Inactivation of the DNA-Repair Gene<i>MGMT</i>and the Clinical Response of Gliomas to Alkylating Agents

Esteller, Manel; Garcı́a-Foncillas, Jesús; Andion, Esther; Goodman, Steven N.; Hidalgo, O. Fernández; Vanaclocha, Vicente; Baylin, Stephen B.; Herman, James G.

doi:10.1056/nejm200011093431901

Cited by 2,018 publications

(1,465 citation statements)

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“…42,43 However, it is a predictive marker of a favorable outcome in patients with temozolomide-treated glioblastomas. [44][45][46][47] Temozolomide also reportedly enhances radiation responsiveness in MGMTnegative human glioblastoma cell lines. 48 …”

Section: Temozolomidementioning

confidence: 98%

Treatment of pituitary neoplasms with temozolomide

Syro

Ortíz

Scheithauer

et al. 2010

Cancer

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Temozolomide, an orally administered alkylating agent, is used to treat malignant gliomas. Recent reports also have documented its efficacy in the treatment of pituitary adenomas and carcinomas. Temozolomide methylates DNA and thereby exhibits an antitumor effect. O 6 -methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, removes alkylating adducts induced by temozolomide, counteracting its effects. The authors of this review conducted a Medline database search regarding temozolomide in the treatment of pituitary tumors. Demographic characteristics, tumor types, and therapeutic responses were noted in all patients. Data regarding MGMT immunoexpression, which was documented in some studies, were correlated with information regarding clinical and radiologic responses. To date, there have been 19 reported cases of adenohypophyseal tumors treated with temozolomide, including 13 adenomas and 6 carcinomas. Ten of those 13 adenomas responded favorably, and 2 nonresponsive tumors had highlevel MGMT immunoexpression. All 6 carcinomas responded to therapy, but data regarding MGMT expression were available for only 3 patients, and each had low MGMT expression. In 2 adenomas, morphologic studies were performed both before and after the patients received temozolomide. The responsive tumor had necrosis, hemorrhage, fibrosis, and neuronal differentiation. The nonresponsive tumor had no changes. There have been no reported complications attributable to temozolomide. The current results indicated that temozolomide is efficacious in the treatment of aggressive pituitary adenomas and pituitary carcinomas. Evidence indicated that low-level MGMT immunoexpression is correlated with a favorable response. A significant proportion of pituitary adenomas and carcinomas had low MGMT immunoexpression. Cancer 2011;117:454-62.

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Section: Temozolomidementioning

confidence: 98%

Treatment of pituitary neoplasms with temozolomide

Syro

Ortíz

Scheithauer

et al. 2010

Cancer

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“…It is likely to expect that clinical efficacy will be more prominent in patients with tumors with MGMT promoter methylation [54,63]. The substantial toxicity profile limits combination with other agents.…”

Section: Nitrosourea Monotherapy and Combination Regimensmentioning

confidence: 99%

Therapeutic options in recurrent glioblastoma—An update

Seystahl

Wick

Weller

2016

Critical Reviews in Oncology/Hematology

177

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“…This may be because of the intrinsic MGMT inactivation by temozolomide alone, which is not the case with other alkylating agents such as nitrosoureas (Kokkinakis et al, 2001). Alternatively, this can also be explained by low levels of MGMT protein in glioblastoma cells as a consequence of promoter silencing observed in glioblastoma cells (Esteller et al, 2000).…”

Section: Figurementioning

confidence: 99%

Temozolomide induces apoptosis and senescence in glioma cells cultured as multicellular spheroids

et al. 2003

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Temozolomide is an alkylating cytostatic drug that finds increasing application in the treatment of melanoma, anaplastic astrocytoma and glioblastoma multiforme. The compound is a prodrug that decomposes spontaneously, independent of an enzymatic activation step. DNA methylation induces futile mismatch repair cycles and depletion of the DNA repair enzyme O 6 -methylguanine-DNA methyltransferase should then initiate programmed cell death. We show drug-dependent inhibition of tumour growth in a threedimensional cell culture model of the glioma cell lines U87MG and GaMG. Migrational behaviour of the glioblastoma cells remained unaltered. However, coincubation of tumour spheroids with primary brain aggregates showed reduced tumour cell invasion into brain tissue in the presence of temozolomide. This was not achieved by slowing cellular migration, as temozolomide-treated cells displayed no reduced motility. By transferase-mediated dUTP nick-end labelling (TUNEL) of apoptotic nuclei, we found that the drug was able to induce apoptosis throughout the tumour cell spheroids. Apoptosis was highest in the core region of the spheroids. Repetitive application of sublethal doses of temozolomide to multicellular spheroids resulted in the development of drug resistance in GaMG cells. We suggest that temozolomide is a strong initiator of apoptosis in glioblastoma tumour cells in a spheroid cell culture system, when cells are already in a stressful environment.

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Inactivation of the DNA-Repair GeneMGMTand the Clinical Response of Gliomas to Alkylating Agents

Abstract: Methylation of the MGMT promoter in gliomas is a useful predictor of the responsiveness of the tumors to alkylating agents.

Cited by 2,018 publications

References 10 publications

Treatment of pituitary neoplasms with temozolomide

Treatment of pituitary neoplasms with temozolomide

Therapeutic options in recurrent glioblastoma—An update

Temozolomide induces apoptosis and senescence in glioma cells cultured as multicellular spheroids

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