CpG Island Hypermethylation of the DNA Repair Enzyme Methyltransferase Predicts Response to Temozolomide in Primary Gliomas

Paz, Maria F.; Yaya-Tur, Ricardo; Rojas-Marcos, Íñigo; Reynés, Gaspar; Pollán, Marina; Aguirre-Cruz, Lucinda; García-López, José Luis; Piquer, José; Safont, M. J.; Balaña, Carmen; Sanchez-Cespedes, Montse; García-Villanueva, Mercedes; Arribas, L.; Esteller, Manel

doi:10.1158/1078-0432.ccr-04-0392

Cited by 236 publications

(149 citation statements)

References 36 publications

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“…Quite low amounts are expressed in brain tumours (Chen et al, 1992;Preuss et al, 1995;Silber et al, 1999;Bobola et al, 2001), presumably due to MGMT promoter methylation (Esteller et al, 1999(Esteller et al, , 2001. MGMT expression level (Chen et al, 1999;Anda et al, 2003) and, as recently shown, MGMT promoter methylation (Esteller et al, 2000;Hegi et al, 2004Hegi et al, , 2005Paz et al, 2004) were predictive for the clinical response to chemotherapy, stressing the critical role of MGMT in determining alkylating drug resistance (for a review see Gerson, 2004). Brain tumours, notably malignant gliomas, are highly therapy-refractory tumours.…”

Section: Introductionmentioning

confidence: 89%

Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine

Roos¹,

et al. 2006

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Methylating drugs such as temozolomide (TMZ) are widely used in the treatment of brain tumours (malignant gliomas). The mechanism of TMZ-induced glioma cell death is unknown. Here, we show that malignant glioma cells undergo apoptosis following treatment with the methylating agents N-methyl-N 0 -nitro-N-nitrosoguanidine (MNNG) and TMZ. Cell death determined by colony formation and apoptosis following methylation is greatly stimulated by p53. Transfection experiments with O 6 -methylguanine-DNA methyltransferase (MGMT) and depletion of MGMT by O 6 -benzylguanine showed that, in gliomas, the apoptotic signal originates from O 6 -methylguanine (O 6 MeG) and that repair of O 6 MeG by MGMT prevents apoptosis. We further demonstrate that O 6 MeGtriggered apoptosis requires Fas/CD95/Apo-1 receptor activation in p53 non-mutated glioma cells, whereas in p53 mutated gliomas the same DNA lesion triggers the mitochondrial apoptotic pathway. This occurs less effectively via Bcl-2 degradation and caspase-9, -2, -7 and -3 activation. O 6 MeG-triggered apoptosis in gliomas is a late response (occurring >120 h after treatment) that requires extensive cell proliferation. Stimulation of cell cycle progression by the Pasteurella multocida toxin promoted apoptosis whereas serum starvation attenuated it. O 6 MeGinduced apoptosis in glioma cells was preceded by the formation of DNA double-strand breaks (DSBs), as measured by cH2AX formation. Glioma cells mutated in DNA-PK cs , which is involved in non-homologous endjoining, were more sensitive to TMZ-induced apoptosis, supporting the involvement of DSBs as a downstream apoptosis triggering lesion. Overall, the data demonstrate that cell death induced by TMZ in gliomas is due to apoptosis and that determinants of sensitivity of gliomas to TMZ are MGMT, p53, proliferation rate and DSB repair.

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Section: Introductionmentioning

confidence: 89%

Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine

Roos¹,

et al. 2006

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“…Although not being subjected to mutations, MGMT downregulation due to promoter methylation has been shown to predict response to temozolomide, but not to temozolomide in concert with cisplatinum in patients with high-grade gliomas or glioblastomas. 278,279 The hypothesis that low levels of MGMT predict temozolomide efficacy is further supported by a study revealing improved survival related to MGMT methylation in glioblastoma patients receiving temozolomide therapy, 280 although in this case study design do not allow a distinction between prediction and prognostication (effect of biology independent of specific therapy).…”

Section: Mismatch Repairmentioning

confidence: 99%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

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Although new agents are implemented to cancer therapy, we lack fundamental understandings of the mechanisms of chemoresistance, the main obstacle to cure in cancer. Here we review clinical evidence linking molecular defects to drug resistance across different tumour forms and discuss contemporary experimental evidence exploring these mechanisms. Although evidence, in general, is sparse and fragmentary, merging knowledge links drug resistance, and also sensitivity, to defects in functional pathways having a key role in cell growth arrest or death and DNA repair. As these pathways may act in concert, there is a need to explore multiple mechanisms in parallel. Taking advantage of massive parallel sequencing and other novel high-throughput technologies and base research on biological hypotheses, we now have the possibility to characterize functional defects related to these key pathways and to design a new generation of studies identifying the mechanisms controlling resistance to different treatment regimens in different tumour forms.

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“…As a result, it inhibits the killing of tumour cells by alkylating agents. Hypermethylation of the MGMT promoter and associated loss of expression correlates with response to temozolamide and BCNU in primary gliomas (Esteller et al, 2000;Paz et al, 2004) and is an independent predictor of overall and progression-free survival in patients with diffuse large B-cell lymphoma treated with cyclophosphamide-containing regimens . Importantly, the methylation status of MGMT in gliomas at presentation does not correlate with the clinical response when temozolamide is used at relapse, demonstrating that the value of biomarkers may depend on when during tumour progression or treatment they are measured.…”

Section: Evidence For the Role Of Epigenetic Mechanisms In Drug Resismentioning

confidence: 99%

Epigenetics as a mechanism driving polygenic clinical drug resistance

Glasspool¹,

Teodoridis²,

Brown³

2006

Br J Cancer

210

166

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Aberrant methylation of CpG islands located at or near gene promoters is associated with inactivation of gene expression during tumour development. It is increasingly recognised that such epimutations may occur at a much higher frequency than gene mutation and therefore have a greater impact on selection of subpopulations of cells during tumour progression or acquisition of resistance to anticancer drugs. Although laboratory-based models of acquired resistance to anticancer agents tend to focus on specific genes or biochemical pathways, such ‘one gene : one outcome' models may be an oversimplification of acquired resistance to treatment of cancer patients. Instead, clinical drug resistance may be due to changes in expression of a large number of genes that have a cumulative impact on chemosensitivity. Aberrant CpG island methylation of multiple genes occurring in a nonrandom manner during tumour development and during the acquisition of drug resistance provides a mechanism whereby expression of multiple genes could be affected simultaneously resulting in polygenic clinical drug resistance. If simultaneous epigenetic regulation of multiple genes is indeed a major driving force behind acquired resistance of patients' tumour to anticancer agents, this has important implications for biomarker studies of clinical outcome following chemotherapy and for clinical approaches designed to circumvent or modulate drug resistance.

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CpG Island Hypermethylation of the DNA Repair Enzyme Methyltransferase Predicts Response to Temozolomide in Primary Gliomas

Cited by 236 publications

References 36 publications

Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine

Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Epigenetics as a mechanism driving polygenic clinical drug resistance

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