dc.contributor.author |
Wang, Jingli |
en |
dc.contributor.author |
Liu, Q |
en |
dc.contributor.author |
Rosario, G |
en |
dc.contributor.author |
McReynolds, C |
en |
dc.contributor.author |
Durnal, A |
en |
dc.contributor.author |
Evans, J |
en |
dc.contributor.author |
Ammons, S |
en |
dc.coverage.spatial |
Los Angeles, USA |
en |
dc.date.accessioned |
2012-06-13T00:43:35Z |
en |
dc.date.issued |
2007 |
en |
dc.identifier.citation |
AACR annual meeting, Los Angeles, USA, 14 Apr 2007 - 18 Apr 2007. |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/18966 |
en |
dc.description.abstract |
Background: A new hypoxia activated phosphoramidate prodrug, TH-302, was identified as a selective hypoxia targeted drug by in vitro screens. Using cell proliferation assays, TH-302 showed greater than 100 fold higher toxicity under anoxic conditions as compared to aerobic conditions across a broad range of cancer cell lines. In this study, we have tested the in vivo anti-cancer efficacy of TH-302 in different human cancer xenograft models. Method: H460-NCI human non-small-cell lung cancer cells, and HT29 human colon cancer cells, were implanted subcutaneously into the flanks of homozygous nude mice. Multiple doses of TH-302 with or without combination with chemotherapeutic agents were administrated when the tumor size reached 100 to 150 mm3. Animal body weight and tumor growth were measured for a maximum of 60 days after tumor implantation. TH-302 in vivo cell killing was also tested with an excision clonogenic assay. Results: Significant tumor growth inhibition was achieved in the H460 model by TH-302 monotherapy at different dose regimens when given IP: 50 mg/kg, QDx5/wkx2wk; 100 mg/kg, Q3Dx5; 150 mg/kg, Q7Dx3 or IP infusion for 14 days using Alzet osmotic pumps. The tumor growth inhibitions (TGIs) were 68%, 81%, 86% and 73% respectively. TH-302 also showed significant anti-cancer efficacy as a monotherapy agent in the HT29 model. Combining TH-302 with the chemotherapeutic agent Cisplatin (6 mg/kg, IV, Q7Dx2), resulted in increased anti-cancer efficacy as compared to Cisplatin alone in both models with 20% cure rate. In H460 model, TH-302 combined with Taxol also produced an increased anti-cancer efficacy than Taxol alone. To confirm the in vivo hypoxia targeted mechanism of TH-302, we performed an excision clonogenic assay. Animals were placed in chambers with different levels of oxygen (10%, 21% or 95% O2) for 2.5 hours before and after TH-302 administration. Tumors were excised 24 h later, and a clonogenic assay was performed to measure the in vivo cytoxicity. The results showed that TH-302 induced cell killing was O2 dependent with lower O2 levels associated with greater cytoxicity. Additionally, in the excision assay, greater than 99% of cells were killed in H460 tumors in vivo after a single dose (150mg/kg, IP) of TH-302 when the animals were breathing in air. These results suggest that the activated drug may kill cells outside of the hypoxic region, perhaps via a bystander effect, because hypoxic cells in H460 tumor were less than 99%. Conclusions: The hypoxic targeting agent TH-302 is clearly an effective anti-cancer agent either as a monotherapeutic agent or in combination with common chemotherapeutic agents in human cancer xenograft models. These results demonstrate that TH-302 should be tested in the treatment of solid tumors in human cancer patients. |
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dc.publisher |
The Authors |
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dc.relation.ispartof |
AACR annual meeting |
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.title |
In vivo anti-cancer efficacy of a hypoxia activated prodrug, TH-302. |
en |
dc.type |
Conference Item |
en |
dc.rights.holder |
Copyright: The Authors |
en |
pubs.author-url |
http://www.aacrmeetingabstracts.org/cgi/content/meeting_abstract/2007/1_Annual_Meeting/3988 |
en |
pubs.finish-date |
2007-04-18 |
en |
pubs.start-date |
2007-04-14 |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Abstract |
en |
pubs.elements-id |
304493 |
en |
pubs.record-created-at-source-date |
2012-02-27 |
en |