The importance of DT-diaphorase and hypoxia in the cytotoxicity of RH1 in human breast and non-small cell lung cancer cell lines.

2.50
Hdl Handle:
http://hdl.handle.net/10541/78139
Title:
The importance of DT-diaphorase and hypoxia in the cytotoxicity of RH1 in human breast and non-small cell lung cancer cell lines.
Authors:
Kim, Joo-Young; Patterson, Adam V; Stratford, Ian J; Hendry, Jolyon H
Abstract:
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.
Affiliation:
Cancer Research UK Group of Experimental Radiation Oncology, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK.
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 Drugs
Journal:
Anticancer Drugs
Issue Date:
Jan-2004
URI:
http://hdl.handle.net/10541/78139
PubMed ID:
15090746
Type:
Article
Language:
en
ISSN:
0959-4973
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorKim, Joo-Young-
dc.contributor.authorPatterson, Adam V-
dc.contributor.authorStratford, Ian J-
dc.contributor.authorHendry, Jolyon H-
dc.date.accessioned2009-08-21T10:39:47Z-
dc.date.available2009-08-21T10:39:47Z-
dc.date.issued2004-01-
dc.identifier.citationThe 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 Drugsen
dc.identifier.issn0959-4973-
dc.identifier.pmid15090746-
dc.identifier.urihttp://hdl.handle.net/10541/78139-
dc.description.abstractThe 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.en
dc.language.isoenen
dc.subjectBreast Canceren
dc.subjectLung Canceren
dc.subjectCell Line Tumouren
dc.subject.meshAerobiosis-
dc.subject.meshAntineoplastic Agents-
dc.subject.meshAziridines-
dc.subject.meshBenzoquinones-
dc.subject.meshBreast Neoplasms-
dc.subject.meshCarcinoma, Non-Small-Cell Lung-
dc.subject.meshCell Hypoxia-
dc.subject.meshCell Line, Tumor-
dc.subject.meshCell Survival-
dc.subject.meshColony-Forming Units Assay-
dc.subject.meshHumans-
dc.subject.meshInhibitory Concentration 50-
dc.subject.meshLung Neoplasms-
dc.subject.meshNAD(P)H Dehydrogenase (Quinone)-
dc.subject.meshNADPH-Ferrihemoprotein Reductase-
dc.subject.meshSpectrophotometry-
dc.subject.meshTransfection-
dc.subject.meshTriazines-
dc.titleThe importance of DT-diaphorase and hypoxia in the cytotoxicity of RH1 in human breast and non-small cell lung cancer cell lines.en
dc.typeArticleen
dc.contributor.departmentCancer Research UK Group of Experimental Radiation Oncology, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK.en
dc.identifier.journalAnticancer Drugsen
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