9-Amino acridine pharmacokinetics, brain distribution, and in vitro/in vivo efficacy against malignant glioma

Purpose The delivery of drugs to the brain is a major obstacle in the design and development of useful treatments for malignant glioma. Previous studies by our laboratory have identified a series of 9-amino acridine compounds that block the catalytic cycle of topoisomerase II resulting in apoptosis...

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Bibliographic Details
Published in:Cancer chemotherapy and pharmacology 2012-06, Vol.69 (6), p.1519-1527
Main Authors: Teitelbaum, Aaron M., Gallardo, Jose L., Bedi, Jessica, Giri, Rajan, Benoit, Adam R., Olin, Michael R., Morizio, Kate M., Ohlfest, John R., Remmel, Rory P., Ferguson, David M.
Format: Article
Language:English
Subjects:
Aminacrine - pharmacokinetics
Aminacrine - therapeutic use
Animals
Antineoplastic agents
Biological and medical sciences
Biological Availability
Brain - metabolism
Brain Neoplasms - drug therapy
Cancer Research
Cells, Cultured
Dogs
Female
Glioma - drug therapy
Humans
Medical sciences
Medicine
Medicine & Public Health
Mice
Mice, Inbred C57BL
Neurology
Oncology
Original Article
Pharmacology. Drug treatments
Pharmacology/Toxicology
Tumors of the nervous system. Phacomatoses
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Summary:Purpose The delivery of drugs to the brain is a major obstacle in the design and development of useful treatments for malignant glioma. Previous studies by our laboratory have identified a series of 9-amino acridine compounds that block the catalytic cycle of topoisomerase II resulting in apoptosis and cell death in a variety of cancer cell lines. Methods This study reports the in vitro and in vivo activity of two promising lead compounds, [{9-[2-(1 H -Indol-3-yl)-ethylamino]-acridin-4-yl}-(4-methyl-piperazin-1-yl)-methanone ( 1 ) and [9-(1-Benzyl-piperidin-4-ylamino)-acridin-3-yl]-(4-methyl-piperazin-1-yl)-methanone] ( 2 ), using an orthotopic glioblastoma mouse model. In addition, the absorption, distribution, and metabolism properties are characterized by determining metabolic stability, MDCK accumulation, Pgp efflux transport, plasma protein binding, and brain distribution in mouse pharmacokinetic studies. Results The efficacy results indicate low micromolar ED 50 values against glioma cells and a significant increase in the survival of glioma-bearing mice dosed with ( 2) ( p  
ISSN:0344-5704
1432-0843
DOI:10.1007/s00280-012-1855-5