The DNA repair protein O 6 -methylguanine-DNA methyltransferase (MGMT) plays a pivotal role in alkylating drug resistance. Here, we determined MGMT activity in primary and recurrent glioblastomas (GBM, WHO grade IV) of patients who received radiation therapy (RT) or RT plus chemotherapy with alkylating agents (temozolomide, chloroethylnitrosoureas). The mean MGMT activity of untreated GBM was 37 6 45 (range 0-205) fmol/mg proteins. In the 1st, 2nd and 3rd recurrences, MGMT activity increased from 66 6 50 (13-194) to 68 6 44 (14-143) and 182 6 163 (64-423) fmol/mg protein, respectively. Comparing patients who received RT only with RT plus chemotherapy, a significant increase of MGMT in 1st recurrences was only found after treatment with RT plus chemotherapy, indicating either selection of MGMT expressing cells or induction of the MGMT gene by alkylating agents. The p53 status was not significantly related to the MGMT expression level, although a trend for lower MGMT activity in p53 positively stained tumors was observed. Patients expressing MGMT activity of 30 fmol/mg protein in the pretreatment tumor had a significant better therapeutic response than patients expressing MGMT above this level, which was shown by Kaplan-Meyer curves and the recurrence free interval after primary tumor resection. In patients who received RT only, this correlation was not found. The data revealed a threshold of MGMT expression (30 fmol/mg protein) below which patients respond better to alkylating agents. Therefore, determination of MGMT activity in the primary tumor appears to be useful in predicting the outcome of GBM therapy. ' 2007 Wiley-Liss, Inc.Key words: DNA repair; alkyltransferase; MGMT; glioblastomas; drug resistance; temozolomide Despite the enormous progress in the treatment of various types of tumors, human gliomas still have a low curative response. In the therapy of gliomas, notably the most severe form glioblastoma multiforme (GBM, WHO grade IV), radiation therapy (RT) or RT concomitant with methylating agents such as temozolomide 1 is applied. Methylating and chloroethylating agents such as BCNU (carmustine), CCNU (lomustine) or ACNU (nimustine) are also administered during adjuvant therapy. 2 Unfortunately, only a minority of glioblastoma patients respond to temozolomide and chloroethylating nitrosoureas. A likely explanation for this is the development of either primary or acquired glioblastoma cell resistance that leads to protection of the tumor against alkylating drugs.Methylating and chloroethylating agents attack DNA at nucleophilic sites like the O 6 position of guanine, forming O 6 -alkylguanine. 3 This lesion is considered to be the major cause of mutations and malignant transformation induced by O 6 -alkylating agents. 4 It also provokes cell death by inducing apoptosis 5,6 and, therefore, is considered to be mainly responsible for the antineoplastic effect of O 6 -alkylating agents. O 6 -alkylguanine is repaired by the suicide DNA repair protein O 6 -methylguanine-DNA methyltransferase (MGMT) that transf...
The DNA repair protein O 6 -methylguanine-DNA methyltransferase (MGMT) is a key player in tumor cell resistance. Promoter methylation, MGMT activity and immunohistochemistry are used for determining the MGMT status. However, it is unclear whether MGMT promoter methylation correlates with MGMT activity and whether MGMT promoter methylation of the pretreatment tumor predicts the MGMT status of recurrences. To address these questions, we determined MGMT activity promoter methylation and immunoreactivity in pretreatment and recurrent glioblastomas (GB, WHO Grade IV), and in astrocytomas (WHO Grade III). We show that GB that were promoter methylated display a range of 0-62 fmol/mg MGMT and tumors that were nonmethylated 0-423 fmol/mg protein. For astrocytomas, promoter-methylated samples displayed 0-28 fmol/mg and, nonmethylated samples, 23-107 fmol/mg. No correlation was found between the intensity of promoter methylation and MGMT activity. Given a threshold level of 30 fmol/mg of protein, we found a correlation between promoter methylation and no/low MGMT activity in 82.4% of the tumors. This high correlation level was only observed when tumors were excluded showing a hemimethylated promoter (20%). Therefore, classification of hemimethylated tumors remains questionable. Further, we show that 39.1% of pretreatment GB and 5.3% of recurrences were promoter methylated, which is in line with the observed increase of MGMT activity in recurrences. Although individual exceptions were found, the data show an overall correlation between promoter methylation and lack/low MGMT activity in GB and astrocytomas. We also show that promoter methylation assay is superior over immunohistochemistry in determining the MGMT status defined by a given MGMT activity level.Glioblastoma (GB, WHO Grade IV) is the most aggressive brain tumor. For decades, the standard GB treatment was surgery followed by radiotherapy (RT). In 2005, the Phase III trial of Stupp et al.1 showed a significantly longer 2-year survival by applying concomitant and adjuvant treatment with temozolomide (TMZ) plus RT compared with RT alone. Also, the final results of this study with a median follow-up of more than 5 years showed benefits of adjuvant therapy using TMZ and RT.2 Based on these studies, chemoradiotherapy is considered the current standard in GB management. However, despite TMZ, almost 80% of the patients die within the first 2 years after diagnosis, underlining the need for further improved chemotherapy protocols. Hence, intensified TMZ 3 or the combination with other anticancer drugs such as CCNU are currently under investigation in clinical Phase II trials, showing acceptable toxicity and promising survival data. 4 The DNA repair protein O 6 -methylguanine-DNA methyltransferase (MGMT) is presumably the best-established molecular marker that correlates with the response of tumor cells to alkylating agents. MGMT removes methyl and chloroethyl groups from the O 6 position of guanine in a damage reversal reaction (for review see Refs. 5 and 6). If not repaire...
