dc.contributor.author |
Gu, Yongchuan |
en |
dc.contributor.author |
Patterson, Adam |
en |
dc.contributor.author |
Atwell, Graham |
en |
dc.contributor.author |
Chernikova, SB |
en |
dc.contributor.author |
Brown, JM |
en |
dc.contributor.author |
Thompson, LH |
en |
dc.contributor.author |
Wilson, William |
en |
dc.date.accessioned |
2012-05-24T23:00:34Z |
en |
dc.date.issued |
2009-06-01 |
en |
dc.identifier.citation |
MOLECULAR CANCER THERAPEUTICS 8(6):1714-1723 01 Jun 2009 |
en |
dc.identifier.issn |
1535-7163 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/18398 |
en |
dc.description.abstract |
PR-104 is a dinitrobenzamide mustard currently in clinical trial as a hypoxia-activated prodrug. Its major metabolite, PR-104A, is metabolized to the corresponding hydroxylamine (PR-104H) and amine (PR-104M), resulting in activation of the nitrogen mustard moiety. We characterize DNA damage responsible for cytotoxicity of PR-104A by comparing sensitivity of repair-defective hamster Chinese hamster ovary cell lines with their repair-competent counterparts. PR-104H showed a repair profile similar to the reference DNA cross-linking agents chlorambucil and mitomycin C, with marked hypersensitivity of XPF(-/-) ERCC1(-/-), and Rad51D(-/-) cells but not of XPD(-/-) or DNA-PK(CS)(-/-) cells. This pattern confirmed the expected dependence on the ERCC1-XPF endonuclease, implicated in unhooking DNA interstrand cross-links at blocked replication forks, and homologous recombination repair (HRR) in restarting collapsed forks. However, even under anoxia, the hypersensitivity of XPF(-/-), ERCC1(-/-) and Rad51D(-/-) cells to PR-104A itself was lower than for chlorambucil. To test whether this reflects inefficient PR-104A reduction, a soluble form of human NADPH:cytochrome P450 oxidoreductase was stably expressed in Rad51D(-/-) cells and their HRR-restored counterpart. This expression increased hypoxic metabolism of PR-104A to PR-104H and PR-104M as well as hypoxia-selective cytotoxicity of PR-104A and its dependence on HRR. We conclude that PR-104A cytotoxicity is primarily due to DNA interstrand cross-linking by its reduced metabolites, although under conditions of inefficient PR-104A reduction (low reductase expression or aerobic cells), a second mechanism contributes to cell killing. This study shows that hypoxia, reductase activity, and DNA interstrand cross-link repair proficiency are key variables that interact to determine PR-104A sensitivity. [Mol Cancer Ther 2009;8 (6):1714-23] |
en |
dc.language |
English |
en |
dc.publisher |
American Association for Cancer Research |
en |
dc.relation.ispartofseries |
Molecular Cancer Therapeutics |
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. |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.subject |
Science & Technology |
en |
dc.subject |
Life Sciences & Biomedicine |
en |
dc.subject |
Oncology |
en |
dc.subject |
HAMSTER OVARY CELLS |
en |
dc.subject |
SELECTIVE ANTITUMOR AGENTS |
en |
dc.subject |
NUCLEOTIDE EXCISION-REPAIR |
en |
dc.subject |
HOMOLOGOUS RECOMBINATION |
en |
dc.subject |
BIOREDUCTIVE DRUGS |
en |
dc.subject |
TUMOR OXYGENATION |
en |
dc.subject |
PRODRUG PR-104A |
en |
dc.subject |
CYTO-TOXICITY |
en |
dc.subject |
CROSS-LINKS |
en |
dc.subject |
NECK-CANCER |
en |
dc.title |
Roles of DNA repair and reductase activity in the cytotoxicity of the hypoxia-activated dinitrobenzamide mustard PR-104A |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1158/1535-7163.MCT-08-1209 |
en |
pubs.issue |
6 |
en |
pubs.begin-page |
1714 |
en |
pubs.volume |
8 |
en |
dc.rights.holder |
Copyright: American Association for Cancer Research |
en |
dc.identifier.pmid |
19509245 |
en |
pubs.author-url |
http://mct.aacrjournals.org/content/8/6/1714.full.pdf+html |
en |
pubs.end-page |
1723 |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
117407 |
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 |
Science |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
pubs.record-created-at-source-date |
2012-05-25 |
en |
pubs.dimensions-id |
19509245 |
en |