Oxygen dependence and extravascular transport of hypoxia-activated prodrugs: Comparison of the dinitrobenzamide mustard PR-104A and tirapazamine

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dc.contributor.author Hicks, Kevin en
dc.contributor.author Myint, H en
dc.contributor.author Patterson, Adam en
dc.contributor.author Pruijn, Frederik en
dc.contributor.author Siim, BG en
dc.contributor.author Patel, Kashyap en
dc.contributor.author Wilson, William en
dc.date.accessioned 2012-01-24T23:09:45Z en
dc.date.issued 2007-10-01 en
dc.identifier.citation International Journal of Radiation Oncology - Biology - Physics 69(2):560-571 01 Oct 2007 en
dc.identifier.issn 0360-3016 en
dc.identifier.uri http://hdl.handle.net/2292/10702 en
dc.description.abstract Purpose To compare oxygen dependence and tissue transport properties of a new hypoxia-activated prodrug, PR-104A, with tirapazamine, and to evaluate the implications for antitumor activity when combined with radiotherapy. Methods and Materials Oxygen dependence of cytotoxicity was measured by clonogenic assay in SiHa cell suspensions. Tissue transport parameters were determined using SiHa multicellular layers. Spatially resolved pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to predict cell killing in SiHa tumors and tested by clonogenic assay 18 h after treatment with the corresponding phosphate ester, PR-104. Results The K-value (oxygen concentration to halve cytotoxic potency) of PR-104A was 0.126 ± 0.021 μM (10-fold lower than tirapazamine at 1.30 ± 0.28 μM). The diffusion coefficient of PR-104A in multicellular layers (4.42 ± 0.15 × 10−7 cm2 s−1) was lower than that of tirapazamine (1.30 ± 0.05 × 10−6 cm2 s−1) but PK modeling predicted better penetration to hypoxic cells in tumors because of its slower metabolism. The tirapazamine PK/PD model successfully predicted the measured activity in combination with single-dose radiation against SiHa tumors, and the PR-104A model underpredicted the activity, which was greater for PR-104 than for tirapazamine (at equivalent host toxicity) both with radiation and as a single agent. Conclusion PR-104/PR-104A has different PK/PD properties from tirapazamine and superior activity with single-dose radiotherapy against SiHa xenografts. We have inferred that PR-104A is better able to kill cells at intermediate partial pressure of oxygen in tumors than implied by the PK/PD model, most likely because of a bystander effect resulting from diffusion of its activated metabolites from severely hypoxic zones. en
dc.language EN en
dc.publisher Elsevier Inc. en
dc.relation.ispartofseries International Journal of Radiation Oncology Biology Physics 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. Details obtained from http://www.sherpa.ac.uk/romeo/issn/0360-3016/ en
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.subject tumor hypoxia en
dc.subject hypoxia-activated prodrugs en
dc.subject PR-104 en
dc.subject tirapazamine en
dc.subject extravascular drug transport en
dc.subject multicellular layers en
dc.subject EXPLOITING TUMOR HYPOXIA en
dc.subject HAMSTER OVARY CELLS en
dc.subject BIOREDUCTIVE DRUGS en
dc.subject MITOMYCIN-C en
dc.subject DIFFUSIBLE CYTOTOXINS en
dc.subject METABOLIC-ACTIVATION en
dc.subject CYTO-TOXICITY en
dc.subject NECK-CANCER en
dc.subject HEAD en
dc.subject MISONIDAZOLE en
dc.title Oxygen dependence and extravascular transport of hypoxia-activated prodrugs: Comparison of the dinitrobenzamide mustard PR-104A and tirapazamine en
dc.type Journal Article en
dc.identifier.doi 10.1016/j.ijrobp.2007.05.049 en
pubs.issue 2 en
pubs.begin-page 560 en
pubs.volume 69 en
dc.rights.holder Copyright: Elsevier Inc. en
dc.identifier.pmid 17869669 en
pubs.end-page 571 en
dc.rights.accessrights http://purl.org/eprint/accessRights/RestrictedAccess en
pubs.subtype Article en
pubs.elements-id 114226 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 2012-01-25 en
pubs.dimensions-id 17869669 en


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