The importance of DT-diaphorase and hypoxia in the cytotoxicity of RH1 in human breast and non-small cell lung cancer cell lines.
Affiliation
Cancer Research UK Group of Experimental Radiation Oncology, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK.Issue Date
2004-01
Metadata
Show full item recordAbstract
The diaziridiny/benzoquinone RH1 is shortly to enter a phase I clinical trial. The drug was originally designed as a substrate for the enzyme DT-diaphorase (DTD) such that metabolic activation of the drug would lead to toxicity. To evaluate this, we have measured the toxicity of RH1 in a pair of non-small cell lung cancer (NSCLC) cell lines of widely differing levels of DTD and in MDA231 breast cancer cells which have been engineered to overexpress DTD. In addition, we have explored the importance of the putative one-electron reductase, P450 reductase, by assessing the toxicity of RH1 in MDA231 cells engineered to overexpress the enzyme. All drug exposures were carried out under hypoxic and aerobic conditions. Those cells with the highest levels of DTD, i.e. D7 versus MDA231 wt and H460 versus H596, are substantially more sensitive to RH1 than the cell lines expressing low DTD activity. Those cells with the lowest levels of DTD activity, i.e. MDA231 wt, R4 and H596, show much greater sensitivity to RH1 under hypoxic conditions compared to aerobic conditions. Finally, overexpression of P450 reductase, i.e. comparing MDA231 wt with R4, has little, if any, impact on the toxicity of RH1 under hypoxic or aerobic conditions. In summary, RH1 can be effective in killing cells containing high levels of DTD and may be useful in treating tumors expressing this enzyme.Citation
The importance of DT-diaphorase and hypoxia in the cytotoxicity of RH1 in human breast and non-small cell lung cancer cell lines. 2004, 15 (1):71-7 Anticancer DrugsJournal
Anticancer DrugsPubMed ID
15090746Type
ArticleLanguage
enISSN
0959-4973Collections
Related articles
- Cytotoxicity of the bioreductive agent RH1 and its lack of interaction with radiation.
- Authors: Kim JY, West CM, Valentine H, Ward TH, Patterson AV, Stratford IJ, Roberts SA, Hendry JH
- Issue date: 2004 Mar
- Pharmacological properties of a new aziridinylbenzoquinone, RH1 (2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone), in mice.
- Authors: Loadman PM, Phillips RM, Lim LE, Bibby MC
- Issue date: 2000 Apr 1
- A new screening system for NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor quinones: identification of a new aziridinylbenzoquinone, RH1, as a NQO1-directed antitumor agent.
- Authors: Winski SL, Hargreaves RH, Butler J, Ross D
- Issue date: 1998 Dec
- Dissecting the role of multiple reductases in bioactivation and cytotoxicity of the antitumor agent 2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone (RH1).
- Authors: Yan C, Kepa JK, Siegel D, Stratford IJ, Ross D
- Issue date: 2008 Dec
- Nicotinamide adenine dinucleotide (phosphate): quinone oxidoreductase (DT-diaphorase) as a target for bioreductive antitumor quinones: quinone cytotoxicity and selectivity in human lung and breast cancer cell lines.
- Authors: Beall HD, Murphy AM, Siegel D, Hargreaves RH, Butler J, Ross D
- Issue date: 1995 Sep