Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our understanding and treatment of chronic myelogenous leukemia (CML) has progressed since 1960 in parallel with work on cancer in general. CML provided the first evidence of a specific genetic change associated with a human cancer (the Philadelphia chromosome) and the clonal nature of these disorders. With improved cytogenetic and molecular techniques over subsequent decades, the specific genetic rearrangements of CML and many other tumors were defined and the complex mechanisms of carcinogenesis gradually unraveled. During this period, improved treatments for CML (chemotherapy, interferon, bone marrow transplantation) were implemented, and therapy targeted to the specific genetic change in the leukemic cells has recently been brought to promising clinical trials. Similar efforts are under way for other human cancers, and although the problem is enormously complex, there is real hope for major improvements in controlling these disorders.
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PMID:Progress with chronic myelogenous leukemia: a personal perspective over four decades. 1181 60

Xenopus Strabismus (Stbm) is a negative regulator of the WNT - beta-catenin signaling pathway. Strabismus 1 (STB1/VangL2) and Strabismus 2 (STB2/Vangl1) are human homologues of Xenopus Stbm and Drosophila Stbm/ Van Gogh (Vang) STB1 and STB2 are four-transmembrane-type proteins with Dishevelled-binding motif. STB2 and CASQ2 genes are located on human chromosome 1p13.3-p11 with an interval less than 5 kb. Here, STB1 gene and CASQ1 gene were found to be located on human chromosome 1q21-q23 with an interval of about 210 kb including Nicastrin, COPA, PXF, H326 and PEA15 genes. Exon-intron structure was well conserved between STB1 and STB2 genes. STB1-CASQ1 gene cluster and STB2-CASQ2 gene cluster might be generated due to duplication of ancestral gene cluster, and several genes might be inserted into the STB1-CASQ1 intergenic region during or after gene-cluster duplication. STB1 mRNA was relatively highly expressed in prostate, trachea, thymus, lymph node, placenta, fetal kidney, fetal brain, and fetal lung. In adult brain, STB1 mRNA was more highly expressed in cerebellum, corpus callosum, amygdala, and medulla oblongata. STB1 mRNA was moderately expressed in K-562 (chronic myelogenous leukemia), G-361 (melanoma), and MKN7 (gastric cancer). On the other hand, STB1 mRNA was almost undetectable in several human cancer cell lines, and was down-regulated in 4 out of 14 cases of primary kidney tumors, and in 2 out of 3 cases of primary lung cancer. Loss-of-function mutation of STB1 gene might lead to carcinogenesis through activation of the WNT - beta-catenin signaling pathway.
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PMID:Structure and expression of Strabismus 1 gene on human chromosome 1q21-q23. 1201 99

Reactive carbonyl species (RCS) are potent mediators of cellular carbonyl stress originating from endogenous chemical processes such as lipid peroxidation and glycation. Skin deterioration as observed in photoaging and diabetes has been linked to accumulative protein damage from glycation, but the effects of carbonyl stress on skin cell genomic integrity are ill defined. In this study, the genotoxic effects of acute carbonyl stress on HaCaT keratinocytes and CF3 fibroblasts were assessed. Administration of the alpha-dicarbonyl compounds glyoxal and methylglyoxal as physiologically relevant RCS inhibited skin cell proliferation, led to intra-cellular protein glycation as evidenced by the accumulation of N(epsilon)-(carboxymethyl)-L-lysine (CML) in histones, and caused extensive DNA strand cleavage as assessed by the comet assay. These effects were prevented by treatment with the carbonyl scavenger D-penicillamine. Both glyoxal and methylglyoxal damaged DNA in intact cells. Glyoxal caused DNA strand breaks while methylglyoxal produced extensive DNA-protein cross-linking as evidenced by pronounced nuclear condensation and total suppression of comet formation. Glycation by glyoxal and methylglyoxal resulted in histone cross-linking in vitro and induced oxygen-dependent cleavage of plasmid DNA, which was partly suppressed by the hydroxyl scavenger mannitol. We suggest that a chemical mechanism of cellular DNA damage by carbonyl stress occurs in which histone glycoxidation is followed by reactive oxygen induced DNA stand breaks. The genotoxic potential of RCS in cultured skin cells and its suppression by a carbonyl scavenger as described in this study have implications for skin damage and carcinogenesis and its prevention by agents selective for carbonyl stress.
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PMID:DNA damage by carbonyl stress in human skin cells. 1251 11

