NMR and Molecular Modeling Investigation of the Mechanism of Activation of the Antitumor Drug Temozolomide and Its Interaction with DNA

Denny, Brian J.; Wheelhouse, Richard T.; Stevens, Malcolm F. G.; Tsang, Lincoln L. H.; Slack, Joan

doi:10.1021/bi00197a003

Cited by 385 publications

(335 citation statements)

References 24 publications

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“…7 We observed chemical hydrolysis of [3-N-11 C-methyl]TMZ in the final formulation according to analytical HPLC, corroborating previous reports that the compound decomposes at physiological pH. 15 Our purification and preparative method was designed to mitigate this issue; we monitored the stability of the radiopharmaceutical in an undiluted semi-preparative HPLC fraction and found it to be stable for at least 75 minutes in the acidic HPLC mobile phase. The mobile phase is composed of reagents that fall within USP safety limits for human injection; as such, buffering and salinating the mobile phase in accordance with these standards would afford a solution of [ 11 C]TMZ 10 that could immediately be filtered for injection without reformulation.…”

supporting

confidence: 81%

An Efficient and Practical Radiosynthesis of [¹¹C]Temozolomide

Moseley¹,

Carlin²,

Neelamegam³

et al. 2013

Org. Lett.

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Temozolomide (TMZ) is a prodrug for an alkylating agent used for the treatment of malignant brain tumors. A positron emitting version, [ 11 C]TMZ, has been utilized to help elucidate the mechanism and biodistribution of TMZ. Challenges in [ 11 C]TMZ synthesis and reformulation make it difficult for routine production. Herein we report a highly reproducible one-pot radiosynthesis of [ 11 C]TMZ with a radiochemical yield of 17±5% and >97% radiochemical purity.Chemotherapeutic treatment for advanced cancers persists as an area of intense research exploration. Existing treatment options, including surgery, radiation, and chemotherapy, seldom resulted in even one year of median improved survival for aggressive tumors such as malignant glioma. 1,2 Temozolomide (TMZ) is the prodrug to an antineoplastic alkylating agent that has drawn interest among the research community due to growing evidence for its broad range of chemotherapeutic activity in both in vitro and preclinical in vivo studies. TMZ displays activity against tumors which have resistance to other antitumor agents, and shows potential to improve patient survival outcomes when used in conjunction with radiation and anti-angiogenic therapies. 1,3 TMZ was approved for clinical use in the United States in 1999 and has since proven to be effective as an oral treatment for malignant glioma, malignant metastatic melanoma, and other adult central nervous system tumors.TMZ is currently the standard of care for all newly diagnosed glioblastoma. 4 Prior to the development of TMZ, de novo and acquired resistance to available chemotherapeutics, as well as complications from toxicity, prevented any single drug from attaining much more than a modest increase in overall survival rate. 2 In comparison to other chemotherapies, TMZ is well-tolerated by patients and elicits less severe complications due to nonspecific toxicity. Its off-target toxicity is generally considered mild-to-moderate, and side effects are predictable and easily managed in both adult and pediatric patients, usually with the aid of anti-emetics. 2 Patients who receive TMZ treatment also show improved Health-Related Quality-Of-Life (HR-QOL) scores-a

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supporting

confidence: 81%

An Efficient and Practical Radiosynthesis of [¹¹C]Temozolomide

Moseley¹,

Carlin²,

Neelamegam³

et al. 2013

Org. Lett.

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“…9,10 Subsequent futile cell cycles of DNA mismatch repair result in cell death in hematopoietic cancer cells. 11 Recent investigation shows that malignant glioma cells respond to TMZ by undergoing G2/M arrest and very few of glioma cells treated with TMZ underwent apoptosis.…”

