dc.contributor.author |
Jackson, Rosanna |
en |
dc.contributor.author |
Liew, Lydia |
en |
dc.contributor.author |
Hay, Michael |
en |
dc.date.accessioned |
2019-10-01T21:04:48Z |
en |
dc.date.issued |
2019-05 |
en |
dc.identifier.issn |
0936-6555 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/48301 |
en |
dc.description.abstract |
The role of hypoxia in radiation resistance is well established and many approaches to overcome hypoxia in tumours have been explored, with variable success. Two small molecule strategies for targeting hypoxia have dominated preclinical and clinical efforts. One approach has been the use of electron-affinic nitroheterocycles as oxygen-mimetic sensitisers. These agents are best exemplified by the 5-nitroimidazole nimorazole, which has limited use in conjunction with radiotherapy in head and neck squamous cell carcinoma. The second approach seeks to leverage tumour hypoxia as a tumour-specific address for hypoxia-activated prodrugs. These prodrugs are selectively activated by reductases under hypoxia to release cytotoxins, which in some instances may diffuse to kill surrounding oxic tumour tissue. A number of these hypoxia-activated prodrugs have been examined in clinical trial and the merits and shortcomings of recent examples are discussed. There has been an evolution from delivering DNA-interactive cytotoxins to molecularly targeted agents. Efforts to implement these strategies clinically continue today, but success has been elusive. Several issues have been identified that compromised these clinical campaigns. A failure to consider the extravascular transport and the micropharmacokinetic properties of the prodrugs has reduced efficacy. One key element for these 'targeted' approaches is the need to co-develop biomarkers to identify appropriate patients. Hypoxia-activated prodrugs require biomarkers for hypoxia, but also for appropriate activating reductases in tumours, as well as markers of intrinsic sensitivity to the released drug. The field is still evolving and changes in radiation delivery and the impact of immune-oncology will provide fertile ground for future innovation. |
en |
dc.format.medium |
Print-Electronic |
en |
dc.language |
eng |
en |
dc.relation.ispartofseries |
Clinical oncology (Royal College of Radiologists (Great Britain)) |
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 |
Humans |
en |
dc.subject |
Neoplasms |
en |
dc.subject |
Prodrugs |
en |
dc.subject |
Cell Hypoxia |
en |
dc.title |
Overcoming Radioresistance: Small Molecule Radiosensitisers and Hypoxia-activated Prodrugs. |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1016/j.clon.2019.02.004 |
en |
pubs.issue |
5 |
en |
pubs.begin-page |
290 |
en |
pubs.volume |
31 |
en |
dc.rights.holder |
Copyright: The author |
en |
pubs.end-page |
302 |
en |
pubs.publication-status |
Published |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Research Support, Non-U.S. Gov't |
en |
pubs.subtype |
Review |
en |
pubs.subtype |
Journal Article |
en |
pubs.elements-id |
766093 |
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 |
dc.identifier.eissn |
1433-2981 |
en |
pubs.record-created-at-source-date |
2019-03-12 |
en |
pubs.dimensions-id |
30853148 |
en |