Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.1.1.37 (DNA methyltransferase)
 4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

O6-Methylguanine-DNA methyltransferase (MGMT) is an important DNA repair protein that plays a key role in cancer chemotherapy by alkylating agents such as carmustine (BCNU) and Dacarbazine (DTIC). Therapy by BCNU and DTIC is reduced by dose-limiting hematological toxicity as a result of low MGMT repair activity in bone marrow cells. In this study, we have constructed a Moloney murine leukemia virus retroviral vector containing the human mgmt gene. High-titer retrovirus producer cells lines have been generated. Retroviral-mediated transfer of the human mgmt gene into murine multi-potent hematopoietic stem cells, FDCP-1, resulted in the expression of a high level of MGMT activity. In comparison with the control cells that were transduced with the parent vector, the MGMT-expressing clones were considerably more resistant to the cytotoxicity of the methylating agents, such as N-methyl-N'-nitro-N-nitrosoguanidine, N-nitroso-N-methyl-urea, and temozolomide, as well as the chloroethylating agents 1-(2-chloroethyl)-1-nitrosourea and BCNU. The protection provided by MGMT could be eliminated by the MGMT inactivator O6-benzylguanine. Thus, the principal lethal lesions produced by these alkylating agents in the murine hematopoietic stem cells and the MGMT deficiency in these cells can be complemented by retroviral-mediated gene transduction.
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PMID:Retrovirus-mediated transfer of the human O6-methylguanine-DNA methyltransferase gene into a murine hematopoietic stem cell line and resistance to the toxic effects of certain alkylating agents. 864 46

Mutation of the APC gene may be a common denominator of all human colon cancer--polypoid and non-polypoid familial cancer as well as sporadic occurrences. Fearon and Vogelstein (1990) have described a series of molecular changes during the progression of human colon cancer, beginning with mutations in APC. Min is a strain of the laboratory mouse carrying a nonsense mutation in Apc, the mouse homologue of APC. The Min strain has been used to test the effect of germline alterations in certain genes identified in the progression pathway of Fearon and Vogelstein. A deficiency in DNA cytosine methylase leads to a reduction in the tumour multiplicity of Min mice contrary to the a priori expectation based on the global hypomethylation of the DNA of early colonic neoplasms. Alterations in Kras had no perceptible effect on the tumour multiplicity of Min mice but may not have been successfully directed to the proliferative cell population. Constitutional mutation of p53 did not influence the multiplicity or histopathology of early Min induced intestinal tumours. The cause and effect analysis of the genetics of colon cancer is clearly in an early phase. An unlinked genetic factor interacting with Min in controlling intestinal tumour multiplicity is Mom1. A central goal for the near future is to identify the Mom1 gene product and to identify other loci that can interact with the Min mutation and affect tumour multiplicity or progression. Mouse chimaeras will permit an analysis of the clonality and cell autonomy of Min induced neoplasms and also of the action of Mom1. The results of these analyses will inform investigators as to what modes of prevention and therapy might be designed for particular tumour types. The Min strain thereby presents an opportunity to discover protective factors against human colon cancer.
Cancer Surv 1995
PMID:Emergent issues in the genetics of intestinal neoplasia. 871 26

Human breast cancer is often characterized by a progression to an ER (estrogen receptor)-negative, estrogen-independent, antiestrogen-resistant, EGFR (epidermal growth factor receptor)-positive, and highly metastatic phenotype. The molecular and biochemical mechanisms behind this progression are not well defined. Most studies of breast cancer have focused on one or another aspect or this progression but have not found a common pathway. By constructing stable and complete human-human somatic cell fusions between a highly metastatic, undifferentiated, ER-negative line of melanoma lineage and the estrogen-dependent, ER-positive MCF-7 line, this study produced hybrids that were ER negative, highly expressive of EGFR, estrogen independent, estrogen unresponsive, fully tumorigenic, and highly metastatic. ER negativity was on the basis of complete suppression of ER transcription as evidenced by Northern blot analysis and nuclear run-on assay, not on the basis of gene rearrangement. EGFR positivity was not due to gene amplification or rearrangement but rather to increased EGFR transcription. Mechanisms, including ras activation, fibroblast growth factor 4 expression, and human DNA methyltransferase activation causing ER promoter methylation, which are respectively known to induce estrogen-independent growth, induce spontaneous metastasis, and decrease ER levels in breast carcinoma experimentally, were not mechanisms operating in the hybrids. This model demonstrates that many of the common denominators of human breast carcinoma progression can be regulated by dominant trans-acting factors.
Cancer Res 1996 Aug 01
PMID:Human breast cancer progression can be regulated by dominant trans-acting factors in somatic cell hybridization studies. 875 27