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confidence: 99%

Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells

et al. 2004

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Autophagy is originally named as a process of protein recycling. It begins with sequestering cytoplasmic organelles in a membrane vacuole called autophagosome. Autophagosomes then fuse with lysosomes, where the materials inside are degraded and recycled. To date, however, little is known about the role of autophagy in cancer therapy. In this study, we present that temozolomide (TMZ), a new alkylating agent, inhibited the viability of malignant glioma cells in a dose-dependent manner and induced G2/M arrest. At a clinically achievable dose (100 lM), TMZ induced autophagy, but not apoptosis in malignant glioma cells. After the treatment with TMZ, microtubule-associated protein lightchain 3 (LC3), a mammalian homologue of Apg8p/Aut7p essential for amino-acid starvation-induced autophagy in yeast, was recruited on autophagosome membranes. When autophagy was prevented at an early stage by 3-methyladenine, a phosphatidylinositol 3-phosphate kinase inhibitor, not only the characteristic pattern of LC3 localization, but also the antitumor effect of TMZ was suppressed. On the other hand, bafilomycin A1, a specific inhibitor of vacuolar type H þ -ATPase, that prevents autophagy at a late stage by inhibiting fusion between autophagosomes and lysosomes, sensitized tumor cells to TMZ by inducing apoptosis through activation of caspase-3 with mitochondrial and lysosomal membrane permeabilization, while LC3 localization pattern stayed the same. These results indicate that TMZ induces autophagy in malignant glioma cells. Application of an autophagy inhibitor that works after the association of LC3 with autophagosome membrane, such as bafilomycin A1, is expected to enhance the cytotoxicity of TMZ for malignant gliomas.

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“…After administration, temozolomide spontaneously decomposes to 5-(3-methyltriazen-l-yl)imidazole-4-carboxamide (MTIC), which then yields AIC and methyl diazonium (Denny et al, 1994). The latter alkylates DNA, primarily at the O 6 of guanine.…”

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confidence: 99%

Phase I study of temozolomide plus paclitaxel in patients with advanced malignant melanoma and associated in vitro investigations

et al. 2005

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The purpose of this study was to determine activity of temozolomide combined with paclitaxel or epothilone B in vitro, and to investigate the combination of temozolomide with paclitaxel in a Phase I clinical trial. Melanoma cell lines A375P and DX3 were treated with temozolomide and either paclitaxel or epothilone B. Combination indices were determined to assess the degree of synergism. In a clinical study, 21 patients with malignant melanoma were treated with increasing doses of temozolomide (orally, days 1 -5), in combination with a fixed dose of paclitaxel (i.v. infusion day 1), followed by dose escalation of the latter drug. Cycles of treatment were repeated every 3 weeks. Pharmacokinetics of both agents were determined on day 1, with temozolomide pharmacokinetics also assessed on day 5. All three compounds were active against the melanoma cell lines, with epothilone B being the most potent. There was a strong degree of synergism between temozolomide and either paclitaxel or epothilone B. In the clinical study, no pharmacokinetic interaction was observed between temozolomide and paclitaxel. Dose escalation of both drugs to clinically active doses was possible, with no dose-limiting toxicities observed at 200 mg m À2 day À1 temozolomide and 225 mg m À2 day À1 paclitaxel. There were two partial responses out of 15 evaluable patients. One patient remains alive and symptom-free at 4 years after treatment. Temozolomide and paclitaxel may be administered safely at clinically effective doses. Further evaluation of these combinations in melanoma is warranted.

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NMR and Molecular Modeling Investigation of the Mechanism of Activation of the Antitumor Drug Temozolomide and Its Interaction with DNA

Cited by 385 publications

References 24 publications

An Efficient and Practical Radiosynthesis of [¹¹C]Temozolomide

An Efficient and Practical Radiosynthesis of [¹¹C]Temozolomide

Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells

Phase I study of temozolomide plus paclitaxel in patients with advanced malignant melanoma and associated in vitro investigations

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NMR and Molecular Modeling Investigation of the Mechanism of Activation of the Antitumor Drug Temozolomide and Its Interaction with DNA

Cited by 385 publications

References 24 publications

An Efficient and Practical Radiosynthesis of [11C]Temozolomide

An Efficient and Practical Radiosynthesis of [11C]Temozolomide

Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells

Phase I study of temozolomide plus paclitaxel in patients with advanced malignant melanoma and associated in vitro investigations

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An Efficient and Practical Radiosynthesis of [¹¹C]Temozolomide

An Efficient and Practical Radiosynthesis of [¹¹C]Temozolomide