title: Quantification of acylfulvene- and illudin S-DNA adducts in cells with variable bioactivation capacities.
abstract: 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- or illudin S-DNA adducts. The strategy involved identification of novel illudin S-DNA 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.
authors.affiliation: Institute of Food, Nutrition and Health, ETH Zurich , 8092 Zurich, Switzerland.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Pietsch
authors.forename: Paul M
authors.initials: PM
authors.lastname: van Midwoud
authors.forename: Peter W
authors.initials: PW
authors.lastname: Villalta
authors.forename: Shana J
authors.initials: SJ
authors.lastname: Sturla
mesh_terms: D000478:Alkylation; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D002417:Cattle; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry; D018736:DNA Adducts / Q000032:analysis*; D006801:Humans; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D021241:Spectrometry, Mass, Electrospray Ionization; D013141:Spiro Compounds / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D018736:DNA Adducts; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes; D013141:Spiro Compounds; C079422:acylfulvene; D004247:DNA; C427203:calf thymus DNA; C008105:illudin S