DNA methylation is now recognized as an important mechanism regulating different functions of the genome; gene expression, replication, and cancer. Different factors control the formation and maintenance of DNA methylation patterns. The level of activity of DNA methyltransferase (MeTase) is one factor. Recent data suggest that some oncogenic pathways can induce DNA MeTase expression, that DNA MeTase activity is elevated in cancer, and that inhibition of DNA MeTase can reverse the transformed state. What are the pharmacological consequences of our current understanding of DNA methylation patterns formation? This review will discuss the possibility that DNA MeTase inhibitors can serve as important pharmacological and therapeutic tools in cancer and other genetic diseases.
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PMID:The DNA methylation machinery as a target for anticancer therapy. 880 9

Alterations of DNA methylation were investigated in 6 urothelial carcinoma cell lines and 13 tumor tissues. The methylation of L1 LINE sequences was diminished in all cell lines (by 26 +/- 5%; range, 11-49%) and in most tumors (by 21 +/- 5%; range, 0-60%) compared to normal bladder mucosa. Hypermethylation of the calcitonin gene CpG island was restricted to cell lines and was not found in primary tumors, suggesting it had arisen during culture. In single-cell clones of a urothelial carcinoma cell line, both hypomethylation of L1 sequences and hypermethylation of the calcitonin gene persisted, indicating that they coexist within one cell. DNA methyltransferase expression did not correlate with the methylation status of the cell lines, but rather with histone H3 expression. Accordingly, it was down-regulated in quiescent cells. Aberrant expression of DNA methyltransferase is therefore not likely the cause for altered methylation patterns in urothelial carcinoma. L1 LINE hypomethylation seems to prevail in urothelial carcinoma and in this tumor might be useful for diagnostic or prognostic purposes.
Cancer Res 1996 Dec 15
PMID:Hypomethylation of L1 LINE sequences prevailing in human urothelial carcinoma. 897 Nov 78

To determine whether loss of imprinting in cancer might be reversed by altering DNA methylation, we treated tumor cells with 5-aza-2'-deoxycytidine, a specific inhibitor of cytosine DNA methyltransferase. Treated cells showed several significant and reproducible changes. (a) Equal expression of maternal and paternal alleles of insulin-like growth factor 2 switched to predominant expression of a single parental allele. (b) H19 expression was reactivated. (c) Biallelic H19 expression switched to monoallelic expression. (d) Biallelic methylation of H19 switched to preferential allelic methylation. These results imply that abnormally imprinted cells are susceptible to epigenetic modification and that the effect of 5-aza-2'-deoxycytidine on tumor cells with loss of imprinting is not random but specific to one allele.
Cancer Res 1997 Jan 01
PMID:Reversal of loss of imprinting in tumor cells by 5-aza-2'-deoxycytidine. 898 39

This paper tests the hypothesis that cytosine DNA methyltransferase (DNA MeTase) is a candidate target for anticancer therapy. Several observations have suggested recently that hyperactivation of DNA MeTase plays a critical role in initiation and progression of cancer and that its up-regulation is a component of the Ras oncogenic signaling pathway. We show that a phosphorothioate-modified, antisense oligodeoxynucleotide directed against the DNA MeTase mRNA reduces the level of DNA MeTase mRNA, inhibits DNA MeTase activity, and inhibits anchorage independent growth of Y1 adrenocortical carcinoma cells ex vivo in a dose-dependent manner. Injection of DNA MeTase antisense oligodeoxynucleotides i.p. inhibits the growth of Y1 tumors in syngeneic LAF1 mice, reduces the level of DNA MeTase, and induces demethylation of the adrenocortical-specific gene C21 and its expression in tumors in vivo. These results support the hypothesis that an increase in DNA MeTase activity is critical for tumorigenesis and is reversible by pharmacological inhibition of DNA MeTase.
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PMID:Inhibition of tumorigenesis by a cytosine-DNA, methyltransferase, antisense oligodeoxynucleotide. 901 45

