Quantification of Acylfulvene鈥?and Illudin S鈥揇NA Adducts in Cells with Variable Bioactivation Capacities

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• 作者：Kathryn E. Pietsch ; Paul M. van Midwoud ; Peter W. Villalta ; Shana J. Sturla
• 刊名：Chemical Research in Toxicology
• 出版年：2013
• 出版时间：January 18, 2013
• 年：2013
• 卷：26
• 期：1
• 页码：146-155
• 全文大小：379K
• 年卷期：v.26,no.1(January 18, 2013)
• ISSN：1520-5010

文摘

Illudin S and its semisynthetic analogue acylfulvene (AF) are structurally similar but elicit different biological responses. AF is a bioreductive alkylating anticancer agent with a favorable therapeutic index, while illudin S is in general highly toxic. AF toxicity is dependent on the reductase enzyme prostaglandin reductase 1 (PTGR1) for activation to a cytotoxic reactive intermediate. While illudin S can be metabolized by PTGR1, available data suggest that its toxicity does not correspond with PTGR1 function. The goal of this study was to understand how drug cytotoxicity relates to cellular bioactivation capacity and the identity and quantity of AF鈥?or illudin S鈥揇NA adducts. The strategy involved identification of novel illudin S鈥揇NA adducts and their quantitation in a newly engineered SW-480 colon cancer cell line that stably overexpresses PTGR1 (PTGR1-480). These data were compared with cytotoxicity data for both compounds in PTGR1-480 versus normal SW-480 cells, demonstrating that AF forms more DNA adducts and is more cytotoxic in cells with higher levels of PTGR1, whereas illudin S cytotoxicity and adduct formation are not influenced by PTGR1 levels. Results are discussed in the context of an overall model for how changes in relative propensities of these compounds to undergo cellular processes, such as bioactivation, contributes to DNA damage, and cytotoxicity.