MGMT promoter methylation correlates with survival benefit and sensitivity to temozolomide in pediatric glioblastoma

Donson, Andrew M.; Addo-Yobo, Steven O.; Handler, Michael H.; Gore, Lia; Foreman, Nicholas K.

doi:10.1002/pbc.20803

Cited by 174 publications

(106 citation statements)

References 16 publications

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“…The expression level of MGMT is also susceptible to epigenetic silencing (46). Although our data showed that TMZ/ PYR treatment induced more DNA damage through the formation of DSBs (Fig.…”

Section: Discussionmentioning

confidence: 60%

Antifolate Activity of Pyrimethamine Enhances Temozolomide-Induced Cytotoxicity in Melanoma Cells

Chen

Osman

Orlow

2009

Molecular Cancer Research

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Most metastatic melanoma patients fail to respond to available therapy, underscoring the need to develop more effective treatments. We screened 2,000 compounds from the Spectrum Library in human melanoma cell lines to identify compounds that enhanced the cytotoxic effect of temozolomide, a drug used to treat metastatic melanoma. Screening was done with the temozolomide-resistant melanoma cell line SK-MEL-19, and six compounds were identified that had little or no inherent cytotoxicity but significantly enhanced growth-inhibition by temozolomide. These compounds were tested in five additional melanoma cell lines. Cell proliferation and death assays were used to compare the efficacy of single agent temozolomide versus combination treatments. Effects of combination treatment on levels of DNA double-strand breaks, the DNA repair protein O 6 -methylguanine-DNA-methyltransferase, apoptosis[measured by cleaved caspase-3 and poly(ADP-ribose) polymerase], and cell cycle were examined. Pyrimethamine, an antiparasitic, sensitized melanoma cells to temozolomide. Temozolomide combined with Pyrimethamine synergistically inhibited cell proliferation in melanoma cells with combination index values of 0.7 or less. In addition, combination treatment induced cell cycle arrest and increased both DNA damage and apoptosis. The increase in cell death due to combination treatment was rescued by leucovorin. Other folate antagonists were also effective enhancers of temozolomide-induced cytotoxicity, and the effects of antifolates were also evident in gliomas. Our screening approach led to the identification of Pyrimethamine, an orally available drug that efficiently crosses the blood-brain barrier, as a potent enhancer of the efficacy of temozolomide as an antineoplastic agent via inhibition of folate metabolism. (Mol Cancer Res 2009;7(5):703-12)

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“…The expression level of MGMT is also susceptible to epigenetic silencing (46). Although our data showed that TMZ/ PYR treatment induced more DNA damage through the formation of DSBs (Fig.…”

Section: Discussionmentioning

confidence: 60%

Antifolate Activity of Pyrimethamine Enhances Temozolomide-Induced Cytotoxicity in Melanoma Cells

Chen

Osman

Orlow

2009

Molecular Cancer Research

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“…In certain cell lines, an enhancement of the radiation effect has been demonstrated, whereas other cell lines have shown no interaction, but merely an additive effect (78)(79)(80)(81)(82)(83).…”

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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“…For example, a study using commercially available anti-MGMT antibodies to determine MGMT expression reported major interobserver variability (9,14). Furthermore, as MGMT promoter methylation is inversely correlated with MGMT expression (5,6), methylation-specific PCR (MSP) with bisulfate-treated DNA has been widely used to analyze MGMT promoter methylation status (7)(8)(9). However, MSP is only able to detect a limited number of methylated CpG sites in the primer region, and recent studies report that the region commonly investigated by MSP does not cover CpG sites that are most highly associated with expression of MGMT, and that MSP may not be well-suited for predicting the prognosis of patients with glioblastoma (15,16).…”

Section: Cpg Site ---------------------------------------------------mentioning

confidence: 99%

“…Temozolomide is an alkylating agent that is increasingly used for relapsed medulloblastoma (20)(21)(22). Although a significant correlation between MGMT methylation status and temozolomide sensitivity has been confirmed in glioblastoma (7,8), sensitivity to temozolomide in relapsed medulloblastoma may not be predicted from the MGMT status of primarily resected tumor samples. Second, the small sample size prevented further analysis of other clinical factors that may be associated with patient outcome, such as molecular subtypes, pathological characteristics, dissemination status and chemotherapy regimens.…”

Section: Cpg Site ---------------------------------------------------mentioning

confidence: 99%

“…Expression of MGMT is suppressed by methylation of CpG islands in the promoter region (4)(5)(6). It was previously demonstrated that a greater methylation status of the MGMT promoter region is associated with favorable outcomes in adult and pediatric patients with glioblastoma treated with alkylating agents, such as temozolomide (7,8). However, only a limited number of studies have investigated MGMT status in medulloblastoma and its effect on disease outcome (5,(9)(10)(11).…”

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confidence: 99%

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Effect of O6‑methylguanine‑DNA methyltransferase methylation in medulloblastoma

et al. 2017

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Abstract. Medulloblastoma is a highly malignant brain tumor that predominately affects children and requires multimodal treatment, including chemotherapy with alkylating agents. O 6 -methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that plays an important role in tumor resistance to alkylating agents. Recent studies demonstrated that MGMT promoter methylation suppresses the expression of MGMT and is associated with favorable outcomes of malignant glioma patients. However, the MGMT methylation status and its prognostic impact on medulloblastoma have not been fully elucidated to date. The objective of the present study was to investigate the association between MGMT status and clinical outcomes of pediatric medulloblastoma patients. The records of 15 patients with medulloblastoma treated at our institution were reviewed, and the methylation status of 18 CpG sites in the MGMT promoter region was determined using bisulfite sequencing analysis. A larger number of methylated CpG sites was identified in 9 patients with complete remission (median, 5 sites; range, 2-9 sites) compared with that in 6 patients with relapse (median, 2 sites, range, 1-4 sites; P=0.041). These results suggest that a higher number of methylated CpG sites in the MGMT promoter region are associated with a favorable outcome of medulloblastoma.

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MGMT promoter methylation correlates with survival benefit and sensitivity to temozolomide in pediatric glioblastoma

Cited by 174 publications

References 16 publications

Antifolate Activity of Pyrimethamine Enhances Temozolomide-Induced Cytotoxicity in Melanoma Cells

Antifolate Activity of Pyrimethamine Enhances Temozolomide-Induced Cytotoxicity in Melanoma Cells

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

Effect of O6‑methylguanine‑DNA methyltransferase methylation in medulloblastoma

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