In search of effective therapies to overcome resistance to Temozolomide in brain tumours (original) (raw)
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The strategy for enhancing temozolomide against malignant glioma
Frontiers in Oncology, 2012
A combined therapy of the alkylating agent temozolomide (TMZ) and radiotherapy is standard treatment, and it improves the survival of patients with newly diagnosed glioblastoma (GBM). The DNA repair enzyme O 6 -methylguanine-DNA methyltransferase (MGMT) removes the most cytotoxic lesions generated by TMZ, O 6 -methylguanine, establishing MGMT as one of the most important DNA repair mechanisms of TMZ-induced DNA damage. Thus, the expression of MGMT, its activity, and its promoter methylation status are associated with the response of GBM to TMZ, confirming that MGMT promotes clinical resistance to TMZ. Previous studies have shown that a variety of drugs such as interferon-β (IFN-β), levetiracetam (LEV), resveratrol, and valproic acid (VAP) increased the sensitivity of TMZ through MGMT-dependent or MGMT-independent mechanisms. In this review, we describe drugs and promising molecules that influence the responsiveness of GBM to TMZ and discuss their putative mechanism of action. In MGMT-positive GBMs, drugs that modulate MGMT activity could enhance the therapeutic activity of TMZ. Thus, administration of these drugs as an adjunct to TMZ chemotherapy may have clinical applications in patients with malignant gliomas to improve the outcome.
Frontiers in oncology, 2012
Alkylating agents have long played a central role in the adjuvant therapy of glioblastoma (GBM). More recently, inclusion of temozolomide (TMZ), an orally administered methylating agent with low systemic toxicity, during and after radiotherapy has markedly improved survival. Extensive in vitro and in vivo evidence has shown that TMZ-induced O(6)-methylguanine (O(6)-meG) mediates GBM cell killing. Moreover, low or absent expression of O(6)-methylguanine-DNA methyltransferase (MGMT), the sole human repair protein that removes O(6)-meG from DNA, is frequently associated with longer survival in GBMs treated with TMZ, promoting interest in developing inhibitors of MGMT to counter resistance. However, the clinical efficacy of TMZ is unlikely to be due solely to O(6)-meG, as the agent produces approximately a dozen additional DNA adducts, including cytotoxic N3-methyladenine (3-meA) and abasic sites. Repair of 3-meA and abasic sites, both of which are produced in greater abundance than O(6...
Biomedicines
The current standard first-line treatment for adult patients with newly diagnosed glioblastoma includes concurrent radiotherapy and daily oral temozolomide (TMZ), followed by adjuvant TMZ. As a prodrug, TMZ undergoes spontaneous hydrolysis generating a methylating agent. O6-methylguanine is considered the most preponderant toxic damage mechanism at therapeutically relevant TMZ doses, whereas MGMT, which encodes the O6-methylguanine-DNA methyltransferase DNA repair enzyme, is the most relevant resistance mechanism. Speculations on clinically relevant TMZ concentrations, cytotoxic and cytostatic effects of TMZ, and resistance mechanisms exist in the literature. Here, we raise the following principal issues: What are the clinically relevant TMZ concentrations in glioma patients, and which TMZ-induced molecular lesion(s) and corresponding resistance mechanism(s) are important for TMZ therapeutic effects at clinically relevant concentrations? According to clinical data from patients with...
Neuro-Oncology, 2020
Glioblastoma (GBM) is considered one of the most lethal forms of human cancers, and despite considerable advances in multimodality treatments, it remains an incurable disease with an overall survival of 14 to 16 months after diagnosis. Even in the era of personalized medicine and immunotherapy, temozolomide (TMZ), an oral alkylating agent, remains the standard-of-care for GBM. However, intrinisic or acquired resistance to TMZ due to over expression of O6-methylguanine-DNA methyltransferase (MGMT) results in initial treatment inefficacy or tumor relapse, highlighting the significant need for improved treatment strategies. Recently, much effort has been directed towards creating novel TMZ analogs to address the clinical barriers associated with TMZ. While some reported TMZ analogs showed improved brain permeability and anticancer effects in preclinical models, none of them have progressed to testing in humans. There is therefore significant room to improve the brain permeability and a...
