Bioreductive drugs

The mitomycins do not react directly with DNA, but require prior activation by reduction of the quinone. This property of bioreductive activation has inspired the design and development of synthetic anticancer drugs that are also activated by reduction, as this is expected to confer a degree of tumor selectivity [45, 46]. Many solid tumors are short of oxygen relative to normal tissue, so reductive activation of the mitomycins and other bioreductive drugs can proceed in tumors, while it is inhibited by the oxidizing environments in normal tissues. 

Stratford, I. J. Workman, P. Bioreductive drugs into the next millennium. Anti-Cancer Drug Des. 1998, 13, 519-528. 

Workman, P. Enzyme-directed bioreductive drug development revisted a commentary on recent progress and future prospects with emphasis on quinone anticancer agents and quinone metabolizing enzymes, particularly DT-diaphorase. Oncol. Res. 1994, 6, 461 175. 

Wardman P, Dennis MF, Everett SA, Patel KB, Stratford MRL, Tracy M (2003) Radicals from one-electron reduction of nitro compounds, aromatic N-oxides and quinones the kinetic basis for hypoxia-selective, bioreductive drugs. Biochem Soc Symp 61 171-194 Warman JM, de Haas MP, Hummel A, van Lith D, VerberneJB, Loman H (1980) A pulse radiolysis conductivity study of frozen aqueous solutions of DNA. Int J Radiat Biol 38 459-459 Warman JM, de Haas MP, Rupprecht A (1996) DNA a molecular wire Chem Phys Lett 249 319-322 Warters RL, Lyons BW (1992) Variation in radiation-induced formation of DNA double-strand breaks as a function of chromatin structure. Radiat Res 130 309-318 Warters RL, Hofer KG, Harris CR, Smith JM (1977) Radionuclide toxicity in cultured mammalian cells Elucidation of the primary site of radiation damage. Curr Top Radiat Res Q 12 389-407 Weiland B, Huttermann J (1998) Free radicals from X-irradiated, dry and hydrated lyophilized DNA as studies by electron spin resonance spectroscopy analysis of spectral components between 77 K and room temperature. Int J Radiat Biol 74 341-358 Weinfeld M, Soderlind K-JM (1991) 32P-Postlabeling detection of radiation-induced DNA-damage identification and estimation of thymine glycols and phosphoglycolate termini. Biochemistry 30 1091-1097... 

Atkinson S, Loadman P, Sutton C, Patterson L, Clench M (2007) Examination of the distribution of the bioreductive drug AQ4N and its active metabolite AQ4 in solid tumors by imaging matrix-assisted laser desorption/ionization mass spectrometry. Rapid Commun Mass Spectrom 21 1271-1276. doi 1002/rcm.2952... 

Jaffar, M. and Stratford, I.J. (1999) Bioreductive drugs selectivity towards hypoxic tissues. Exp. Opin. Ther. Patents, 9 1371-1380. 

The bioactive benzimidazolequinone 131 has been synthesized by demethylation of the dimethoxybenzimidazole 129 followed by facile oxidation of the intermediate dihydroxy compoimd 130 by ferric chloride to yield the quinone 131 in excellent yield (Scheme 23). Synthesis of the related ben-zimidazolequinones 134 was achieved by dinitration of 132 followed by the reduction of 133 and oxidation as above. The benzimidazole-6,9-dione 134 has been found to be 300 times more cytotoxic towards the human skin fibroblast cell line in the MTT assay than the clinically used bioreductive drug, mitomycin C. Attaching methyl substituents onto the quinone moiety increased reductive potential and decreased cytotoxicity and selectivity towards hypoxia [67]. 

Cliffe, S., Taylor, M. L., Rutland, M Baguley, B. C., Hill, R. P., and Wilson, W. R. (1994) Combining bioreductive drugs (SR 4233 or SN 23862) with the vasoactive agents flavone acetic acid or 5,6-dimethylxanthenone acetic acid. Inti. J. Radiat. Oncol. Biol. Phys. 29, 373-377. 

Bioreductive drugs are designed to be activated by enzymatic reduction in hypoxic re-... 

Some of the flavoproteins which catalyse the reduction of bioreductive drugs show redox-controlled catalysis. The most important of these is probably NADPHxytochrome P-450 reductase, a one-electron donor [147]. At the simplest level, such proteins can be modelled by reduced flavin mononucleotide, FMNHa [148]. 

Kinetics controlling bioreductive drug selectivity towards hypoxic cells... 

There has been must less work directed to exploiting endogenous or targeted oxidative reactivity in tumours, compared to work on bioreductive drugs. Glucose oxidase or hypoxanthine/xanthine oxidase has been explored as sources of hydrogen peroxide or superoxide radicals [154,155], and the effects on tumour growth of ischaemia/reperfusion (which leads to a superoxide burst ) has been studied [156,157]. 

K.I. Priyadarsini, M. Tracy and P. Wardman, The one-electron reduction potential of 3-amino-l,2,4-benzotriazine 1,4-dioxide (tirapazamine) a hypoxia-selective bioreductive drug. Free Radical Res., 25 (1996) 393. 

S.A. Everett, M.A. Naylor, J. Nolan, K.B. Patel and P. Wardman, Indolequinone bioreductive drugs kinetic factors which influence selectivity for hypoxia, Anti-Cancer Dmg Des., 13(1998) 635. 

Cummings, J. et al., Enzymology of mitomycin C metabolic activation in tumor tissue implications for enzyme-directed bioreductive drug development, Biochem. Pharmacol, 56, 405, 1998. 

Olive, P. L. Detection of hypoxia by measurement of DNA damage in individual cells from spheroids and murine tumours exposed to bioreductive drugs. I. Tirapazamine. Br. J. Cancer 1995, 71, 529-536. 

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