title: Bioreductive prodrugs as cancer therapeutics: targeting tumor hypoxia.
abstract: Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain chemotherapeutic drugs. Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. To date, five distinct classes of bioreactive prodrugs have been developed to target hypoxic cells in solid tumors. These hypoxia-activated prodrugs, including nitro compounds, N-oxides, quinones, and metal complexes, generally share a common mechanism of activation whereby they are reduced by intracellular oxidoreductases in an oxygen-sensitive manner to form cytotoxins. Several examples including PR-104, TH-302, and EO9 are currently undergoing phase II and phase III clinical evaluation. In this review, we discuss the nature of tumor hypoxia as a therapeutic target, focusing on the development of bioreductive prodrugs. We also describe the current knowledge of how each prodrug class is activated and detail the clinical progress of leading examples.
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. ding_ke@gibh.ac.cn.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Guise
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Mowday
authors.forename: Amir
authors.initials: A
authors.lastname: Ashoorzadeh
authors.forename: Ran
authors.initials: R
authors.lastname: Yuan
authors.forename: Wan-Hua
authors.initials: WH
authors.lastname: Lin
authors.forename: Dong-Hai
authors.initials: DH
authors.lastname: Wu
authors.forename: Jeff B
authors.initials: JB
authors.lastname: Smaill
authors.forename: Adam V
authors.initials: AV
authors.lastname: Patterson
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
mesh_terms: D000880:Anthraquinones / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001388:Aziridines / Q000737:chemistry / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects*; D006801:Humans; D045563:Indolequinones / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000737:chemistry / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D009588:Nitrogen Mustard Compounds / Q000737:chemistry / Q000494:pharmacology; D009593:Nitroimidazoles / Q000737:chemistry / Q000494:pharmacology; D010752:Phosphoramide Mustards / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D000077704:Tirapazamine; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000880:Anthraquinones; D000970:Antineoplastic Agents; D001388:Aziridines; D045563:Indolequinones; D009588:Nitrogen Mustard Compounds; D009593:Nitroimidazoles; C522381:PR-104; D010752:Phosphoramide Mustards; D011355:Prodrugs; C552526:TH 302; D014227:Triazines; D000077704:Tirapazamine; C094428:AQ4N; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C060817:apaziquone