title: Potentiation of the cytotoxicity of the anticancer agent tirapazamine by benzotriazine N-oxides: the role of redox equilibria.
abstract: Tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide), the lead bioreductive drug with selective toxicity for hypoxic cells in tumors, is thought to act by forming an active oxidizing radical of high one-electron reduction potential, E(1), when reduced by reductases. It has a dual mechanism of action, both generating DNA radicals, following its one-electron reduction and subsequently oxidizing these DNA radicals to form labile cations or hydrolyzable lactones through transferring an O atom, resulting in DNA strand breaks. These parallel secondary reactions have been proposed to be also initiated by its two-electron reduced metabolite, the 1-oxide. We have used pulse radiolysis to show that the benzotriazinyl radical of a highly soluble analogue of tirapazamine, the 3-(N,N-dimethyl-1,2-ethanediamine) analogue, is able to oxidize tirapazamine itself. We have found that both tirapazamine and the 1-oxides are in equilibrium with their respective benzotriazinyl radicals, with high concentrations of the more soluble 1-oxide maintaining a high concentration of the more reactive oxidizing radical of tirapazamine. The one-electron reduction potentials, E(1), of the 1-oxides and related compounds have been measured and, together with the E(1) values of tirapazamine and the 2-nitroimidazole radiosensitizer, misonidazole, are shown to predict the published percentages of electron transfer. This radical chemistry study gives an insight into the mechanisms of the potentiation of radical damage, reported for DNA, that underlies the hypoxic cytotoxicity of electron affinic compounds. The E(1) values of the benzotriazinyl radicals of the benzotriazine compounds govern the position of the redox equilibria, which determine the amount of initial radical damage. The E(1) values of the 1,4-dioxides and 1-oxide compounds govern the degree of potentiation of the initial radical damage once formed.
authors.affiliation: Department of Chemistry and Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland 1, New Zealand. r.anderson@auckland.ac.nz
authors.forename: Robert F
authors.initials: RF
authors.lastname: Anderson
authors.forename: Sujata S
authors.initials: SS
authors.lastname: Shinde
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hay
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004357:Drug Synergism; D005609:Free Radicals / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D010084:Oxidation-Reduction; D000077704:Tirapazamine; D014227:Triazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D003497:Cyclic N-Oxides; D005609:Free Radicals; D014227:Triazines; D000077704:Tirapazamine