dc.contributor.author |
Anderson, Robert F |
|
dc.contributor.author |
Li, Dan |
|
dc.contributor.author |
Hunter, Francis W |
|
dc.coverage.spatial |
United States |
|
dc.date.accessioned |
2020-12-08T23:51:15Z |
|
dc.date.available |
2020-12-08T23:51:15Z |
|
dc.date.issued |
2017-12 |
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dc.identifier.issn |
0891-5849 |
|
dc.identifier.uri |
http://hdl.handle.net/2292/53942 |
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dc.description.abstract |
Hypoxic cells pose a problem in anticancer chemotherapy, in which often drugs require oxygen as an electron acceptor to bring about the death of actively cycling cells. Bioreductive anticancer drugs, which are selectively activated in the hypoxic regions of tumours through enzymatic one-electron reduction, are being developed for combination with chemotherapy-, radiotherapy- and immunotherapy-containing regimens to kill treatment-resistant hypoxic cells. The most clinically-advanced bioreductive drug, evofosfamide (TH-302), which acts by releasing a DNA-crosslinking mustard, failed to extend overall survival in combination with doxorubicin, a topoisomerase II inhibitor, for advanced soft tissue sarcoma in a pivotal clinical trial. However, the reasons for the lack of additive efficacy with this combination are unknown. Here, we show that the radical anion of evofosfamide undergoes electron transfer to doxorubicin in kinetic competition to fragmentation of the radical anion, thus suppressing the release the cytotoxic mustard. This electron transfer process may account, at least in part, for the lack of overall survival improvement in the recent clinical trial. This study underlines the need to consider both redox and electron transfer chemistry when combining bioreductive prodrugs with other redox-active drugs in cancer treatment. |
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dc.format.medium |
Print-Electronic |
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dc.language |
eng |
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dc.publisher |
Elsevier BV |
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dc.relation.ispartofseries |
Free radical biology & medicine |
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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. |
|
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
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dc.subject |
Cell Line, Tumor |
|
dc.subject |
Epithelial Cells |
|
dc.subject |
Humans |
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dc.subject |
Oxygen |
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dc.subject |
Free Radicals |
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dc.subject |
Phosphoramide Mustards |
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dc.subject |
Nitroimidazoles |
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dc.subject |
Doxorubicin |
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dc.subject |
Antineoplastic Agents |
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dc.subject |
Drug Combinations |
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dc.subject |
Treatment Failure |
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dc.subject |
Pulse Radiolysis |
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dc.subject |
Cell Hypoxia |
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dc.subject |
Cell Survival |
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dc.subject |
Electron Transport |
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dc.subject |
Oxidation-Reduction |
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dc.subject |
Kinetics |
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dc.subject |
Electrons |
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dc.subject |
Clinical Trials as Topic |
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dc.subject |
Cytotoxicity |
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dc.subject |
Doxorubicin |
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dc.subject |
Drug antagonism |
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dc.subject |
Electron transfer |
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dc.subject |
Evofosfamide |
|
dc.subject |
Hypoxia-activated prodrug |
|
dc.subject |
Pulse radiolysis |
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dc.subject |
TH-302 |
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dc.subject |
Science & Technology |
|
dc.subject |
Life Sciences & Biomedicine |
|
dc.subject |
Biochemistry & Molecular Biology |
|
dc.subject |
Endocrinology & Metabolism |
|
dc.subject |
Evofosfamide |
|
dc.subject |
Doxorubicin |
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dc.subject |
TH-302 |
|
dc.subject |
Electron transfer |
|
dc.subject |
Drug antagonism |
|
dc.subject |
Hypoxia-activated prodrug |
|
dc.subject |
Pulse radiolysis |
|
dc.subject |
Cytotoxicity |
|
dc.subject |
HYPOXIA-ACTIVATED PRODRUG |
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dc.subject |
SOFT-TISSUE SARCOMA |
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dc.subject |
PRO-DRUG TH-302 |
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dc.subject |
AQUEOUS-SOLUTION |
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dc.subject |
TUMOR HYPOXIA |
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dc.subject |
PULSE-RADIOLYSIS |
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dc.subject |
SELF-ASSOCIATION |
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dc.subject |
SOLID TUMORS |
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dc.subject |
NECK-CANCER |
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dc.subject |
CHEMOTHERAPY |
|
dc.subject |
Cytotoxicity |
|
dc.subject |
Doxorubicin |
|
dc.subject |
Drug antagonism |
|
dc.subject |
Electron transfer |
|
dc.subject |
Evofosfamide |
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dc.subject |
Hypoxia-activated prodrug |
|
dc.subject |
Pulse radiolysis |
|
dc.subject |
TH-302 |
|
dc.subject |
1112 Oncology and Carcinogenesis |
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dc.subject |
Clinical Medicine and Science |
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dc.subject |
Orphan Drug |
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dc.subject |
Rare Diseases |
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dc.subject |
Cancer |
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dc.subject |
Cancer |
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dc.subject |
5.1 Pharmaceuticals |
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dc.subject |
6.1 Pharmaceuticals |
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dc.subject |
0304 Medicinal and Biomolecular Chemistry |
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dc.subject |
0601 Biochemistry and Cell Biology |
|
dc.subject |
1101 Medical Biochemistry and Metabolomics |
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dc.title |
Antagonism in effectiveness of evofosfamide and doxorubicin through intermolecular electron transfer. |
|
dc.type |
Journal Article |
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dc.identifier.doi |
10.1016/j.freeradbiomed.2017.10.385 |
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pubs.begin-page |
564 |
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pubs.volume |
113 |
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dc.date.updated |
2020-11-16T19:07:44Z |
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dc.rights.holder |
Copyright: The author |
en |
pubs.author-url |
https://www.ncbi.nlm.nih.gov/pubmed/29111232 |
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pubs.end-page |
570 |
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pubs.publication-status |
Published |
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dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Research Support, Non-U.S. Gov't |
|
pubs.subtype |
Journal Article |
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pubs.elements-id |
703895 |
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dc.identifier.eissn |
1873-4596 |
|
dc.identifier.pii |
S0891-5849(17)31167-X |
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pubs.online-publication-date |
2017-10-28 |
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