Influence of extracellular pH on the cytotoxicity and DNA damage of a series of indolequinone compounds.

2.50
Hdl Handle:
http://hdl.handle.net/10541/85727
Title:
Influence of extracellular pH on the cytotoxicity and DNA damage of a series of indolequinone compounds.
Authors:
Phillips, R M; Ward, Timothy H
Abstract:
BACKGROUND: The existence of an acidic extracellular pH (pHe) within solid tumours is regarded as a potential target for drug development. The indolequinone EO9 has a complex mechanism of action which includes enhanced potency under acidic pHe conditions in vitro. In order to identify compounds which have a simpler mechanism of action where activation under acidic pHe is the predominant mechanism of toxicity, this study has determined the cytotoxic properties of a series of analogues of EO9 under both physiological and acidic pHe conditions. MATERIALS AND METHODS: H460 human NSCLC cells were exposed to EO compounds under acidic (pH 6.04) and physiological (pH 7.24) pHe conditions for one hour and chemosensitivity assessed 4 days later using the MTT assay. For compounds of interest, DNA damage (both single strand breaks and cross links) in H460 cells was determined using the comet assay. RESULTS: All the compounds tested were more potent under acidic pHe conditions although a broad range of enhancement ratios (defined as the IC50 at pHe 7.24/IC50 at pHe 6.04) were obtained ranging from 3.25 to 116.53. The activity of EO72 was significantly enhanced under acidic conditions and activity was associated with a pH dependent increase in DNA cross linking in H460 cells. As EO72 is a poor substrate for purified human DT-diaphorase, pHe conditions appear to be a major factor determining cell kill. CONCLUSIONS: This study has identified several compounds whose cytotoxic properties in vitro are pHe dependent with EO72 emerging as the lead compound on the basis of the magnitude of the pH dependent chemosensitivity and the fact that it is a poor substrate for DT-diaphorase. Further studies are required to determine whether or not EO72 has suitable pharmacokinetic properties to allow it to reach regions of low pHe within solid tumours.
Affiliation:
Cancer Research Unit, University of Bradford, United Kingdom. r.m.phillips@bradford.ac.uk
Citation:
Influence of extracellular pH on the cytotoxicity and DNA damage of a series of indolequinone compounds., 21 (3B):1795-801 Anticancer Res.
Journal:
Anticancer Research
Issue Date:
2001
URI:
http://hdl.handle.net/10541/85727
PubMed ID:
11497261
Type:
Article
Language:
en
ISSN:
0250-7005
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorPhillips, R Men
dc.contributor.authorWard, Timothy Hen
dc.date.accessioned2009-11-10T09:57:43Z-
dc.date.available2009-11-10T09:57:43Z-
dc.date.issued2001-
dc.identifier.citationInfluence of extracellular pH on the cytotoxicity and DNA damage of a series of indolequinone compounds., 21 (3B):1795-801 Anticancer Res.en
dc.identifier.issn0250-7005-
dc.identifier.pmid11497261-
dc.identifier.urihttp://hdl.handle.net/10541/85727-
dc.description.abstractBACKGROUND: The existence of an acidic extracellular pH (pHe) within solid tumours is regarded as a potential target for drug development. The indolequinone EO9 has a complex mechanism of action which includes enhanced potency under acidic pHe conditions in vitro. In order to identify compounds which have a simpler mechanism of action where activation under acidic pHe is the predominant mechanism of toxicity, this study has determined the cytotoxic properties of a series of analogues of EO9 under both physiological and acidic pHe conditions. MATERIALS AND METHODS: H460 human NSCLC cells were exposed to EO compounds under acidic (pH 6.04) and physiological (pH 7.24) pHe conditions for one hour and chemosensitivity assessed 4 days later using the MTT assay. For compounds of interest, DNA damage (both single strand breaks and cross links) in H460 cells was determined using the comet assay. RESULTS: All the compounds tested were more potent under acidic pHe conditions although a broad range of enhancement ratios (defined as the IC50 at pHe 7.24/IC50 at pHe 6.04) were obtained ranging from 3.25 to 116.53. The activity of EO72 was significantly enhanced under acidic conditions and activity was associated with a pH dependent increase in DNA cross linking in H460 cells. As EO72 is a poor substrate for purified human DT-diaphorase, pHe conditions appear to be a major factor determining cell kill. CONCLUSIONS: This study has identified several compounds whose cytotoxic properties in vitro are pHe dependent with EO72 emerging as the lead compound on the basis of the magnitude of the pH dependent chemosensitivity and the fact that it is a poor substrate for DT-diaphorase. Further studies are required to determine whether or not EO72 has suitable pharmacokinetic properties to allow it to reach regions of low pHe within solid tumours.en
dc.language.isoenen
dc.subjectLung Canceren
dc.subjectCultured Tumour Cellsen
dc.subject.meshAntineoplastic Agents-
dc.subject.meshAziridines-
dc.subject.meshCarcinoma, Non-Small-Cell Lung-
dc.subject.meshColoring Agents-
dc.subject.meshComet Assay-
dc.subject.meshDNA Damage-
dc.subject.meshDose-Response Relationship, Drug-
dc.subject.meshHumans-
dc.subject.meshHydrogen-Ion Concentration-
dc.subject.meshIndolequinones-
dc.subject.meshIndoles-
dc.subject.meshInhibitory Concentration 50-
dc.subject.meshLung Neoplasms-
dc.subject.meshModels, Chemical-
dc.subject.meshRecombinant Proteins-
dc.subject.meshTetrazolium Salts-
dc.subject.meshThiazoles-
dc.subject.meshTime Factors-
dc.subject.meshTumor Cells, Cultured-
dc.titleInfluence of extracellular pH on the cytotoxicity and DNA damage of a series of indolequinone compounds.en
dc.typeArticleen
dc.contributor.departmentCancer Research Unit, University of Bradford, United Kingdom. r.m.phillips@bradford.ac.uken
dc.identifier.journalAnticancer Researchen
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