Prolonged Temozolomide Maintenance Therapy in Newly Diagnosed Glioblastoma

Skardelly, Marco; Dangel, Elena; Gohde, Julia; Noell, Susan; Behling, Felix; Lepski, Guilherme; Borchers, Christian; Koch, Marilin; Schittenhelm, Jens; Bisdas, Sotirios; Naumann, Aline; Paulsen, Frank; Zips, Daniel; Hehn, Ulrike von; Ritz, Rainer; Tatagiba, Marcos; Tabatabai, Ghazaleh

doi:10.1634/theoncologist.2016-0347

Cited by 28 publications

(25 citation statements)

References 17 publications

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“…Such approach appeared to be effective for primary [54] and recurrent glioblastoma [55][56][57]. Also prolonged (> 6 cycles) standard TMZ therapy was proven to be successful [58,59]. There are data showing that this result does not depend on MGMT promoter methylation [55,60], but other indicate such connection [8].…”

Section: Discussionmentioning

confidence: 99%

Revealing the epigenetic effect of temozolomide on glioblastoma cell lines in therapeutic conditions

2020

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Temozolomide (TMZ) is a drug of choice in glioblastoma treatment. Its therapeutic applications expand also beyond high grade gliomas. However, a significant number of recurrences and resistance to the drug is observed. The key factor in each chemotherapy is to achieve the therapeutic doses of a drug at the pathologic site. Nonetheless, the rate of temozolomide penetration from blood to cerebrospinal fluid is only 20-30%, and even smaller into brain intestinum. That makes a challenge for the therapeutic regimens to obtain effective drug concentrations with minimal toxicity and minor side effects. The aim of our research was to explore a novel epigenetic mechanism of temozolomide action in therapeutic conditions. We analyzed the epigenetic effects of TMZ influence on different glioblastoma cell lines in therapeutically achieved TMZ concentrations through total changes of the level of 5-methylcytosine in DNA, the main epigenetic marker. That was done with classical approach of radioactive nucleotide post-labelling and separation on thin-layer chromatography. In the range of therapeutically achieved temozolomide concentrations we observed total DNA hypomethylation. The significant hypermethylating effect was visible after reaching TMZ concentrations of 10-50 μM (depending on the cell line). Longer exposure time promoted DNA hypomethylation. The demethylated state of the glioblastoma cell lines was overcome by repeated TMZ applications, where dosedependent increase in DNA 5-methylcytosine contents was observed. Those effects were not seen in non-cancerous cell line. The increase of DNA methylation resulting in global gene silencing and consecutive down regulation of gene expression after TMZ treatment may explain better glioblastoma patients' survival.questions about its efficacy, patient selection, outcome, and prognosis still remain, and therapy failures are observed in the vast majority of glioblastoma patients. The changing of dosing regimens didn't fulfill the expectations to increase the treatment effectivity [9].Temozolomide (4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo [4.3.0] nona-2,7,9-triene-9-carboxamide) is a small prodrug, with a molecular weight of 194.15, that undergoes chemical conversion at physiological pH to the active species 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC), and generates an active methyl group, that reacts with DNA bases [10]. The cytotoxic activity of TMZ manifests mainly through methylation at the O 6 position of guanine. Although that methyl adduct comprises less than 5% of the total temozolomide induced DNA modifications [11][12][13], O 6 -methylguanine leads to DNA mismatch repair, which results in preservation of the lesion and double-strand breaks, what leads to cell apoptosis [14,15]. Other alkyl adducts, like N 7 -methylguanine and N 3 -methyladenine, comprising ca. 80% of the total TMZ methylation products, are generally not cytotoxic, while they are easily repaired by the base excision repair system [12,13] (Fig 1). Therefore it is believed that generation of O 6 -meth...

