NDLI: Removal of uracil by uracil DNA glycosylase limits pemetrexed cytotoxicity: overriding the limit with methoxyamine to inhibit base excision repair.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Bulgar, A. D. Weeks, L. D. Miao, Y. Yang, S. Xu, Y. Guo, C. Markowitz, S. Oleinick, N. Gerson, S. L. Liu, L.
Description	Country affiliation: United States Author Affiliation: Bulgar AD ( Department of Medicine, Division of Hematology/Oncology, Case Western Reserve University, Cleveland, OH, USA.)
Abstract	Uracil DNA glycosylase (UDG) specifically removes uracil bases from DNA, and its repair activity determines the sensitivity of the cell to anticancer agents that are capable of introducing uracil into DNA. In the present study, the participation of UDG in the response to pemetrexed-induced incorporation of uracil into DNA was studied using isogenic human tumor cell lines with or without UDG (UDG(+/+)/UDG(-/-)). UDG(-/-) cells were very sensitive to pemetrexed. Cell killing by pemetrexed was associated with genomic uracil accumulation, stalled DNA replication, and catastrophic DNA strand breaks. By contrast, UDG(+/+) cells were >10 times more resistant to pemetrexed due to the rapid removal of uracil from DNA by UDG and subsequent repair of the resultant AP sites (abasic sites) via the base excision repair (BER). The resistance to pemetrexed in UDG(+/+) cells could be reversed by the addition of methoxyamine (MX), which binds to AP sites and interrupts BER pathway. Furthermore, MX-bound AP sites induced cell death was related to their cytotoxic effect of dual inactivation of UDG and topoisomerase II , two genes that are highly expressed in lung cancer cells in comparison with normal cells. Thus, targeting BER-based therapy exhibits more selective cytotoxicity on cancer cells through a synthetic lethal mechanism.
File Format	HTM / HTML
e-ISSN	20414889
DOI	10.1038/cddis.2011.135
Journal	Cell Death and Disease
Volume Number	3
Language	English
Publisher	Nature Publishing Group
Publisher Date	2012-01-12
Publisher Place	Great Britain (UK)
Access Restriction	Open
Subject Keyword	Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Dna Repair Dna-binding Proteins Uracil-dna Glycosidase Hydroxylamines Guanine Dna Damage Antagonists & Inhibitors Genetics Glutamates Gene Expression Antigens, Neoplasm Signal Transduction Deficiency Antineoplastic Agents Pharmacology Gene Knockout Techniques Metabolism Drug Effects Dna Topoisomerases, Type Ii Pemetrexed Xenograft Model Antitumor Assays Discipline Cell Biology Animals Mice, Nude Cell Line, Tumor Mice Uracil Analogs & Derivatives
Content Type	Text
Resource Type	Article

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