Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials

“…3,4 TMZ has several advantages over other existing alkylating agents because of its unique characteristics. [5][6][7][8] Because TMZ is a small lipophilic molecule with a molecular weight of 194 Da, it can be administered orally and it crosses the blood-brain barrier effectively. The levels of TMZ in the brain or cerebrospinal fluid are about 30-40% of the plasma concentration.…”

Section: Introductionmentioning

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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“…Among the outstanding successes of the Phase I/II Clinical Trials Committee as a mechanism for the evaluation of new anticancer agents and diagnostics, is the development of the methylating agent temozolomide (I -Temodal s ) (Stevens and Newlands, 1993;Newlands et al, 1997). This drug arose as a result of multidisciplinary research in which interaction between medicinal chemists and pharmacologists was critical.…”

Section: Chemistry-driven Drug Discovery -N-methylformamide To Phortrmentioning

confidence: 99%

Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK

et al. 2003

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Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials

Cited by 727 publications

References 65 publications

Potentiation of anti-cancer agent cytotoxicity by the potent poly(ADP-ribose) polymerase inhibitors NU1025 and NU1064

Potentiation of anti-cancer agent cytotoxicity by the potent poly(ADP-ribose) polymerase inhibitors NU1025 and NU1064

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

Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK

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