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Section: Discussionmentioning

confidence: 99%

Revealing the epigenetic effect of temozolomide on glioblastoma cell lines in therapeutic conditions

2020

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“…One of them included the dose-dense TMZ to deplete MGMT in tumor cells by continuous daily TMZ treatment 19 , which failed to demonstrate improved efficacy in a phase III clinical trial 20 . Another approach was to extend the cycle of adjuvant TMZ treatment 8,21–24 . Hau et al .…”

Section: Discussionmentioning

confidence: 99%

Feasibility study of finalizing the extended adjuvant temozolomide based on methionine positron emission tomography (Met-PET) findings in patients with glioblastoma

Hirono

Hasegawa

Sakaida

et al. 2019

Sci Rep

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In the management of patients with newly diagnosed glioblastoma, there is no standard duration for adjuvant temozolomide treatment. This study aimed to assess the feasibility of finalizing adjuvant temozolomide treatment on the basis of methionine uptake in methionine positron emission tomography (Met-PET). We conducted a retrospective review of glioblastoma patients who underwent more than twelve cycles of temozolomide (extended temozolomide) treatment after resection and concomitant chemoradiotherapy with no evidence of recurrence on MRI. In addition to the methionine uptake value at the completion of extended temozolomide, local and distant recurrence and progression-free survival were also analyzed. Forty-four patients completed the extended temozolomide treatment. Among these, 18 experienced some type of tumor recurrence within one year. A Tmax/Nave value of 2.0 was the optimal cut-off value indicating progression. More than 80% of the patients with low methionine uptake completed the temozolomide treatment, and subsequent basic MRI observations showed no recurrence within one year after Met-PET. Subgroups with high uptake (≥2.0), even with continuation of temozolomide treatment, showed more frequent tumor progression than patients with low uptake (<2.0) who completed the extended temozolomide treatment (p < 0.001, odds ratio 14.7, 95% CI 3.46–62.3). The tumor recurrence rate increased in stepwise manner according to methionine uptake. Finalization of the extended temozolomide treatment on the basis of low uptake value was feasible with a low recurrence rate. Compared to MRI, Met-PET shows better ability to predict tumor progression in long-term glioblastoma survivors with extended temozolomide use.

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“…The relationship between number of adjuvant cycles received and outcome has not been clearly elucidated. Three studies found that patients who received more than 6 cycles of TMZ had improved survival compared to those who received less [15][16][17], while two other studies found no survival difference between these two groups of patients [18,19]. Taken together, these suggest that an as yet unidentified subset of patients may derive benefit from more than 6 cycles of TMZ and drive this difference when observed.…”

Section: Methods and Findingsmentioning

confidence: 97%

Image-based metric of invasiveness predicts response to adjuvant temozolomide for primary glioblastoma

et al. 2020

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BackgroundTemozolomide (TMZ) has been the standard-of-care chemotherapy for glioblastoma (GBM) patients for more than a decade. Despite this long time in use, significant questions remain regarding how best to optimize TMZ therapy for individual patients. Understanding the relationship between TMZ response and factors such as number of adjuvant TMZ cycles, patient age, patient sex, and image-based tumor features, might help predict which GBM patients would benefit most from TMZ, particularly for those whose tumors lack O 6 -methylguanine-DNA methyltransferase (MGMT) promoter methylation. OPEN ACCESS Citation: Massey SC, White H, Whitmire P, Doyle T, Johnston SK, Singleton KW, et al. (2020) Imagebased metric of invasiveness predicts response to adjuvant temozolomide for primary glioblastoma. PLoS ONE 15(3): e0230492. https://doi.org/ 10.

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Prolonged Temozolomide Maintenance Therapy in Newly Diagnosed Glioblastoma

Cited by 28 publications

References 17 publications

Revealing the epigenetic effect of temozolomide on glioblastoma cell lines in therapeutic conditions

Revealing the epigenetic effect of temozolomide on glioblastoma cell lines in therapeutic conditions

Feasibility study of finalizing the extended adjuvant temozolomide based on methionine positron emission tomography (Met-PET) findings in patients with glioblastoma

Image-based metric of invasiveness predicts response to adjuvant temozolomide for primary glioblastoma

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