title: Radiolytic activation of a cytarabine prodrug possessing a 2-oxoalkyl group: one-electron reduction and cytotoxicity characteristics.
abstract: An anti-tumour agent of cytarabine (ara-C) was conjugated with a 2-oxopropyl group at the N(4) position to obtain a radiation-activated prodrug (oxo-ara-C) that targeted hypoxic tumour tissues with selective cytotoxicity. The parent anti-tumour agent, ara-C, was confirmed to be released from oxo-ara-Cvia one-electron reduction upon hypoxic X-ray treatment. The prodrug oxo-ara-C had dramatically reduced cytotoxicity against human lung adenocarcinoma A549 cells relative to ara-C because of the effect of 2-oxopropyl substituent. In contrast, X-ray treatment of hypoxic A549 cells containing oxo-ara-C enhanced the cytotoxic effect, indicating that toxic ara-C was preferentially released in hypoxic cells via radiolytic one-electron reduction by hydrated electrons (e(aq)(-)).
authors.affiliation: Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Katsura Campus, Kyoto, 615-8510, Japan.
authors.forename: Nao
authors.initials: N
authors.lastname: Hirata
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Fujisawa
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Tanabe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Harada
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hiraoka
authors.forename: Sei-ichi
authors.initials: S
authors.lastname: Nishimoto
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000528:radiation effects; D003561:Cytarabine / Q000737:chemistry* / Q000528:radiation effects; D016503:Drug Delivery Systems / Q000379:methods; D004583:Electrons; D006801:Humans; D000860:Hypoxia; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000737:chemistry / Q000528:radiation effects*; D014965:X-Rays
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D003561:Cytarabine