Inactivation of O6-alkylguanine DNA alkyltransferase as a means to enhance chemotherapy

Rabik, Cara A; Njoku, Maria Chidiamara; Dolan, M. Eileen

doi:10.1016/j.ctrv.2006.03.004

Cited by 85 publications

(56 citation statements)

References 111 publications

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“…Correspondingly, the patient responded to monotherapy with this agent after the first relapse. This might implicate that temozolomide as a strong mutagen in the absence of MGMT activity (Rabik et al, 2006) might have selected the less aggressive BTL3 cell subclone by preferentially killing the highly proliferative and not density-arrested BTL2 cell population. This is especially notable as temozolomide treatment was recently shown to significantly prolong overall survival of glioblastoma patients and thus has largely replaced nitrosoureas in the treatment of glioma (van den Bent et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Dynamics of chemosensitivity and chromosomal instability in recurrent glioblastoma

et al. 2007

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Glioblastoma multiforme is characterised by invasive growth and frequent recurrence. Here, we have analysed chromosomal changes in comparison to tumour cell aggressiveness and chemosensitivity of three cell lines established from a primary tumour and consecutive recurrences (BTL1 to BTL3) of a long-term surviving glioblastoma patient together with paraffin-embedded materials of five further cases with recurrent disease. Following surgery, the BTL patient progressed under irradiation/ lomustine but responded to temozolomide after re-operation to temozolomide. The primary tumour -derived BTL1 cells showed chromosomal imbalances typical of highly aggressive glioblastomas. Interestingly, BTL2 cells established from the first recurrence developed under therapy showed signs of enhanced chromosomal instability. In contrast, BTL3 cells from the second recurrence resembled a less aggressive subclone of the primary tumour. Although BTL2 cells exhibited a highly aggressive phenotype, BTL3 cells were characterised by reduced proliferative and migratory potential. Despite persistent methylation of the O 6 -methylguanine-DNA methyltransferase promoter, BTL3 cells exhibited the highest temozolomide sensitivity. A comparable situation was found in two out of five glioblastoma patients, both characterised by enhanced survival time, who also relapsed after surgery/chemotherapy with less aggressive recurrences. Taken together, our data suggest that pretreated glioblastoma patients may relapse with highly chemosensitive tumours confirming the feasibility of temozolomide treatment even in case of repeated recurrence.

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Section: Discussionmentioning

confidence: 99%

Dynamics of chemosensitivity and chromosomal instability in recurrent glioblastoma

et al. 2007

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“…S9 and Table S1 in the supplemental material). Mechanistically, MGMT acts as a suicide enzyme, whereby transfer of the alkyl group from the guanine to its acceptor site (Cys-145) leads to irreversible inactivation of the protein; it is then ubiquitinated and targeted for proteasomal degradation (240,241). Our bioinformatic analysis revealed that homologs of MGMT are present in L. major, T. brucei, and T. cruzi (see Table S1 in the supplemental material).…”

Section: The Alkyltransferase Pathwaymentioning

confidence: 99%

DNA Repair Pathways in Trypanosomatids: from DNA Repair to Drug Resistance

Genois

Paquet

Laffitte

et al. 2014

Microbiol Mol Biol Rev

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SUMMARY All living organisms are continuously faced with endogenous or exogenous stress conditions affecting genome stability. DNA repair pathways act as a defense mechanism, which is essential to maintain DNA integrity. There is much to learn about the regulation and functions of these mechanisms, not only in human cells but also equally in divergent organisms. In trypanosomatids, DNA repair pathways protect the genome against mutations but also act as an adaptive mechanism to promote drug resistance. In this review, we scrutinize the molecular mechanisms and DNA repair pathways which are conserved in trypanosomatids. The recent advances made by the genome consortiums reveal the complete genomic sequences of several pathogens. Therefore, using bioinformatics and genomic sequences, we analyze the conservation of DNA repair proteins and their key protein motifs in trypanosomatids. We thus present a comprehensive view of DNA repair processes in trypanosomatids at the crossroads of DNA repair and drug resistance.

