dc.contributor.author |
Guise, Christopher |
en |
dc.contributor.author |
Abbattista, Maria |
en |
dc.contributor.author |
Nair, Smitha |
en |
dc.contributor.author |
Lambie, NK |
en |
dc.contributor.author |
Su, J |
en |
dc.contributor.author |
Li, D |
en |
dc.contributor.author |
Wilson, William |
en |
dc.contributor.author |
Dachs, GU |
en |
dc.contributor.author |
Patterson, Adam |
en |
dc.coverage.spatial |
United States |
en |
dc.date.accessioned |
2012-02-08T20:12:16Z |
en |
dc.date.issued |
2012 |
en |
dc.identifier.citation |
Molecular Pharmacology 81(1):31-40 Jan 2012 |
en |
dc.identifier.issn |
0026-895X |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/10944 |
en |
dc.description.abstract |
The clinical agent PR-104 is converted systemically to PR-104A, a nitrogen mustard prodrug designed to target tumor hypoxia. Reductive activation of PR-104A is initiated by one-electron oxidoreductases in a process reversed by oxygen. The identity of these oxidoreductases is unknown, with the exception of cytochrome P450 reductase (POR). To identify other hypoxia-selective PR-104A reductases, nine candidate oxidoreductases were expressed in HCT116 cells. Increased PR-104A-cytotoxicity was observed in cells expressing methionine synthase reductase (MTRR), novel diflavin oxidoreductase 1 (NDOR1), and inducible nitric-oxide synthase (NOS2A), in addition to POR. Plasmid-based expression of these diflavin oxidoreductases also enhanced bioreductive metabolism of PR-104A in an anoxia-specific manner. Diflavin oxidoreductase-dependent PR-104A metabolism was suppressed >90% by pan-flavoenzyme inhibition with diphenyliodonium chloride. Antibodies were used to quantify endogenous POR, MTRR, NDOR1, and NOS2A expression in 23 human tumor cell lines; however, only POR protein was detectable and its expression correlated with anoxic PR-104A reduction (r(2) = 0.712). An anti-POR monoclonal antibody was used to probe expression using human tissue microarrays; 13 of 19 cancer types expressed detectable POR with 21% of cores (185 of 874) staining positive; this heterogeneity suggests that POR is a useful biomarker for PR-104A activation. Immunostaining for carbonic anhydrase 9 (CAIX), reportedly an endogenous marker of hypoxia, revealed only moderate coexpression (9.6%) of both CAIX and POR across a subset of five cancer types. |
en |
dc.language |
eng |
en |
dc.publisher |
The American Society for Pharmacology and Experimental Therapeutics |
en |
dc.relation.ispartofseries |
Molecular Pharmacology |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. Details obtained from http://www.sherpa.ac.uk/romeo/issn/0026-895X/ |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.title |
Diflavin oxidoreductases activate the bioreductive prodrug PR-104A under hypoxia. |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1124/mol.111.073759 |
en |
pubs.issue |
1 |
en |
pubs.begin-page |
31 |
en |
pubs.volume |
81 |
en |
dc.rights.holder |
Copyright: The American Society for Pharmacology and Experimental Therapeutics |
en |
dc.identifier.pmid |
21984255 |
en |
pubs.end-page |
40 |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
232701 |
en |
pubs.org-id |
Medical and Health Sciences |
en |
pubs.org-id |
Medical Sciences |
en |
pubs.org-id |
Auckland Cancer Research |
en |
pubs.org-id |
School of Medicine |
en |
pubs.org-id |
Surgery Department |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
dc.identifier.eissn |
1521-0111 |
en |
dc.identifier.pii |
mol.111.073759 |
en |
pubs.record-created-at-source-date |
2012-02-09 |
en |
pubs.dimensions-id |
21984255 |
en |