1. Temozolomide analogs with improved brain/plasma ratios - Exploring the possibility of enhancing the therapeutic index of temozolomide
- Author
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Sandip Middya, Monali Banerjee, Eduardo Riquelme, Sarvajit Chakravarty, Pankaj Melkani, Vikas Dixit, Felipe Olivares, Shyamraj Yadav, Umesh K. Patil, David T. Hung, Andrew A. Protter, Shailendra Tripathi, Roopa Rai, Javier Sanchez Guerrero, Ashu Gupta, Emma McCullagh, Darren H. Wong, Sebastian Bernales, Ramnivas Jangir, Arjun Surya, Son Minh Pham, Ritesh Shrivastava, and Mohd. Raja
- Subjects
0301 basic medicine ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Therapeutic index ,Downregulation and upregulation ,In vivo ,Tandem Mass Spectrometry ,Cell Line, Tumor ,Drug Discovery ,medicine ,Temozolomide ,Animals ,Humans ,Molecular Biology ,Antineoplastic Agents, Alkylating ,Chemistry ,Organic Chemistry ,Brain ,Limiting ,medicine.disease ,Rats ,Dacarbazine ,DNA Alkylation ,030104 developmental biology ,Systemic toxicity ,030220 oncology & carcinogenesis ,Area Under Curve ,Molecular Medicine ,medicine.drug ,Glioblastoma ,Chromatography, Liquid - Abstract
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 O6-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.
- Published
- 2016