Search results for "TEMOZOLOMIDE"
showing 10 items of 58 documents
MGMT in primary and recurrent human glioblastomas after radiation and chemotherapy and comparison with p53 status and clinical outcome
2007
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 +/- 45 (range 0-205) fmol/mg proteins. In the 1st, 2nd and 3rd recurrences, MGMT activity increased from 66 +/- 50 (13-194) to 68 +/- 44 (14-143) and 182 +/- 163 (64-423) fmol/mg protein, respectively. Comparing patients who received RT only with RT plus chemotherapy, a significant increase of MGMT …
Abstract 2935: Novel combination of repurposed drugs induces complete cell invasion arrest of glioblastoma in vitro
2019
Abstract Introduction: Glioblastoma multiforme (GBM) is an aggressive and lethal cancer with a poor prognosis even after conventional treatment (surgery, radiation, chemotherapy). Temozolomide (TMZ) is a standard cyotoxic agent used, despite resistance leading to recurrence. Therefore, additional strategies for targeting the tumor environment are needed. We demonstrate a combination of approved drugs (CAD) repurposed to target GBM leads to complete arrest of GBM cell invasion. Each drug in the combination individually targets diverse tumor pathways: 1) invasion via MMP2 (doxycycline); 2) angiogenesis, inflammation, and proliferation via p53-dependent G1 cell-cycle arrest (celecoxib); 3) aut…
Differential Sensitivity of Malignant Glioma Cells to Methylating and Chloroethylating Anticancer Drugs: p53 Determines the Switch by Regulating xpc,…
2007
Abstract Glioblastoma multiforme is the most severe form of brain cancer. First line therapy includes the methylating agent temozolomide and/or the chloroethylating nitrosoureas [1-(2-chloroethyl)-1-nitrosourea; CNU] nimustine [1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea; ACNU], carmustine [1,3-bis(2-chloroethyl)-1-nitrosourea; BCNU], or lomustine [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea; CCNU]. The mechanism of cell death after CNU treatment is largely unknown. Here we show that ACNU and BCNU induce apoptosis in U87MG [p53 wild-type (p53wt)] and U138MG [p53 mutant (p53mt)] glioma cells. However, contrary to what we observed previously for temozolomide, chl…
Temozolomide- and fotemustine-induced apoptosis in human malignant melanoma cells: response related to MGMT, MMR, DSBs, and p53
2009
Malignant melanomas are highly resistant to chemotherapy. First-line chemotherapeutics used in melanoma therapy are the methylating agents dacarbazine (DTIC) and temozolomide (TMZ) and the chloroethylating agents BCNU and fotemustine. Here, we determined the mode of cell death in 11 melanoma cell lines upon exposure to TMZ and fotemustine. We show for the first time that TMZ induces apoptosis in melanoma cells, using therapeutic doses. For both TMZ and fotemustine apoptosis is the dominant mode of cell death. The contribution of necrosis to total cell death varied between 10 and 40%. The O(6)-methylguanine-DNA methyltransferase (MGMT) activity in the cell lines was between 0 and 1100 fmol m…
Abstract B63: Targeting cancer cells with a glucose-conjugated DNA repair inhibitor.
2011
Abstract Alkylating agents are important chemotherapeutic drugs used for the treatment of several types of cancers, including brain tumors, melanoma and lymphoma. These chemotherapeutic agents have a strong affinity towards oxygen atoms in DNA giving rise to the important genotoxic DNA lesions O6-methylguanine and O6-chloroethylguanine, which are responsible for the cytotoxic effects of several alkylating anticancer drugs (e.g. temozolomide and lomustine). The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is considered as an important player of drug resistance because it removes these DNA adducts from the DNA. The MGMT protein restores guanine in the DNA by a suicide repa…
Abstract 3015: Precise investigation of cancer stem cells in mouse glioblastoma
2018
Abstract In this study, we employ mouse models to investigate features and roles of cancer stem cells (CSCs) in glioblastoma (GBM). A nestin-TK-GFP transgene is firstly used to label CSCs in a fully penetrant mouse model of GBM (M7: hGFAP-Cre; Nf1fl/+; p53fl/fl; Ptenfl/+). Food-mediated ganciclovir (GCV) delivery kills proliferative transgene positive cells and significantly prolongs the lives of the transgene bearing mice. Isolation and transplantation of the tumor cells indicates the GFP+ cells are more tumorigenic than the GFP- cells. We then generate and characterize a novel transgene (CGD: nestin-CreERT2-H2BeGFP-hDTR) that labels all the neural stem/progenitor cells in the subventricul…
Abstract 4258: Preliminarily results of the Oncohabitats Study: A multicentre validation of overall survival (OS) estimation of patients with gliobla…
2019
Abstract We report preliminarily results of an international retrospective study (NCT03439332) analyzing the prognostic value of the early assessment of vascular architecture of glioblastoma (GBM). The initial cohort included 300 pts treated at 7 European hospitals. Multiparametric images were processed by Oncohabitats (www.oncohabitats.upv.es) to obtain the cerebral blood volume (CBV) and cerebral blood flow (CBF) from 4 automatically delimited regions of interest (ROIs): high angiogenic tumor (HAT), low angiogenic tumor (LAT), infiltrating peripherial edema (IPE), and vasogenic peripherial edema (VPE). Uniparametric Cox regression models and Kaplan-Meier analysis were developed to test pr…
Novel Approaches for Glioblastoma Treatment: Focus on Tumor Heterogeneity, Treatment Resistance, and Computational Tools
2019
BACKGROUND: Glioblastoma (GBM) is a highly aggressive primary brain tumor. Currently, the suggested line of action is the surgical resection followed by radiotherapy and treatment with the adjuvant temozolomide (TMZ), a DNA alkylating agent. However, the ability of tumor cells to deeply infiltrate the surrounding tissue makes complete resection quite impossible, and in consequence, the probability of tumor recurrence is high, and the prognosis is not positive. GBM is highly heterogeneous and adapts to treatment in most individuals. Nevertheless, these mechanisms of adaption are unknown. RECENT FINDINGS: In this review, we will discuss the recent discoveries in molecular and cellular heterog…
Rad51 and BRCA2 - New Molecular Targets for Sensitizing Glioma Cells to Alkylating Anticancer Drugs
2011
First line chemotherapeutics for brain tumors (malignant gliomas) are alkylating agents such as temozolomide and nimustine. Despite growing knowledge of how these agents work, patients suffering from this malignancy still face a dismal prognosis. Alkylating agents target DNA, forming the killing lesion O(6)-alkylguanine, which is converted into DNA double-strand breaks (DSBs) that trigger apoptosis. Here we assessed whether inhibiting repair of DSBs by homologous recombination (HR) or non-homologous end joining (NHEJ) is a reasonable strategy for sensitizing glioma cells to alkylating agents. For down-regulation of HR in glioma cells, we used an interference RNA (iRNA) approach targeting Ra…
The Translesion Polymerase Rev3L in the Tolerance of Alkylating Anticancer Drugs
2009
Temozolomide and fotemustine, representing methylating and chloroethylating agents, respectively, are used in the treatment of glioma and malignant melanoma. Because chemoresistance of these tumors is a common phenomenon, identification of the underlying mechanisms is needed. Here we show that Rev3L, the catalytic subunit of the translesion DNA polymerase zeta, mediates resistance to both temozolomide and fotemustine. Rev3L knockout cells are hypersensitive to both agents. It is remarkable that cells heterozygous for Rev3L showed an intermediate sensitivity. Rev3L is not involved in the tolerance of the toxic O6-methylguanine lesion. However, a possible role of Rev3L in the tolerance of O6-…