scholarly journals Effect of temozolomide combined with radiotherapy on survival and MGMT protein expression in recurrent malignant glioma patients

2021 ◽  
Vol 18 (4) ◽  
pp. 857-862
Author(s):  
Feng Yun ◽  
Huang Honghui ◽  
Gao Jing ◽  
Liu Shizhu
Keyword(s):  
Malignant Glioma ◽  
Dna Methyltransferase ◽  
Combined Treatment ◽  
Clinical Effectiveness ◽  
Control Group ◽  
Study Group ◽  
Recurrent Malignant Glioma ◽  
Mgmt Gene ◽  
Methylguanine Dna Methyltransferase ◽  
Mgmt Protein

Purpose: To investigate the effect of temozolomide (TMZ) combined with radiotherapy (RT) on O-6- methylguanine-DNA methyltransferase (MGMT) protein and survival of recurrent malignant glioma patients. Methods: Ninety-two patients with malignant glioma in our hospital from January 2014 to January 2015 were assigned to study and control groups using the random table method. Subjects in the control group received radiotherapy (total dose in the range of 60 – 75 Gy), while those in the study group were given TMZ orally (75 mg/m2) daily in addition to radiotherapy, as well as TMZ at 150 – 200 mg/m2. After treatment, clinical effectiveness was compared for the two groups. Changes in methylation of MGMT gene were determined in the two groups. The patients were followed up for 3 years, and the degrees of survival and recurrence were recorded. Results: Total effectiveness of clinical treatment was markedly higher in the study group (76.09 %) than in the control group (45.65 %; p < 0.05). One month after radiotherapy, significant decrease in MGMT gene methylation was seen in patients in the study group, relative to control patients (p < 0.05). Patients in the study group had lower median recurrence but higher degree of survival in the 2nd and 3rd years, relative to control patients (p < 0.05). Conclusion: The combination of temozolomide and radiotherapy is more effective than radiotherapy in the treatment of recurrent malignant glioma. The combined treatment significantly inhibits tumor recurrence in patients, and improves their prognosis and standard of life.

scholarly journals Impact of Temozolomide on Immune Response during Malignant Glioma Chemotherapy

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Sadhak Sengupta ◽  
Jaclyn Marrinan ◽  
Caroline Frishman ◽  
Prakash Sampath
Keyword(s):  
Immune Response ◽  
Malignant Glioma ◽  
Dna Methyltransferase ◽  
Opportunistic Infections ◽  
Immune Surveillance ◽  
Drug Resistant ◽  
Methylguanine Dna Methyltransferase ◽  
Drug Resistant Mutation ◽  
Resistant Mutation

Malignant glioma, or glioblastoma, is the most common and lethal form of brain tumor with a median survival time of 15 months. The established therapeutic regimen includes a tripartite therapy of surgical resection followed by radiation and temozolomide (TMZ) chemotherapy, concurrently with radiation and then as an adjuvant. TMZ, a DNA alkylating agent, is the most successful antiglioma drug and has added several months to the life expectancy of malignant glioma patients. However, TMZ is also responsible for inducing lymphopenia and myelosuppression in malignant glioma patients undergoing chemotherapy. Although TMZ-induced lymphopenia has been attributed to facilitate antitumor vaccination studies by inducing passive immune response, in general lymphopenic conditions have been associated with poor immune surveillance leading to opportunistic infections in glioma patients, as well as disrupting active antiglioma immune response by depleting both T and NK cells. Deletion of O6-methylguanine-DNA-methyltransferase (MGMT) activity, a DNA repair enzyme, by temozolomide has been determined to be the cause of lymphopenia. Drug-resistant mutation of the MGMT protein has been shown to render chemoprotection against TMZ. The immune modulating role of TMZ during glioma chemotherapy and possible mechanisms to establish a strong TMZ-resistant immune response have been discussed.

scholarly journals MGMT-activated DUB3 stabilizes MCL1 and drives chemoresistance in ovarian cancer

2019 ◽  
Vol 116 (8) ◽  
pp. 2961-2966 ◽  
Author(s):  
Xiaowei Wu ◽  
Qingyu Luo ◽  
Pengfei Zhao ◽  
Wan Chang ◽  
Yating Wang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Dna Methyltransferase ◽  
Essential Role ◽  
Histone Deacetylase Inhibitors ◽  
Combined Treatment ◽  
Ovarian Cancer Cells ◽  
Methylguanine Dna Methyltransferase

Chemoresistance is a severe outcome among patients with ovarian cancer that leads to a poor prognosis. MCL1 is an antiapoptotic member of the BCL-2 family that has been found to play an essential role in advancing chemoresistance and could be a promising target for the treatment of ovarian cancer. Here, we found that deubiquitinating enzyme 3 (DUB3) interacts with and deubiquitinates MCL1 in the cytoplasm of ovarian cancer cells, which protects MCL1 from degradation. Furthermore, we identified that O6-methylguanine-DNA methyltransferase (MGMT) is a key activator of DUB3 transcription, and that the MGMT inhibitor PaTrin-2 effectively suppresses ovarian cancer cells with elevated MGMT-DUB3-MCL1 expression both in vitro and in vivo. Most interestingly, we found that histone deacetylase inhibitors (HDACis) could significantly activate MGMT/DUB3 expression; the combined administration of HDACis and PaTrin-2 led to the ideal therapeutic effect. Altogether, our results revealed the essential role of the MGMT-DUB3-MCL1 axis in the chemoresistance of ovarian cancer and identified that a combined treatment with HDACis and PaTrin-2 is an effective method for overcoming chemoresistance in ovarian cancer.