Normal cell development and function is dependent upon controlled gene expression. DNA methylation is an epigenetic modification that can play an important role in the control of gene expression. DNA methylation at cytosine residues in gene promoter CpG sequences is known to inhibit gene transcription. Inappropriate inhibition of the transcription of tumour suppressor genes, genes that inhibit angiogenesis and metastasis and genes involved in DNA repair by uncontrolled methylation, can lead to unregulated growth and proliferation of a cell and carcinogenesis. Promoter hypermethylation affecting the p16 gene, resulting in gene silencing, has been shown to occur in many human solid tumours and a 'hypermethylation profile' in some leukaemias has been defined. The molecular mechanisms by which aberrant DNA methylation takes place during carcinogenesis are still not clear. However, the large number of target genes (involved in tumorigenesis) that are silenced by aberrant methylation suggests that inhibition of this process may have potential as cancer therapy. Decitabine (NSC-127716, Dacogen; SuperGen) is a potent and specific hypomethylating agent and an inhibitor of the DNA methyltransferase activity that mediates DNA methylation. Decitabine has been shown to have a broad range of antineoplastic activity in preclinical studies. This agent has exhibited significant activity in the treatment of patients with myelodysplastic syndrome, chronic myeloid leukaemia and acute myeloid leukaemia, although clinical Phase I and II studies with solid tumours have not been very promising. Phase II and III studies are currently ongoing to evaluate decitabine, both alone and in combination, in various stages of these haematological malignancies.
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PMID:DNA methylation in haematological malignancies: the role of decitabine. 1464 Sep 42

A search for new agents that can sensitise cancer cells to ionising radiation is of continual interest and mainly due to the use of radiation in cancer therapy. Resveratrol, a powerful antioxidant has been shown to inhibit carcinogenesis in animal models. The purpose of this study was to examine whether resveratrol can sensitise cancer cells to X-irradiation. The human cancer cell lines examined were HELA (cervix carcinoma), K-562 (chronic myeloid leukemia) and IM-9 (multiple myeloma). The assays that were performed following X-irradiation (doses from 0 to 8 Gy) and/or incubation in the presence of resveratrol (concentrations ranging from 0 to 200 microM), were the following: trypan blue exclusion test to determine cell viability, cell morphology after May-Grunwald Giemsa staining, DNA profile analysis by flow cytometry to assess cell cycle distribution and the presence of the sub-G1 peak. The cell lines showed different radiation sensitivity (IM-9, high radiation sensitivity, K-562, intermediate radiation sensitivity and HELA, low radiation sensitivity) as seen by the X-irradiation dose related inhibition of cell growth and induction of apoptosis. The addition of resveratrol alone to the cell cultures induced apoptosis and inhibited cell growth from 50 (IM-9), 100 (EOL-1) or 200 microM (HELA) resveratrol concentrations. Concomitant treatment of the cells with either resveratrol and X-irradiation induced a synergical effect at the highest dose of 200 microM. These results show that resveratrol can act as a potential radiation sensitiser at high concentrations. Further studies need to address the toxicity of resveratrol on normal cells.
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PMID:Enhanced radiation-induced apoptosis of cancer cell lines after treatment with resveratrol. 1513 32

Cancer is the second leading cause of death in the western world. Despite advances in diagnosis and treatment, overall survival of patients remains poor. Scientific advances in recent years have enhanced our understanding of the biology of cancer. Human protein tyrosine kinases (PTKs) play a central role in human carcinogenesis and have emerged as the promising new targets. Several approaches to inhibit tyrosine kinase have been developed. These agents have shown impressive anticancer effects in preclinical studies and are emerging as promising agents in the clinic. The remarkable success of BCR-ABL tyrosine kinase inhibitor imatinib (STI571) in the treatment of chronic myeloid leukaemia has particularly stimulated intense research in this field. At least 30 inhibitors are in various stages of clinical development in cancer, and about 120 clinical trials are ongoing worldwide. In this review, we focus on the role of tyrosine kinases in cancer and the development of specific small molecule inhibitors for therapy. We also provide a critical analysis of the current data on tyrosine kinase inhibitors and highlight areas for future research. Issues with regards to the design of clinical trials with such agents are also discussed. Innovative approaches are needed to fully evaluate the potential of these agents, and a concerted international effort will hopefully help to integrate these inhibitors in cancer therapy in the near future.
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PMID:Tyrosine kinase inhibitors in cancer therapy. 1523 43

