O6-Alkylguanine-DNA alkyltransferase activity of human malignant glioma and its clinical implications

Hotta, Tsukasa; Saito, Yuji; Fujita, Hiroshi; Mikami, Takashi; Kurisu, Kaoru; Kiya, Katsuzo; Uozumi, Tohru; Isowa, Gohei; Ishizaki, Kanji; Ikenaga, Masahiro

doi:10.1007/bf01052897

Cited by 68 publications

(32 citation statements)

References 11 publications

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“…A key role of the O-6-methylguanine-DNA methyltransferase (MGMT) as a mechanism of resistance to alkylating agents in tumors has been repeatedly suggested (1)(2)(3). This enzyme efficiently removes methyl adducts at the O-6-position of guanine, one of the most prominent and biologically important targets of alkylating agents.…”

Section: Introductionmentioning

confidence: 99%

Clinical Trial Substantiates the Predictive Value of O-6-Methylguanine-DNA Methyltransferase Promoter Methylation in Glioblastoma Patients Treated with Temozolomide

Hegi

Diserens²,

Godard³

et al. 2004

Clinical Cancer Research

734

484

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Purpose: In the setting of a prospective clinical trial, we determined the predictive value of the methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter for outcome in glioblastoma patients treated with the alkylating agent temozolomide. Expression of this excision repair enzyme has been associated with resistance to alkylating chemotherapy.Experimental Design: The methylation status of MGMT in the tumor biopsies was evaluated in 38 patients undergoing resection for newly diagnosed glioblastoma and enrolled in a Phase II trial testing concomitant and adjuvant temozolomide and radiation. The epigenetic silencing of the MGMT gene was determined using methylation-specific PCR.Results: Inactivation of the MGMT gene by promoter methylation was associated with longer survival (P ‫؍‬ 0.0051; Log-rank test). At 18 months, survival was 62% (16 of 26) for patients testing positive for a methylated MGMT promoter but reached only 8% (1 of 12) in absence of methylation (P ‫؍‬ 0.002; Fisher's exact test). In the presence of other clinically relevant factors, methylation of the MGMT promoter remains the only significant predictor (P ‫؍‬ 0.017; Cox regression).Conclusions: This prospective clinical trial identifies MGMT-methylation status as an independent predictor for glioblastoma patients treated with a methylating agent. The association of the epigenetic inactivation of the DNA repair gene MGMT with better outcome in this homogenous cohort may have important implications for the design of future trials and supports efforts to deplete MGMT by O-6-benzylguanine, a noncytotoxic substrate of this enzyme.

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Section: Introductionmentioning

confidence: 99%

Clinical Trial Substantiates the Predictive Value of O-6-Methylguanine-DNA Methyltransferase Promoter Methylation in Glioblastoma Patients Treated with Temozolomide

Hegi

Diserens²,

Godard³

et al. 2004

Clinical Cancer Research

734

484

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“…O 6 -methylguanine-DNA methyltransferase is a cytoprotective DNA repair protein that can remove the methyl group from the O 6 position of guanine. Therefore, presence of this repair protein may undo, in part, the cytotoxic effect of alkylating agents, hence resulting in tumour resistance to TMZ (73,74). Hypermethylation of the CpG islands in the promoter region of the MGMT gene has been found to be associated with transcriptional silencing (74,75) and, subsequently, with a good clinical response to alkylating agents in glioma patients (76,77).…”

Section: Temozolomidementioning

confidence: 99%

Cell survival and radiosensitisation: Modulation of the linear and quadratic parameters of the LQ model

Franken

Oei

Kok

et al. 2013

International Journal of Oncology

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Abstract.The linear-quadratic model (LQ model) provides a biologically plausible and experimentally established method to quantitatively describe the dose-response to irradiation in terms of clonogenic survival. In the basic LQ formula, the clonogenic surviving fraction S d ̸S 0 following a radiation dose d (Gy) is described by an inverse exponential approximation:, wherein α and β are experimentally derived parameters for the linear and quadratic terms, respectively. Radiation is often combined with other agents to achieve radiosensitisation. In this study, we reviewed radiation enhancement ratios of hyperthermia (HT), halogenated pyrimidines (HPs), various cytostatic drugs and poly(ADP-ribose) polymerase-1 (PARP1) inhibitors expressed in the parameters α and β derived from cell survival curves of various mammalian cell cultures. A significant change in the α/β ratio is of direct clinical interest for the selection of optimal fractionation schedules in radiation oncology, influencing the dose per fraction, dose fractionation and dose rate in combined treatments. The α/β ratio may increase by a mutually independent increase of α or decrease of β. The results demonstrated that the different agents increased the values of both α and β. However, depending on culture conditions, both parameters can also be separately influenced. Moreover, it appeared that radiosensitisation was more effective in radioresistant cell lines than in radiosensitive cell lines. Furthermore, radiosensitisation is also dependent on the cell cycle stage, such as the plateau or exponentially growing phase, as well as on post-treatment plating conditions. The LQ model provides a useful tool in the quantification of the effects of radiosensitising agents. These insights will help optimize fractionation schedules in multimodality treatments.

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“…The methylguanine methyltransferase (MGMT) excision repair enzyme, also known as alkylguanine alkyltransferase (AGAT), has been associated with tumor resistance, because it may reverse, in part, the Stupp,Hegi,van den Bent et al 167 www.TheOncologist.com impact of alkylating drugs by removing alkyl groups from the O 6 position of guanine, one of the targets of alkylating agents [11][12][13][14][15][16][17][18]. In this exhaustible process, the enzyme is consumed.…”

Section: Treatment Of Newly Diagnosed Patients Glioblastomamentioning

confidence: 99%

Changing Paradigms—An Update on the Multidisciplinary Management of Malignant Glioma

Stupp

Hegi

Bent³

et al. 2006

The Oncologist

370

241

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Learning ObjectivesAfter completing this course, the reader will be able to:1. List the different major subtypes of glioma and identify the appropriate treatment strategies for patients with high-grade and low-grade gliomas.2. Discuss the available evidence for the treatment of newly diagnosed glioblastoma, anaplastic astrocytoma, and anaplastic oligodendroglioma.3. Identify approved agents and other active or investigational agents used to treat patients with newly diagnosed and recurrent glioma. shown that early neoadjuvant or adjuvant administration of procarbazine, lomustine, and vincristine chemotherapy prolongs disease-free survival; however, it has no impact on overall survival. Temozolomide, a novel alkylating agent, has shown modest activity against recurrent glioma. In combination with radiotherapy in newly diagnosed patients with glioblastoma, temozolomide significantly prolongs survival. Molecular studies have demonstrated that the benefit is mainly observed Access and take the CME test online and receive 1 AMA PRA category 1 credit at CME.TheOncologist.com CME CME This material is protected by U.S.

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O6-Alkylguanine-DNA alkyltransferase activity of human malignant glioma and its clinical implications

Cited by 68 publications

References 11 publications

Clinical Trial Substantiates the Predictive Value of O-6-Methylguanine-DNA Methyltransferase Promoter Methylation in Glioblastoma Patients Treated with Temozolomide

Clinical Trial Substantiates the Predictive Value of O-6-Methylguanine-DNA Methyltransferase Promoter Methylation in Glioblastoma Patients Treated with Temozolomide

Cell survival and radiosensitisation: Modulation of the linear and quadratic parameters of the LQ model

Changing Paradigms—An Update on the Multidisciplinary Management of Malignant Glioma

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