Gliomatosis cerebri (GC) is presently considered a distinct astrocytic glioma entity according to the WHO classification for CNS tumors. It is characterized by widespread, typically bilateral infiltration of the brain involving three or more lobes. Genetic studies of GC have to date been restricted to the analysis of individual glioma-associated genes, which revealed mutations in the isocitrate dehydrogenase 1 (IDH1) and tumor protein p53 (TP53) genes in subsets of patients. Here, we report on a genome-wide analysis of DNA methylation and copy number aberrations in 25 GC patients. Results were compared with those obtained for 105 patients with various types of conventional, i.e., non-GC gliomas including diffuse astrocytic gliomas, oligodendrogliomas and glioblastomas. In addition, we assessed the prognostic role of methylation profiles and recurrent DNA copy number aberrations in GC patients. Our data reveal that the methylation profiles in 23 of the 25 GC tumors corresponded to either IDH mutant astrocytoma (n = 6), IDH mutant and 1p/19q codeleted oligodendroglioma (n = 5), or IDH wild-type glioblastoma including various molecular subgroups, i.e., H3F3A-G34 mutant (n = 1), receptor tyrosine kinase 1 (RTK1, n = 4), receptor tyrosine kinase 2 (classic) (RTK2, n = 2) or mesenchymal (n = 5) glioblastoma groups. Two tumors showed methylation profiles of normal brain tissue due to low tumor cell content. While histological grading (WHO grade IV vs. WHO grade II and III) was not prognostic, the molecular classification as classic/RTK2 or mesenchymal glioblastoma was associated with worse overall survival. Multivariate Cox regression analysis revealed MGMT promoter methylation as a positive prognostic factor. Taken together, DNA-based large-scale molecular profiling indicates that GC comprises a genetically and epigenetically heterogeneous group of diffuse gliomas that carry DNA methylation and copy number profiles closely matching the common molecularly defined glioma entities. These data support the removal of GC as a distinct glioma entity in the upcoming revision of the WHO classification. 3
A B S T R A C T PurposeTo evaluate long-term survival in a prospective series of patients newly diagnosed with glioblastoma and treated with a combination of lomustine (CCNU), temozolomide (TMZ), and radiotherapy. Patients and MethodsThirty-nine patients received radiotherapy of the tumor site only (60 Gy) and CCNU/TMZ chemotherapy (n ϭ 31 received standard-dose CCNU, 100 mg/m 2 on day 1 and TMZ 100 mg/m 2 /d on days 2 to 6; n ϭ 8 received intensified-dose CCNU 110 mg/m 2 on day 1 and TMZ 150 mg/m 2 on days 2 to 6) for up to six courses. ResultsIn the whole cohort, the median overall survival (mOS) was 23.1 months; 47.4% survived for 2 years, and 18.5% survived for 4 years. After a median follow-up of 41.5 months, mOS had not been reached in the intensified group and was significantly higher than in the standard group (22.6 months; P ϭ .024). In the intensified group, four of eight patients survived for at least 56 months, two of them without recurrence. O 6 -methylguanine-DNA methyltransferase (MGMT) gene promotor methylation in the tumor tissue was associated with significantly longer mOS (methylated, 34.3 months v nonmethylated, 12.5 months). A multivariate Cox proportional hazard model revealed MGMT status (methylated v nonmethylated; relative risk [RR] of death, 0.43; P ϭ .003) and chemotherapy dose (intensified v standard; RR, 0.37; P ϭ .012) as independent prognostic factors. WHO grade 4 hematoxicity was observed more frequently in the intensified group (57% v 16%). ConclusionThe combination of radiotherapy, CCNU, and TMZ yielded promising long-term survival data in patients with newly diagnosed glioblastoma. Intensification of CCNU/TMZ chemotherapy may add an additional survival benefit, albeit with greater acute toxicity.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.