Molecular Cancer Therapeutics, 2014
The cellular responses to two new temozolomide (TMZ) analogues, DP68 and DP86, acting against glioblastoma multiforme (GBM) cell lines and primary culture models are reported. Dose-response analysis of cultured GBM cells revealed that DP68 is more potent than DP86 and TMZ and that DP68 was effective even in cell lines resistant to TMZ. On the basis of a serial neurosphere assay, DP68 inhibits repopulation of these cultures at low concentrations. The efficacy of these compounds was independent of MGMT and MMR functions. DP68-induced interstrand DNA cross-links were demonstrated with H 2 O 2 -treated cells. Furthermore, DP68 induced a distinct cell-cycle arrest with accumulation of cells in S phase that is not observed for TMZ. Consistent with this biologic response, DP68 induces a strong DNA damage response, including phosphorylation of ATM, Chk1 and Chk2 kinases, KAP1, and histone variant H2AX. Suppression of FANCD2 expression or ATR expression/kinase activity enhanced antiglioblastoma effects of DP68. Initial pharmacokinetic analysis revealed rapid elimination of these drugs from serum. Collectively, these data demonstrate that DP68 is a novel and potent antiglioblastoma compound that circumvents TMZ resistance, likely as a result of its independence from MGMT and mismatch repair and its capacity to cross-link strands of DNA.
Acta Neuropathologica, 2015
Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O 6-methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT-mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we
Journal of biomedical research, 2010
Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor in adults. Current therapy includes surgery, radiation and chemotherapy with temozolomide (TMZ). Major determinants of clinical response to TMZ include methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter and mismatch repair (MMR) status. Though the MGMT promoter is methylated in 45% of cases, for the first nine months of follow-up, TMZ does not change survival outcome. Furthermore, MMR deficiency makes little contribution to clinical resistance, suggesting that there exist unrecognized mechanisms of resistance. We generated paired GBM cell lines whose resistance was attributed to neither MGMT nor MMR. We show that, responding to TMZ, these cells exhibit a decoupling of DNA damage response (DDR) from ongoing DNA damages. They display methylation-resistant synthesis in which ongoing DNA synthesis is not inhibited. They are also defective in the activation of the S and G2 phase checkpo...
Inhibition of DNA repair for sensitizing resistant glioma cells to temozolomide
Journal of Neurosurgery, 2003
ALIGNANT gliomas are the most prevalent type of brain tumor and are often refractory to even the most aggressive therapy. 2 With such treatment, including surgery, radiotherapy, and chemotherapy, the median survival time in a patient with GBM remains between 12 and 15 months. Obviously, considering the devastating effects of this neoplasm and the limited success of currently available treatments, new therapeutic approaches are needed.
Mismatch Repair Deficiency Does Not Mediate Clinical Resistance to Temozolomide in Malignant Glioma
Clinical Cancer Research, 2008
Purpose: A major mechanism of resistance to methylating agents, including temozolomide, is the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT). Preclinical data indicates that defective DNA mismatch repair (MMR) results in tolerance to temozolomide regardless of AGT activity. The purpose of this study was to determine the role of MMR deficiency in mediating resistance in samples from patients with both newly diagnosed malignant gliomas and those who have failed temozolomide therapy. Experimental Design: The roles of AGT and MMR deficiency in mediating resistance in glioblastoma multiforme were assessed by immunohistochemistry and microsatellite instability (MSI), respectively. The mutation status of the MSH6 gene, a proposed correlate of temozolomide resistance, was determined by direct sequencing and compared with data from immunofluorescent detection of MSH6 protein and reverse transcription-PCR amplification of MSH6 RNA. Results: Seventy percent of newly diagnosed a...
Oncotarget, 2018
Via extensive analyses of genetic databases, we have characterized the DNA-repair capacity of glioblastoma with respect to patient survival. In addition to elevation of O-methylguanine DNA methyltransferase (MGMT), down-regulation of three DNA repair pathways; canonical mismatch repair (MMR), Non-Homologous End-Joining (NHEJ), and Homologous Recombination (HR) are correlated with poor patient outcome. We have designed and tested both and , a monoamine oxidase B (MAOB) specific prodrug, PAM-OBG, that is converted by glioma MAOB into the MGMT inhibitor O-benzylguanine (OBG) and the DNA crosslinking agent acrolein. In cultured glioma cells, we show that PAM-OBG is converted to OBG, inhibiting MGMT and sensitizing cells to DNA alkylating agents such as BCNU, CCNU, and Temozolomide (TMZ). In addition, we demonstrate that the acrolein generated is highly toxic in glioma treated with an inhibitor of Nucleotide Excision Repair (NER). In mouse intracranial models of primary human glioma, we ...