Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 26, Issue 20, Pages 5103-5109Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2016.08.064
Keywords
Temozolomide; Glioblastoma; Chemotheraphy; O-6-Methyl-2 '-deoxyguanosine (O-6-MedG)
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- Medivation
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Temozolomide is a chemotherapeutic agent that is used in the treatment of glioblastoma and other malignant gliomas. It acts through DNA alkylation, but treatment is limited by its systemic toxicity and neutralization of DNA alkylation by upregulation of the O-6-methylguanine-DNA methyltransferase gene. Both of these limiting factors can be addressed by achieving higher concentrations of TMZ in the brain. Our research has led to the discovery of new analogs of temozolomide with improved brain: plasma ratios when dosed in vivo in rats. These compounds are imidazotetrazine analogs, expected to act through the same mechanism as temozolomide. With reduced systemic exposure, these new agents have the potential to improve efficacy and therapeutic index in the treatment of glioblastoma. (C) 2016 Published by Elsevier Ltd.
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