The Min mouse, generated by random germline mutagenesis, carries a mutation in the mouse homolog of APC and is a model of inherited human intestinal tumorigenesis. To identify other genes in the pathway(s) of intestinal tumorigenesis, genes that modify the Min phenotype have been sought. Several have been identified, including Mom1 and the genes for the 5-cytosine DNA methyltransferase and the DNA mismatch repair factor Msh2. Min-dependent tumorigenesis also occurs in mammary glands, the pancreas, and the body wall. The Min mouse has therefore become a model for tumorigenesis in a variety of organs. Identifying modifiers of its phenotype will help in piecing together the pathways of tumorigenesis in each of these tissues.
Semin Cancer Biol 1996 Oct
PMID:Manipulation of the mouse germline in the study of Min-induced neoplasia. 911 Apr 2

Cytosine methylation is an important mechanism of gene regulation in mammals. Mouse embryos with reduced DNA methylation due to targeted disruption of the DNA methyltransferase gene show deregulated expression of imprinted genes. Loss of imprinting associated with loss of allele-specific methylation is one example of an epigenetic alteration found in tumor cells. Changes in DNA methylation may also be associated with facilitating protooncogene expression and inactivating tumor suppressor genes. However, cytosine methylation has additional deleterious consequences for the genome as well. CpG dinucleotides, the target of DNA methylation, are five-fold underpresented in the genome due to the high mutability of methylated cytosine. C-T transition mutations resulting from deamination of 5-methylcytosine are involved in both genetic disease and cancer. Lastly, aberrant DNA methylation may promote the genetic instability of a chromosomal locus. We review the genetic and epigenetic roles for DNA methylation during tumorigenesis gleaned from altered methycytosine patterns in tumor cells, and from pharmacologic, dietary or genetic manipulation of DNA methylation levels.
Semin Cancer Biol 1996 Oct
PMID:Experimental manipulation of genomic methylation. 911 Apr 3

The cytosine analog 5-aza-2'-deoxycytidine has been used clinically to reactivate genes silenced by DNA methylation. In particular, patients with beta-thalassemia show fetal globin expression after administration of this hypomethylating drug. In addition, silencing of tumor suppressor gene expression by aberrant DNA methylation in tumor cells may potentially be reversed by a similar regimen. Consistent with its function in maintaining tumor suppressor gene expression, 5-aza-2'-deoxycytidine significantly reduces intestinal tumor multiplicity in the predisposed Min mouse strain. Despite its utility as an anti-cancer agent, the drug is highly mutagenic by an unknown mechanism. To gain insight into how 5-aza-2'-deoxycytidine induces mutations in vivo, we examined the mutational spectrum in an Escherichia coli lac I transgene in colonic DNA from 5-aza-2'-deoxycytidine-treated mice. Mutations induced by 5-aza-2'-deoxycytidine were predominantly at CpG dinucleotides, which implicates DNA methyltransferase in the mutagenic mechanism. C:G-->G:C transversions were the predominant class of mutations observed. We suggest a model for how the mammalian DNA methyltransferase may be involved in facilitating these mutations. The observation that 5-aza-2'-deoxycytidine-induced mutations are mediated by the enzyme suggests that novel inhibitors of DNA methyltransferase, which can inactivate the enzyme before its interaction with DNA, are needed for chemoprevention or long term therapy.
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PMID:Mutagenicity of 5-aza-2'-deoxycytidine is mediated by the mammalian DNA methyltransferase. 911 51


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