Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The effect of 3-alkyl substituted imidazotetrazinones on methylation of DNA has been studied in drug sensitive and resistant cell lines. The 3-methyl analogue (Temozolomide) has been shown to cause a decrease in the level of 5-methylcytosine in newly synthesized DNA in both cell lines, although the effect occurred at lower drug concentrations in the drug sensitive cell line. In order to investigate the mechanism of hypomethylation of DNA, calf thymus DNA was alkylated in vitro by both Temozolomide and the 3-ethyl analogue, CCRG 82019, and the alkylated DNA was shown to inhibit the transfer of methyl groups from S-adenosyl-L-methionine to M. lysodeikticus DNA by purified eukaryotic DNA methylase. Neither free drug alone or unmodified DNA affected the methylase reaction. Calf thymus DNA modified with CCRG 82019 was more effective as a methylase inhibitor than DNA modified with Temozolomide, which was a reverse of the order of potencies of the free drugs against tumour cells in culture. CCRG 82019 modified DNA also formed a more stable complex with nuclear proteins. Alterations in the level of 5-methylcytosine in DNA may be important in the alteration of gene expression by these agents.
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PMID:Antitumour imidazotetrazines and gene expression. 320 8

Temozolomide (TMZ) is a methylating agent which prolongs survival when administered during and after radiotherapy in the first-line treatment of glioblastoma and which also has significant activity in recurrent disease. O6-methylguanine DNA methyltransferase (MGMT) is a DNA repair enzyme attributed a role in cancer cell resistance to O6-alkylating agent-based chemotherapy. Using a panel of 12 human glioma cell lines, we here defined the sensitivity to TMZ in acute cytotoxicity and clonogenic survival assays in relation to MGMT, mismatch repair and p53 status and its modulation by dexamethasone, irradiation and BCL-X(L). We found that the levels of MGMT expression were a major predictor of TMZ sensitivity in human glioma cells. MGMT activity and clonogenic survival after TMZ exposure are highly correlated (p < 0.0001, r2 = 0.92). In contrast, clonogenic survival after TMZ exposure does not correlate with the expression levels of the mismatch repair proteins mutS homologue 2, mutS homologue 6 or post-meiotic segregation increased 2. The MGMT inhibitor O6-benzylguanine sensitizes MGMT-positive glioma cells to TMZ whereas MGMT gene transfer into MGMT-negative cells confers protection. The antiapoptotic BCL-X(L) protein attenuates TMZ cytotoxicity in MGMT-negative LNT-229 but not in MGMT-positive LN-18 cells. Neither ionizing radiation (4 Gy) nor clinically relevant concentrations of dexamethasone modulate MGMT activity or TMZ sensitivity. Abrogation of p53 wild-type function strongly attenuates TMZ cytotoxicity. Conversely, p53 mimetic agents designed to stabilize the wild-type conformation of p53 sensitize glioma cells for TMZ cytotoxicity. Collectively, these results suggest that the determination of MGMT expression and p53 status will help to identify glioma patients who will or will not respond to TMZ.
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PMID:O6-methylguanine DNA methyltransferase and p53 status predict temozolomide sensitivity in human malignant glioma cells. 1640 12

Temozolomide (TMZ) is an alkylating agent earlier approved for recurrent anaplastic astrocytoma and approved for the treatment of newly diagnosed glioblastoma in the USA and Europe in 2005. TMZ shows good blood-brain barrier penetration and exhibits a favorable side effect profile. Its key mode of action appears to be methylation at N(7) and O(6)-positions of guanine. The level of expression and activity of the DNA repair enzyme O(6)-methylguanine DNA methyltransferase is thought to be a major predictor of response to TMZ. The demonstration of prolonged survival when TMZ was added to radiotherapy in the European Organisation for Research and Treatment of Cancer 26981/22981/NCIC CE.3 trial has been a breakthrough in the treatment of newly diagnosed glioblastoma. The early preliminary evidence for activity in recurrent malignant gliomas further resulted in a broad evaluation of TMZ for other tumors in neuro-oncology, mainly low-grade gliomas, brain metastases and primary cerebral lymphomas.
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PMID:Temozolomide: a milestone in the pharmacotherapy of brain tumors. 1655 52

Glioblastoma multiforme (GBM) are among the most devastating neoplasms claiming the lives of patients within a median of 1 year after diagnosis. Treatment of GBM requires a multidisciplinary approach. Treatments include surgery, radiotherapy, chemotherapy and so on. Temozolomide (TMZ) has emerged as an active agent against malignant gliomas. On the basis of the work by the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada, concurrent radiotherapy and the oral alkylating agent TMZ followed by adjuvant TMZ has become the standard of care for patients with newly diagnosed GBM, although the methylation status of the O(6)-mehylguanine-DNA methyltransferase promoter is predictive for survival of GBM patients. Gliadel is a biodegradable polymer wafer impregnated with carmustine. Gliadel has been one of the few treatment modalities to demonstrate a statistical benefit in patients with malignant glioma. These new FDA approved drugs advanced the treatment of malignant glioma, but more progress is needed. Patients require improvements in chemotherapy, surgery, radiotherapy, molecular targeted therapy, immunotoxin using the convection-enhanced delivery and more.
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PMID:Management of glioblastoma. 1803 58