Chromosomal localization of human O6-methylguanine-DNA methyltransferase (MGMT) gene by in situ hybridization

Mutagenesis ◽  
1992 ◽  
Vol 7 (1) ◽  
pp. 83-85 ◽  
Author(s):  
A.T. Natarajan ◽  
Sylvia Vermeulen ◽  
F. Darroudi ◽  
Marcus B. Valentine ◽  
Thomas P. Brent ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Dna Methyltransferase ◽  
Chromosomal Localization ◽  
Mgmt Gene ◽  
Methylguanine Dna Methyltransferase

scholarly journals Inducibility of the DNA repair gene encoding O6-methylguanine-DNA methyltransferase in mammalian cells by DNA-damaging treatments.

1991 ◽  
Vol 11 (9) ◽  
pp. 4660-4668 ◽  
Author(s):  
G Fritz ◽  
K Tano ◽  
S Mitra ◽  
B Kaina
Keyword(s):  
Dna Repair ◽  
Cell Lines ◽  
Dna Methyltransferase ◽  
Hepatoma Cells ◽  
X Rays ◽  
Gene Encoding ◽  
Mgmt Gene ◽  
Methylguanine Dna Methyltransferase ◽  
Rat Hepatoma ◽  
Rat Hepatoma Cells

The inducibility of the mammalian O6-methylguanine-DNA methyltransferase (MGMT) gene encoding the MGMT protein (EC 2.1.1.63) responsible for removal of the procarcinogenic and promutagenic lesion O6-alkylguanine from DNA was examined by an analysis of transcription of the MGMT gene following exposure of repair-competent (Mex+) and repair-deficient (Mex-) cells to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). While human and rodent Mex- cells (CHO-9, V79, HeLa MR) showed no detectable MGMT mRNA despite the presence of the gene in their genome, the amount of it in several Mex+ lines (NIH 3T3, HeLa S3, HepG2) paralleled their MGMT activity. However, none of these cell lines showed an increase in the MGMT mRNA level after treatment with various concentrations of MNNG. In contrast, MNNG-treated rat hepatoma cells, H4IIE and FTO-2B, both Mex+, had three- to fivefold more MGMT mRNA than the corresponding untreated controls as measured 12 to 72 h after alkylation. N-Methyl-N-nitrosourea, methyl methanesulfonate, N-hydroxyethyl-N-chloroethylnitrosourea, UV light, and X rays caused a similar accumulation of MGMT mRNA in rat hepatoma cells. Studies with inhibitors of RNA and protein synthesis indicate that the induced increase in the amount of MGMT mRNA was due to enhanced transcription of the gene. Furthermore, they revealed the turnover of the MGMT mRNA to be relatively low (half-life, greater than 7 h). Mutagen-induced increase of transcription of MGMT mRNA in H4IIE cells was accompanied by elevation of MGMT repair activity and resulted in reduction of mutation frequency after a challenge dose of MNNG. Although induction of MGMT mRNA transcription has been observed in two rodent hepatoma cell lines so far, this appears to be the first demonstration of inducibility of a mammalian gene encoding a clearly define DNA repair function. The transcription activation of the MGMT gene protects cells from the mutagenic effects of methylating agents.

scholarly journals Evaluation of MGMT gene methylation in neuroendocrine neoplasms

2021 ◽  
Author(s):  
Rosa Della Monica ◽  
Mariella Cuomo ◽  
Roberta Visconti ◽  
Annabella di Mauro ◽  
Michela Buonaiuto ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Alkylating Agents ◽  
Methylation Status ◽  
Neuroendocrine Neoplasms ◽  
Mgmt Methylation ◽  
Gene Methylation ◽  
Mgmt Gene ◽  
Methylguanine Dna Methyltransferase ◽  
Specific Pcr ◽  
Well Differentiated

Unresectable neuroendocrine neoplasms (NENs) often poorly respond to standard therapeutic approaches. Alkylating agents, in particular temozolomide, commonly used to treat high-grade brain tumors including glioblastomas, have recently been tested in advanced or metastatic NENs, where they showed promising response rates. In glioblastomas, prediction of response to temozolomide is based on the assessment of the methylation status of the MGMT gene, as its product, O-6-methylguanine-DNA methyltransferase, may counteract the damaging effects of the alkylating agent. However, in NENs, such a biomarker has not been validated yet. Thus, we have investigated MGMT methylation in 42 NENs of different grades and from various sites of origin by two different approaches: in contrast to methylation-specific PCR (MSP), which is commonly used in glioblastoma management, amplicon bisulfite sequencing (ABS) is based on high resolution next-generation sequencing and interrogates several additional CpG sites compared to those covered by MSP. Overall, we found MGMT methylation in 74% (31/42) of the NENs investigated. A higher methylation degree was observed in well-differentiated tumors and in tumors originating in the gastrointestinal tract. Comparing MSP and ABS results, we demonstrate that the region analyzed by the MSP test is sufficiently informative of the MGMT methylation status in NENs, suggesting that this predictive parameter could routinely be interrogated also in NENs

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