Several studies, performed according to hypotheses based on teratogenesis and carcinogenesis have tried to answer the question: Do parents of children with congenital anomalies have a higher cancer risk? If the general answer is no, however, a higher risk for cancer was reported in the parents of children with cleft lip/palate (Zhu et al. [2002: Br J Cancer 87:524-528]). In achondroplasia, the neo-mutations are from paternal origin raising the hypothesis of the existence of a "mutator" gene acting in male meiosis and in somatic, mitotic cells in both sexes which may favor also the occurrence of cancer. In order to test this hypothesis, a questionnaire was sent to people with non-familial achondroplasia, asking for cancer, lymphoma, and leukemia in their parents and grandparents. In the hypothesis tested, the maternal lineage was the control. One hundred forty eight answers were obtained from 76 males and 72 females with achondroplasia. Out of them 68 had parents and/or grandparents with cancer. Among the grandparents of people with achondroplasia there were 36 cancers including two lymphomas in the paternal grandparents, 20 cancers including two chronic myeloid leukemia (CML) in the paternal grandmothers, 22 cancers including two CML in the maternal grandfathers, and two cancers in the maternal grandmothers. Paternal grandfathers and grandmothers had significantly more cancers (56) than maternal grandfathers and grandmothers (24) (chi(2)-test = 14.80, P < 0.001). In conclusion, paternal grandfathers and grandmothers of people with achondroplasia had significantly more cancers than maternal grandfathers and grandmothers. This result raises hypotheses in relationship with the paternal origin of neo-mutations in achondroplasia.
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PMID:Do parents and grandparents of patients with achondroplasia have a higher cancer risk? 1537 18

A specific treatment for gastrointestinal stromal tumors (GIST) has been found through improved understanding of the molecular mechanism of carcinogenesis. GIST are radio and chemo-resistant (less than 10 objective responses). Stromal tumors originate from the multiplication of the cells of Cajal, which intervene in intestinal motility and express the c-Kit gene, also called CD117, on their surface. CD117 is a protein with tyrosine kinase activity, and can be demonstrated through immunohistochemical staining techniques. Treatment with Imatinib mesylate (Glivec), a recently discovered selective inhibitor of tyrosine kinases already used in chronic myeloid leukemia (in which an overexpression of tyrosine kinase is observed) was associated with tumor regression of more than 50% in the initial series of patients with GIST treated in 2001. Since then, approximately 2,000 patients have been included in therapeutic trials, with an objective response rate between 60% and 70% 12 to 18 months after inclusion. The clinical benefit has been estimated at 80% to 90% in patients whose chance of survival until now has been less than 30% at one year (median survival 18 months). Nonetheless, imatinib mesylate has not shown any activity in CD117-negative sarcoma (10% of sarcoma). The therapeutic importance of this drug in the treatment of solid GI tumors deemed inoperable is considerable.
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PMID:Treatment of gastrointestinal stromal tumors with imatinib mesylate: a major breakthrough in the understanding of tumor-specific molecular characteristics. 1570 44

Despite its decreasing frequency in the Western world during recent decades, gastric cancer is still one of the leading causes of cancer-related deaths worldwide. Due to the oligosymptomatic course of early gastric cancer, most cases are diagnosed in the advanced stages of the disease. The curative potential of current standard treatment continues to be unsatisfactory, despite multimodal approaches involving surgery, chemotherapy and radiotherapy. Novel therapeutics including small molecules and monoclonal antibodies are being developed and have been partially introduced into clinical use in connection with neoplastic diseases such as chronic myeloid leukemia, non-Hodgkin's lymphoma and colorectal cancer. Thorough understanding of the changes in gene expression occurring during gastric carcinogenesis may help to develop targeted therapies and improve the treatment of this disease. Novel molecular biology techniques have generated a wealth of data on up- and down-regulation, activation and inhibition of specific pathways in gastric cancer. Here, we provide an overview of the different aspects of aberrant gene expression patterns in gastric cancer.
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PMID:Gene deregulation in gastric cancer. 1615 15

The transcription factor aryl hydrocarbon receptor (AhR) has relevant functions in cell proliferation. Interestingly, the AhR can either promote or inhibit proliferation depending on the cell phenotype. Although recent data reveal potential pathways for AhR signaling in cell proliferation, the mechanisms that regulate its activity in tumor cells remain unknown. Here, we have analyzed promoter hypermethylation as a potential mechanism controlling AhR expression in human tumor cells. AhR promoter CpG methylation was sporadic in a panel of 19 tumor cell lines except for the chronic myeloid leukemia (CML) K562 and the acute lymphoblastic leukemia (ALL) REH. When compared with normal lymphocytes, REH had very low constitutive AhR expression that could be attributed to promoter hypermethylation since treatment with the DNA demethylating agent 5-aza-2'-deoxycitidine (AZA) significantly increased AhR mRNA and protein. These results in leukemia-derived cell lines were further confirmed in primary ALL, where 33% of the patients (7/21) had AhR promoter hypermethylation. Chromatin immunoprecipitation (ChIP) showed that methylation impaired binding of the transcription factor Sp1 to the AhR promoter, thus providing a mechanism for AhR downregulation in REH cells. Therefore, promoter hypermethylation represents a novel epigenetic mechanism downregulating AhR activity in hematological malignancies such as ALL.
Carcinogenesis 2006 May
PMID:The dioxin receptor is silenced by promoter hypermethylation in human acute lymphoblastic leukemia through inhibition of Sp1 binding. 1641 Feb 62


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