dc.contributor.author |
Abbattista, Maria |
en |
dc.contributor.author |
Jamieson, Stephen |
en |
dc.contributor.author |
Gu, Yongchuan |
en |
dc.contributor.author |
Nickel, JE |
en |
dc.contributor.author |
Pullen, Susan |
en |
dc.contributor.author |
Patterson, Adam |
en |
dc.contributor.author |
Wilson, William |
en |
dc.contributor.author |
Guise, Christopher |
en |
dc.date.accessioned |
2017-07-12T00:10:57Z |
en |
dc.date.issued |
2015-04 |
en |
dc.identifier.citation |
Cancer Biology and Therapy 16(4):610-622 Apr 2015 |
en |
dc.identifier.issn |
1538-4047 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/34175 |
en |
dc.description.abstract |
PR-104 is a clinical stage bioreductive prodrug that is converted in vivo to its cognate alcohol, PR-104A. This dinitrobenzamide mustard is reduced to activated DNA cross-linking metabolites (hydroxylamine PR-104H and amine PR-104M) under hypoxia by one-electron reductases and independently of hypoxia by the 2-electron reductase aldo-keto reductase 1C3 (AKR1C3). High expression of AKR1C3, along with extensive hypoxia, suggested the potential of PR-104 for treatment of hepatocellular carcinoma (HCC). However, a phase IB trial with sorafenib demonstrated significant toxicity that was ascribed in part to reduced PR-104A clearance, likely reflecting compromised glucuronidation in patients with advanced HCC. Here, we evaluate the activity of PR-104 in HCC xenografts (HepG2, PLC/PRF/5, SNU-398, Hep3B) in mice, which do not significantly glucuronidate PR-104A. Cell line differences in sensitivity to PR-104A in vitro under aerobic conditions could be accounted for by differences in both expression of AKR1C3 (high in HepG2 and PLC/PRF/5) and sensitivity to the major active metabolite PR-104H, to which PLC/PRF/5 was relatively resistant, while hypoxic selectivity of PR-104A cytotoxicity and reductive metabolism was greatest in the low-AKR1C3 SNU-398 and Hep3B lines. Expression of AKR1C3 in HepG2 and PLC/PRF/5 xenografts was in the range seen in 21 human HCC specimens. PR-104 monotherapy elicited significant reductions in growth of Hep3B and HepG2 xenografts, and the combination with sorafenib was significantly active in all 4 xenograft models. The results suggest that better-tolerated analogs of PR-104, without a glucuronidation liability, may have the potential to exploit AKR1C3 and/or hypoxia in HCC in humans. |
en |
dc.format.medium |
Print-Electronic |
en |
dc.language |
eng |
en |
dc.publisher |
Landes Bioscience |
en |
dc.relation.ispartofseries |
Cancer Biology and Therapy |
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 |
Cell Line, Tumor |
en |
dc.subject |
Animals |
en |
dc.subject |
Mice, Inbred NOD |
en |
dc.subject |
Humans |
en |
dc.subject |
Mice |
en |
dc.subject |
Mice, SCID |
en |
dc.subject |
Carcinoma, Hepatocellular |
en |
dc.subject |
Liver Neoplasms |
en |
dc.subject |
Nitrogen Mustard Compounds |
en |
dc.subject |
Phenylurea Compounds |
en |
dc.subject |
Niacinamide |
en |
dc.subject |
Prodrugs |
en |
dc.subject |
Xenograft Model Antitumor Assays |
en |
dc.subject |
Cell Hypoxia |
en |
dc.subject |
Female |
en |
dc.subject |
Hep G2 Cells |
en |
dc.title |
Pre-clinical activity of PR-104 as monotherapy and in combination with sorafenib in hepatocellular carcinoma |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1080/15384047.2015.1017171 |
en |
pubs.issue |
4 |
en |
pubs.begin-page |
610 |
en |
pubs.volume |
16 |
en |
dc.rights.holder |
Copyright: Landes Bioscience |
en |
dc.identifier.pmid |
25869917 |
en |
pubs.end-page |
622 |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/OpenAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
486252 |
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 |
Pharmacology |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
dc.identifier.eissn |
1555-8576 |
en |
pubs.record-created-at-source-date |
2017-07-12 |
en |
pubs.dimensions-id |
25869917 |
en |