Contribution of O6‐methylguanine‐DNA methyltransferase to monofunctional alkylating‐agent resistance in human brain tumor—derived cell lines

Bobola, Michael S.; Blank, A.; Berger, Mitchel S.; Silber, John R.

doi:10.1002/mc.2940130203

Cited by 35 publications

(46 citation statements)

References 39 publications

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“…Although the cytotoxicity of chloroethylating agents and methylating agents can be attributed to quite different DNA lesions, both depend upon initial adduct formation at the O 6 -position of guanine (9,55,56). Several preclinical and clinical studies have strongly suggested that the DNA repair enzyme MGMT, with reverse alkylation at the O 6 -position of guanine, plays an important role in cellular resistance to chlorethylation or methylation damage at the O 6 -position of guanine DNA (10,(13)(14)(15)(16)(17)(18)26,(57)(58)(59)(60)(61)(62). In human cancer, the MGMT gene is not commonly mutated or deleted, and loss of MGMT function is most frequently due to epigenetic changes, particularly promoter hypermethylation (22,28,63), which cause MGMT transcriptional silencing in cells with defective O 6 -methylguanine repair (22,28,64,65).…”

Section: Discussionmentioning

confidence: 99%

“…One of the key factors controlling sensitivity to O 6 alkylating agents including TMZ in tumors is therefore considered to be the action of MGMT (10)(11)(12)(13). Indeed, several investigators have reported that, in malignant gliomas, MGMT expression is closely correlated with experimental and clinical resistance to these chemotherapeutic agents (14)(15)(16)(17)(18). Furthermore, recent studies have indicated that, since MGMT protein loss may be a result of promoter hypermethylation, methylation of the MGMT promoter is significantly correlated with clinical outcome in malignant glioma patients treated with alkylating agents including TMZ (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

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Effect of IFN-β on human glioma cell lines with temozolomide resistance

Yoshino

Ogino²,

Yachi³

et al. 2009

Int J Oncol

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Abstract. Human interferon-ß (IFN-ß) is known to exhibit pleiotropic biological activities including antitumor effects. On the other hand, temozolomide (TMZ), an oral bioavailable alkylating agent with excellent tolerability, has demonstrated efficacy and has become a key therapeutic agent in patients with malignant gliomas; however, its survival benefit remains unsatisfactory. More recent studies have indicated that there might be favorable therapeutic interactions between IFN-ß and TMZ, although the therapeutic advantages of such a combination have not yet been fully explored. The main aim of the present study was to determine whether an antitumor effect could be potentiated by a combination of IFN-ß and TMZ. The antitumor effect of and cell sensitivity to IFN-ß and TMZ and the synergistic potential of IFN-ß and TMZ in combination were evaluated in six malignant glioma cell lines. Correlations among the MGMT methylation status, quantitative level of MGMT mRNA, MGMT protein expression and the antitumor effect of these agents were also evaluated, since one of the most prominent resistance mechanisms to TMZ involves the DNA repair protein MGMT. The cell growth inhibitory effects of IFN-ß and TMZ on all tumor cell lines were observed in a dose-dependent manner, and the human malignant glioma-derived cell lines differed in their sensitivity to TMZ. The MGMT status, including promoter hypermethylation, quantitative mRNA expression and protein expression, was strongly correlated with TMZ sensitivity. A synergistic cell growth inhibitory effect and down-regulated MGMT mRNA levels were significantly observed when a clinically achievable CNS dose of IFN-ß was combined with TMZ, as compared to treatment with IFN-ß or TMZ alone in TMZ-resistant T98G cells. Furthermore, significant amounts of endogenous IFN-ß protein were detected in TMZ-treated T98G cells by ELISA. These results suggest that the clinical therapeutic efficacy of TMZ might be improved by a combination with IFN-ß in malignant gliomas unmethylated at the MGMT gene. The data provide an experimental basis for future strategies in TMZ chemotherapy, although further studies are needed to determine the detailed role of combined IFN-ß and TMZ chemotherapy in increasing tumor sensitivity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of IFN-β on human glioma cell lines with temozolomide resistance

Yoshino

Ogino²,

Yachi³

et al. 2009

Int J Oncol

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“…Paclitaxel sensitivity was determined by clonogenic assay as described previously (Bobola et al, 1995a). Brie y, 12-well trays were inoculated with 2 mL of medium containing 750 cells and incubated overnight.…”

