Show simple item record

dc.contributor.authorPhillips, Roger M.*
dc.contributor.authorLoadman, Paul M.*
dc.contributor.authorReddy, G.*
dc.date.accessioned2019-06-07T11:33:20Z
dc.date.accessioned2019-06-13T09:40:30Z
dc.date.available2019-06-07T11:33:20Z
dc.date.available2019-06-13T09:40:30Z
dc.date.issued2019-06
dc.identifier.citationPhillips RM, Loadman PM and Reddy G (2019) Inactivation of apaziquone by haematuria: implications for the design of phase III clinical trials against non-muscle invasive bladder cancer. Cancer Chemotherapy and Pharmacology. 83(6): 1183-1189.en_US
dc.identifier.urihttp://hdl.handle.net/10454/17119
dc.descriptionYesen_US
dc.description.abstractPurpose: Despite positive responses in phase II clinical trials, the bioreductive prodrug apaziquone failed to achieve statistically significant activity in non-muscle invasive bladder cancer in phase III trials. Apaziquone was administered shortly after transurethral resection and here we test the hypothesis that haematuria inactivates apaziquone. Methods: HPLC analysis was used to determine the ability of human whole blood to metabolise apaziquone ex vivo. An in vitro model of haematuria was developed and the response of RT112 and EJ138 cells following a 1-h exposure to apaziquone was determined in the presence of urine plus or minus whole blood or lysed whole blood. Results: HPLC analysis demonstrated that apaziquone is metabolised by human whole blood with a half-life of 78.6±23.0 min. As a model for haematuria, incubation of cells in media containing up to 75% buffered (pH 7.4) urine and 25% whole blood was not toxic to cells for a 1-h exposure period. Whole blood (5% v/v) significantly (p<0.01) reduced the potency of apaziquone in this experimental model. Lysed whole blood also significantly (p<0.05) reduced cell growth, although higher concentrations were required to achieve an effect (15% v/v). Conclusions: The results of this study demonstrate that haematuria can reduce the potency of apaziquone in this experimental model. These findings impact upon the design of further phase III clinical trials and strongly suggest that apaziquone should not be administered immediately after transurethral resection of non-muscle invasive bladder cancer when haematuria is common.en_US
dc.description.sponsorshipFinancial support from Spectrum Pharmaceuticals Inc. for the conduct of the experiments.en_US
dc.language.isoenen_US
dc.relation.isreferencedbyhttps://doi.org/10.1007/s00280-019-03812-7en_US
dc.rights© The Author(s) 2019. Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.en_US
dc.subjectApaziquoneen_US
dc.subjectNon-muscle invasive bladder canceren_US
dc.subjectHaematuriaen_US
dc.titleInactivation of apaziquone by haematuria: implications for the design of phase III clinical trials against non-muscle invasive bladder canceren_US
dc.status.refereedYesen_US
dc.date.Accepted2019-03-08
dc.date.application2019-03-13
dc.typeArticleen_US
dc.type.versionPublished versionen_US
dc.date.updated2019-06-07T10:33:21Z
refterms.dateFOA2019-06-13T09:41:18Z


Item file(s)

Thumbnail
Name:
Loadman_Cancer_Chemotherapy_an ...
Size:
669.7Kb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record