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Identification of one-electron reductases that activate both the hypoxia prodrug SN30000 and diagnostic probe EF5
2015, Biochemical PharmacologyCitation Excerpt :In the present study, we demonstrate that reduction of the TPZ analogue SN30000 is strongly inhibited by the flavoreductase suicide inhibitor DPI. We have previously identified SN30000 and TPZ as substrates for POR in overexpressing cell lines [39,44], consistent with the known ability of POR to reduce TPZ in mouse liver preparations [56] and reported correlations between POR expression and TPZ [39,57] or SN30000 [39] reduction in human tumour cell lines. However, we have also shown that multi-allelic knockout of POR in either SiHa or HCT116 using zinc finger nucleases has no significant effect on SN30000 reduction or sensitivity [44].
Zinc finger nuclease knock-out of NADPH:cytochrome P450 oxidoreductase (POR) in human tumor cell lines demonstrates that hypoxia-activated prodrugs differ in POR dependence?
2013, Journal of Biological ChemistryCitation Excerpt :Similarly, a cell line selected for mitomycin C resistance under aerobic conditions had reduced POR activity, but no change in sensitivity to the HAP was seen under hypoxia (26). An inhibitory antibody has been used to estimate that POR is responsible for 20–30% of the anoxic metabolism of tirapazamine in mouse liver microsomes (27). Guise et al. (22) investigated the role of endogenous levels of POR in the activation of PR-104A in SiHa cells using siRNA and antisense methods; knocking down POR resulted in a significant (but less than proportional) decrease in anoxic cytotoxic potency, although residual POR enzymatic activity was not quantified.
DNA strand cleaving properties and hypoxia-selective cytotoxicity of 7-chloro-2-thienylcarbonyl-3-trifluoromethylquinoxaline 1,4-dioxide
2010, Bioorganic and Medicinal ChemistryMultiple NADPH-cytochrome P450 reductases from Trypanosoma cruzi. Suggested role on drug resistance
2008, Molecular and Biochemical ParasitologyMetabolism of nilutamide in rat lung
2006, Biochemical PharmacologyCitation Excerpt :The enzyme(s) responsible for nilutamide reduction have not yet been identified precisely. Involvement of P450 and P450R have been cited [12] and there is growing evidence that these membrane-bound enzymes participate in the reduction of several nitro-compounds [39–43]. The implication of a flavoprotein in nilutamide nitroreduction in rat lung is suggested by: (i) the requirement for both FMN and NADPH, and (ii) the inhibition by DPIC, a non-selective inhibitor of flavoproteins.
Aerobic 2- and 4-nitroreduction of CB 1954 by human liver
2005, Toxicology
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Present address: The Institute of Cancer Research, Royal Cancer Hospital, Drug Development Section, 15 Cotswold Road, Belmont, Sutton, Surrey SM2 5NG, U.K.