Temozolomide in malignant gliomas: current use and future targets

Villanó, John L.; Seery, Tara Elisabeth; Bressler, Linda R.

doi:10.1007/s00280-009-1050-5

Cited by 169 publications

(145 citation statements)

References 56 publications

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“…At physiologic pH, it undergoes rapid chemical conversion to methyl-triazeno-imidazole-carboxamide, the active drug. 28 This exerts its cytotoxic effect through methylation of deoxyribonucleic acid (DNA) at the O 6 position of guanine, 29 which then mispairs with thymine during the next cycle of DNA replication. The sequence of mismatch-repair events initiated leads to apoptosis.…”

Section: Temozolomidementioning

confidence: 99%

Treatment of pituitary neoplasms with temozolomide

Syro

Ortíz

Scheithauer

et al. 2010

Cancer

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Temozolomide, an orally administered alkylating agent, is used to treat malignant gliomas. Recent reports also have documented its efficacy in the treatment of pituitary adenomas and carcinomas. Temozolomide methylates DNA and thereby exhibits an antitumor effect. O 6 -methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, removes alkylating adducts induced by temozolomide, counteracting its effects. The authors of this review conducted a Medline database search regarding temozolomide in the treatment of pituitary tumors. Demographic characteristics, tumor types, and therapeutic responses were noted in all patients. Data regarding MGMT immunoexpression, which was documented in some studies, were correlated with information regarding clinical and radiologic responses. To date, there have been 19 reported cases of adenohypophyseal tumors treated with temozolomide, including 13 adenomas and 6 carcinomas. Ten of those 13 adenomas responded favorably, and 2 nonresponsive tumors had highlevel MGMT immunoexpression. All 6 carcinomas responded to therapy, but data regarding MGMT expression were available for only 3 patients, and each had low MGMT expression. In 2 adenomas, morphologic studies were performed both before and after the patients received temozolomide. The responsive tumor had necrosis, hemorrhage, fibrosis, and neuronal differentiation. The nonresponsive tumor had no changes. There have been no reported complications attributable to temozolomide. The current results indicated that temozolomide is efficacious in the treatment of aggressive pituitary adenomas and pituitary carcinomas. Evidence indicated that low-level MGMT immunoexpression is correlated with a favorable response. A significant proportion of pituitary adenomas and carcinomas had low MGMT immunoexpression. Cancer 2011;117:454-62.

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Section: Temozolomidementioning

confidence: 99%

Treatment of pituitary neoplasms with temozolomide

Syro

Ortíz

Scheithauer

et al. 2010

Cancer

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“…Although surgery followed by chemotherapy is the normal treatment regimen for gliomas, most malignant gliomas are resistant to chemotherapeutic agents. Because the blood-brain barrier (BBB) restricts and regulates the delivery of chemotherapy agents, the prognosis for glioma is poor (Stupp et al, 2007;Villano et al, 2009). Therefore, it is necessary to develop highly permeable agents that cross the BBB for the chemotherapeutic treatment of patients with malignant glioma.…”

Section: Introductionmentioning

confidence: 99%

Caffeine Inhibits Cell Proliferation and Regulates PKA/GSK3β Pathways in U87MG Human Glioma Cells

Lee

Jeong

et al. 2011

Molecules and Cells

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“…To date, a number of methods have been described to inhibit MGMT; however, their significance in clinical use for the purpose of overcoming temozolomide resistance is still limited or unknown [3,37,38]. Here, we have shown that the molecular pathway linking MEK to MGMT expression could offer novel and rational targets for MGMT inactivation, specifically MEK (by SL327) and MDM2 (by Nutlin-3).…”

Section: Resultsmentioning

confidence: 88%

“…The standard of care for glioblastoma is composed of maximal surgical resection followed by radiotherapy with concomitant and adjuvant chemotherapy [1,2]. Temozolomide is a monofunctional alkylating agent currently used as the first-line chemotherapeutic agent against newly diagnosed glioblastoma and is also a drug of choice for recurrent disease [3,4]. Sensitivity of tumor cells to temozolomide is therefore key to successful management of this intractable disease; however, unfortunately glioblastoma cells often exhibit resistance against this alkylating agent.…”

Section: Introductionmentioning

confidence: 99%

MEK-ERK Signaling Dictates DNA-Repair Gene MGMT Expression and Temozolomide Resistance of Stem-Like Glioblastoma Cells via the MDM2-p53 Axis

et al. 2011

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Overcoming the resistance of glioblastoma cells against temozolomide, the first-line chemotherapeutic agent of choice for newly diagnosed glioblastoma, is a major therapeutic challenge in the management of this deadly brain tumor. The gene encoding O 6 -methylguanine DNA methyltransferase (MGMT), which removes the methyl group attached by temozolomide, is often silenced by promoter methylation in glioblastoma but is nevertheless expressed in a significant fraction of cases and is therefore regarded as one of the most clinically relevant mechanisms of resistance against temozolomide. However, to date, signaling pathways regulating MGMT in MGMT-expressing glioblastoma cells have been poorly delineated. Here in this study, we provide lines of evidence that the mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-extracellular signal-regulated kinase (ERK)-murine double minute 2 (MDM2)-p53 pathway plays a critical role in the regulation of MGMT expression, using stem-like glioblastoma cells directly derived from patient tumor samples and maintained in the absence of serum, which not only possess stem-like properties but are also known to phenocopy the characteristics of the original tumors from which they are derived. We show that, in stem-like glioblastoma cells, MEK inhibition reduced MDM2 expression and that inhibition of either MEK or MDM2 resulted in p53 activation accompanied by p53-dependent downregulation of MGMT expression. MEK inhibition rendered otherwise resistant stem-like glioblastoma cells sensitive to temozolomide, and combination of MEK inhibitor and temozolomide treatments effectively deprived stem-like glioblastoma cells of their tumorigenic potential. Our findings suggest that targeting of the MEK-ERK-MDM2-p53 pathway in combination with temozolomide could be a novel and promising therapeutic strategy in the treatment of glioblastoma. STEM CELLS

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Temozolomide in malignant gliomas: current use and future targets

Cited by 169 publications

References 56 publications

Treatment of pituitary neoplasms with temozolomide

Treatment of pituitary neoplasms with temozolomide

Caffeine Inhibits Cell Proliferation and Regulates PKA/GSK3β Pathways in U87MG Human Glioma Cells

MEK-ERK Signaling Dictates DNA-Repair Gene MGMT Expression and Temozolomide Resistance of Stem-Like Glioblastoma Cells via the MDM2-p53 Axis

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