Previously, we demonstrated that demethylation with 5-Aza-2'-deoxycytidine (5azadC) resulted in reduced levels of telomerase that led to telomere shortening, enhanced MGMT expression and enhanced chemosensitivity. Although the results were encouraging, the fact that 5azadC is highly toxic and nonspecific, thus is not favored as a therapeutic molecule. The aim of this research is to downregulate the DNA methyltransferase (DNMT1) gene using three sets of double-stranded RNA oligos designed to align different regions of DNMT1 sequence. Results showed the small-interfering RNA (siRNA) 1 and 3 demonstrated significant levels of silencing DNMT1 and hTERT transcription after 24-hour treatment (p = 0.01) and approximately 90% and 70% transcriptional downregulation of DNMT1 and hTERT, respectively after 48 hours. However, siRNA 2 downregulated DNMT1, hTERT, and MGMT in GOS-3 and U87-MG cells that was attributed to sequence homology between oligo 2 and MGMT complementary DNA. The siRNA-treated glioma cell lines GOS-3 and U87-MG were subjected to two chemotherapeutic agents; taxol and Temozolomide (TMZ). Results suggest that either a combination of siRNA 1 or 3 followed by taxol (2-6 muM) after 48 hours or a combination of siRNA 1 or 3 followed by TMZ (600-1000 microM) after 24 hours would be novel and effective glioma therapies.
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PMID:Silencing DNA methyltransferase (DNMT) enhances glioma chemosensitivity. 1892 31

Although temozolomide has shown clinical activity against neuroblastoma, this activity is likely limited by the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT). We hypothesized that IFN-beta could sensitize neuroblastoma cells to the cytotoxic effects of temozolomide through its ability to down-regulate MGMT expression. In vitro proliferation of three neuroblastoma cell lines treated with IFN-beta and temozolomide alone or in combination was examined. Antitumor activity was assessed in both localized and disseminated neuroblastoma xenografts using single-agent and combination therapy, with continuous delivery of IFN-beta being established by a liver-targeted adeno-associated virus-mediated approach. Two neuroblastoma cell lines (NB-1691 and SK-N-AS) were found to have high baseline levels of MGMT expression, whereas a third cell line (CHLA-255) had low levels. Temozolomide had little effect on in vitro proliferation of the neuroblastoma cell lines with high MGMT expression, but pretreatment with IFN-beta significantly decreased MGMT expression and cell counts (NB-1691: 36 +/- 3% of control, P = 0.0008; SK-N-AS: 54 +/- 7% control, P = 0.003). In vivo, NB-1691 tumors in CB17-SCID mice treated with the combination of IFN-beta and temozolomide had lower MGMT expression and a significantly reduced tumor burden, both localized [percent initial tumor volume: 2,516 +/- 680% (control) versus 1,272 +/- 330% (temozolomide), P = 0.01; 1,348 +/- 220%, P = 0.03 (IFN-beta); 352 +/- 110%, P = 0.0001 (combo)] and disseminated [bioluminescent signal: control (1.32e10 +/- 6.5e9) versus IFN-beta (2.78e8 +/- 3.09e8), P = 0.025, versus temozolomide (2.06e9 +/- 1.55e9), P = 0.1, versus combination (2.13e7 +/- 7.67e6), P = 0.009]. IFN-beta appears to sensitize neuroblastoma cells to the cytotoxic effects of temozolomide through attenuation of MGMT expression. Thus, IFN-beta and temozolomide may be a useful combination for treating children with this difficult disease.
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PMID:IFN-beta sensitizes neuroblastoma to the antitumor activity of temozolomide by modulating O6-methylguanine DNA methyltransferase expression. 1905 75

Pituitary adenomas are being recognized and diagnosed with increasing frequency. One of the most common forms of pituitary lesion is the clinically non-functioning pituitary adenoma (NFPA), which is often diagnosed incidentally. The vast majority of pituitary adenomas are sporadic, but familial adenomas can occur in the multiple pituitary adenoma type 1 syndrome, in Carney complex or in familial isolated pituitary adenoma. Distinguishing NFPA from prolactinomas can occasionally cause a differential diagnostic problem due to the 'stalk effect'. NFPA often show hormone synthesis on tissue immunostaining without causing clinical symptoms. Most often these are silent gonadotroph adenomas, with silent corticotroph or somatotroph adenomas occurring less frequently. It is unclear why these silent adenomas do not release hormones at a clinically recognizable level, although it is probable that there is a continuum between fully functional and completely silent adenomas. Another intriguing feature of NFPAs is the lack of clinical response to somatostatin analogues, despite the presence of somatostatin receptors and an often good response in the in vitro setting. Temozolomide has been successfully used for the treatment of a few aggressive pituitary adenomas, and the response to this drug could be influenced by the expression of the DNA repair enzyme O-6-methylguanine DNA methyltransferase. The early diagnosis, prediction of long-term outcome and treatment of NFPAs remain a challenge for endocrinologists.
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PMID:Recent clinical and pathophysiological advances in non-functioning pituitary adenomas. 1940 8

Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant tumor that mostly occurs in early childhood and has poor prognosis despite aggressive therapy. Adult cases are rare and, as far as we are aware, only 30 cases have been reported to date. Here we present the case of a 27-year-old female with left parietal AT/RT with the chief complaint of numbness of the right superior limb. First, the tumor was surgically removed and the diagnosis was grade II glioma. With additional radiotherapy, the clinical course after surgery was favorable. After 6 years, she had an operation for recurrence and the diagnosis was grade III glioma. Temozolomide was prescribed, and a disease-free period of 2 years followed. Surgery was performed for a third time for second recurrence with histology of diffuse growth of rhabdoid cells. Immunohistochemistry was partially positive for vimentin and epithelial membrane antigen. Ki-67 labeling index was extremely high and tumor cells showed no staining of INI1 suggestive of diagnosis of AT/RT. We re-evaluated past specimens and none had immunoreactivity of INI1. Ki-67 labeling index and O-6 methylguanine DNA methyltransferase (MGMT) staining were also re-examined and both increased gradually. She is still alive without recurrence for more than 1 year. As far as we are aware, this is the second longest survival of an adult with AT/RT.
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PMID:Case of atypical teratoid/rhabdoid tumor in an adult, with long survival. 2118 49

At present, no effective medical treatment exists for recurrent and aggressive craniopharyngiomas that are resistant to conventional therapies, including surgery and adjuvant radiotherapy. Temozolomide is an alkylating chemotherapeutic agent used routinely in the management of high grade gliomas. The response to temozolomide is suggested to be dependent on the tumoral expression of O-6 methylguanine DNA methyltransferase (MGMT). Evidence supports that low MGMT immunoexpression correlates with positive response to temozolomide. Therefore, we aimed to assess MGMT immunoexpression in adamantinomatous craniopharyngiomas, in an effort to predict the likelihood of response to temozolomide. The MGMT immunostaining was performed on 23 adamantinomatous craniofaryngiomas operated at the Sisli Etfal Training and Research Hospital and identified by histological analysis. Paraffin embedded tissue sections were immunostained for MGMT and were evaluated semi-quantitatively. Of the 23 cases evaluated, 22 (96%) demonstrated negative (<10%) and 1 (4%) demonstrated low (10%) MGMT immunoexpression. Data from this study suggest a high proportion of adamantinomatous craniopharyngiomas exhibit negative/low MGMT immunoreactivity and could be treated with temozolomide, if conventional therapy fails.
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PMID:MGMT immunoexpression in adamantinomatous craniopharyngiomas. 2131 29

The efficacy of temozolomide in melanoma treatment is low (response rate <20%) and may depend on the activity of O-methylguanine DNA methyltransferase (MGMT) and mismatch repair. We identified melanoma cell lines with different sensitivities to single versus prolonged clinical dosing regimens of temozolomide treatment and assessed a variety of potential resistance mechanisms using this model. We measured mRNA expression and promoter methylation of MGMT and essential mismatch repair genes (MLH1, MSH2). Cell cycle distribution, apoptosis/necrosis induction, O-methylguanine-adduct formation, and ABCB1 gene expression were assessed. We found that three cell lines, MelA, MelB, and MelC, were more sensitive to a single dose regimen than to a prolonged regimen, which would be expected to exhibit higher cytotoxicity. KAII and LIBR cell sensitivity was higher with regard to the prolonged treatment regimen, as expected. Only MelC expressed MGMT. Gene expression correlated well with promoter methylation. Temozolomide exposure did not alter mRNA expression. Different sensitivities to temozolomide were caused neither by delayed apoptosis induction due to early cell cycle arrest nor by O-methylguanine-adduct formation or efflux transporter expression. MelC was the most resistant cell line with rapid elimination of O-methylguanine adducts. This was in good agreement with its MGMT expression. The sensitive cell lines KAII and LIBR accumulated O-methylguanine adducts after a second treatment cycle with temozolomide in contrast with the other three cell lines. We conclude that MGMT expression and DNA adduct accumulation are relevant factors in temozolomide chemosensitivity. Considering individualized temozolomide treatment regimens either by quantification of DNA adducts or by chemosensitivity testing seems worthwhile clinically.
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PMID:Temozolomide chemoresistance heterogeneity in melanoma with different treatment regimens: DNA damage accumulation contribution. 2146 Jul 49


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