In the current study, the relationship between acetylator phenotype and susceptibility to the genotoxicities of benzidine, 4-aminobip...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1983-07-01 00:00:00
abstract::Among the many proteases associated with human cancer, seprase or fibroblast activation protein alpha, a type II transmembrane glycoprotein, has two types of EDTA-resistant protease activities: dipeptidyl peptidase and a 170-kDa gelatinase activity. To test if activation of gelatinases associated with seprase could be...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-06-1499
更新日期:2006-10-15 00:00:00