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“…In preclinical experiments, pretreatment with BG significantly improved the activity of TEM against different tumors with a range of MGMT activity due to the depletion of MGMT protein by this ''decoy alkylating agent'' (reviewed in ref. 19). Phase II clinical trials in adults and children are now under way to evaluate the clinical activity of BG combined with TEM in patients with brain tumors.…”

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confidence: 99%

Targeting Methylguanine-DNA Methyltransferase in the Treatment of Neuroblastoma

Wagner

McLendon

Yoon

et al. 2007

Clinical Cancer Research

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Purpose: The combination of temozolomide and irinotecan has preclinical schedule-dependent synergy against neuroblastoma but is not curative for relapsed high-risk patients. We hypothesized that the DNA repair protein methylguanine-DNA methyltransferase (MGMT) is an important resistance factor, and that inactivation of MGMT would sensitize neuroblastoma cells to these agents. Experimental Design: MGMT protein expression was assessed in 74 primary neuroblastoma tumors. Growth inhibition assays were done to determine the IC 50 and the extent of synergy observed with various concentrations of temozolomide, irinotecan, and the MGMT-inactivating agent O 6 -benzylguanine, using cultured syngeneic neuroblastoma cells with either low or high levels of MGMT expression. We then assessed efficacy in a mouse xenograft model of metastatic neuroblastoma. Results: MGMT was expressed by all 74 tumors evaluated. Pretreatment of neuroblastoma cells with O 6 -benzylguanine reduced the IC 50 of temozolomide by 10-fold regardless of level of MGMT expression, and pretreatment with BG followed by temozolomide + irinotecan further reduced the IC 50 in cells with high MGMT expression another 10-fold, to well below clinically achievable concentrations.The combination index was 0.27 to 0.30 for all three drugs in both cell lines, indicating strong synergy. Survival at 100 days for mice with metastatic neuroblastoma was 56% with three-drug treatment, compared with untreated controls (0%, P < 0.001) or temozolomide + irinotecan (10%, P = 0.081). Conclusions: MGMT is widely expressed in primary neuroblastoma tumors, and is a relevant therapeutic target. Both in vitro and in vivo studies suggest inactivation of MGMT with O 6 -benzylguanine may increase the activity of temozolomide and irinotecan against neuroblastoma.Neuroblastoma is the most common extracranial solid tumor of childhood, and accounts for 15% of all pediatric cancer deaths. Fewer than half of all children diagnosed with high-risk neuroblastoma will survive 5 years after diagnosis (1). The identification of new active agents or drug combinations is essential to improving the prognosis for these patients. One potentially promising regimen is the combination of the DNA methylating agent temozolomide with the topoisomerase I inhibitor irinotecan. Both drugs have single-agent activity against neuroblastoma (2, 3), and preclinical studies have shown that administration of TEM followed by IRN results in schedule-dependent synergy against mouse models of this disease (4). Based on encouraging preliminary reports of this combination in children with relapsed solid tumors (5 -7), the Children's Oncology Group is now conducting a national phase II trial of this drug pair to define its activity for neuroblastoma in first relapse. It is unlikely, however, that this two-drug combination will be curative for the majority of patients with high-risk disease at relapse due to drug resistance.One recognized mechanism of TEM resistance is a high level of expression of methylguanine-DNA m...

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Inactivation of O6-alkylguanine DNA alkyltransferase as a means to enhance chemotherapy

Cited by 85 publications

References 111 publications

Dynamics of chemosensitivity and chromosomal instability in recurrent glioblastoma

Dynamics of chemosensitivity and chromosomal instability in recurrent glioblastoma

DNA Repair Pathways in Trypanosomatids: from DNA Repair to Drug Resistance

Targeting Methylguanine-DNA Methyltransferase in the Treatment of Neuroblastoma

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