Section: Cytotoxicity Assaymentioning

confidence: 99%

“…For biphasic curves, LD 10 re ects D 37 for each subpopulation and the fraction of cells in each subpopulation. Graphical derivation of D 37 and LD 10 from survival curves is presented in detail in Bobola et al (1995a).…”

Section: Cytotoxicity Assaymentioning

confidence: 99%

“…For example, numerous studies have shown that the DNA repair protein O 6 -methylguanine-DNA methyltransferase limits alkylating agent-induced killing in human brain tumor-derived cell lines and xenografts (Bobola et al, 1995a(Bobola et al, , 1995b(Bobola et al, , 1996Friedman et al, 1995; by removing lethal alkyl adducts from the O-6 atom of guanine . Moreover, results from our laboratory (Bobola et al, 1995a(Bobola et al, , 1995b(Bobola et al, , 1996 indicate that brain tumor alkylating agent resistance is multifactorial, which will complicate the development of antiresistance therapies. In light of the limited ef cacy of alkylators, new chemotherapeutic agents need to be evaluated for malignant brain tumors.…”

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confidence: 99%

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Characterization of paclitaxel (Taxol®) sensitivity in human glioma- and medulloblastoma-derived cell lines

Tseng¹,

Bobola²,

Berger³

et al. 1999

Neuro-Oncol

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Paclitaxel (Taxol ® ), a cytotoxic natural product that disrupts microtubule integrity, is being clinically evaluated for use against gliomas. We examined paclitaxel-induced killing in seven cell lines derived from human malignant astrocytic gliomas and medulloblastomas with the goal of characterizing range of sensitivity, contribution of Pglycoprotein 170-mediated drug ef ux to resistance, and cross-resistance with alkylating agents. Exposure to paclitaxel for 8 h or less produced biphasic survival curves for all lines, with 40-75% of cells comprising a subpopulation that was 9-26 times more resistant to paclitaxel than the more sensitive fraction. Increasing exposure to 24 h eliminated the resistant subpopulation, increasing sensitivity 50-to 400-fold. The dose producing one log of kill (LD 10 ) after a 24-h exposure ranged from 4 to 18 nM, comparable to concentrations in the cerebrospinal uid of brain tumor patients given a 3-h infusion of paclitaxel. Concurrent exposure to paclitaxel and either nimodipine or verapamil, inhibitors of P-glycoprotein activity, did not increase sensitivity, demonstrating that the vefold range in sensitivity was not due to P-glycoprotein-mediated drug ef ux. Importantly, there was no correlation between LD 10 for paclitaxel and LD 10 for 1,3-bis(2-chloroethyl)-1-nitrosourea, streptozotocin, and temozolomide, indicating no expression of cross-resistance to these different classes of tumoricidal agents. Our results suggest that greater clinical ef cacy of paclitaxel against malignant brain tumors may be obtained by infusion for 24 h or longer and support the use of paclitaxel in combination with alkylating agents. Neuro-Oncology 1, 101-108, 1999 (Posted to NeuroOncology [serial online], Doc. 98-12, April 30, 1999 T he continuing poor prognosis for malignant brain tumors is, in part, a consequence of the lack of effective chemotherapy for newly diagnosed and recurrent disease. During the last three decades, the methylating agent procarbazine, and the chloroethylating agents BCNU 3 (carmustine) and CCNU (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea; lomustine) have been the most commonly used tumoricidal drugs for malignant gliomas and medulloblastomas (Prados and Russo, 1998). The cytotoxicity of these agents is mediated by the formation of approximately 15 alkyl base adducts in DNA, including the lethal lesions O 6 -alkylguanine and N 3 -alkyladenine (Beranek, 1990;Ludlum, 1997). Unfortunately, intrinsic or acquired resistance limits clinical response to alkylators in most malignant brain tumors. In vitro evidence implicates DNA repair as one mechanism of resistance to alkylating agents. For example, numerous studies have shown that the DNA Abbreviations used are as follows: BCNU, 1,3-bis(2-chloroethyl)-1-nitrosourea; D 37 , dose required to reduce survival on linear portion(s) of survival curves by 63%; LD 10 , dose that produces one log kill and thus reduces survival to 10%; P-pg, P-glycoprotein 170.

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