학술논문
Bioreductive prodrug PR-104 improves the tumour distribution and titre of the nitroreductase-armed oncolytic adenovirus ONYX-411 NTR leading to therapeutic benefit.
Document Type
Academic Journal
Author
Singleton DC; Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand. d.singleton@auckland.ac.nz.; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand. d.singleton@auckland.ac.nz.; Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand. d.singleton@auckland.ac.nz.; Mowday AM; Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand.; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.; Guise CP; Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand.; Syddall SP; Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand.; Bai SY; Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand.; Li D; Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand.; Ashoorzadeh A; Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand.; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.; Smaill JB; Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand.; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.; Wilson WR; Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand.; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.; Patterson AV; Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand.; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
Source
Publisher: Nature Publishing Group Country of Publication: England NLM ID: 9432230 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5500 (Electronic) Linking ISSN: 09291903 NLM ISO Abbreviation: Cancer Gene Ther Subsets: MEDLINE
Subject
Language
English
Abstract
Advances in the field of cancer immunotherapy have stimulated renewed interest in adenoviruses as oncolytic agents. Clinical experience has shown that oncolytic adenoviruses are safe and well tolerated but possess modest single-agent activity. One approach to improve the potency of oncolytic viruses is to utilise their tumour selectivity to deliver genes encoding prodrug-activating enzymes. These enzymes can convert prodrugs into cytotoxic species within the tumour; however, these cytotoxins can interfere with viral replication and limit utility. In this work, we evaluated the activity of a nitroreductase (NTR)-armed oncolytic adenovirus ONYX-411 NTR in combination with the clinically tested bioreductive prodrug PR-104. Both NTR-expressing cells in vitro and xenografts containing a minor population of NTR-expressing cells were highly sensitive to PR-104. Pharmacologically relevant prodrug exposures did not interfere with ONYX-411 NTR replication in vitro. In vivo, prodrug administration increased virus titre and improved virus distribution within tumour xenografts. Colonisation of tumours with high ONYX-411 NTR titre resulted in NTR expression and prodrug activation. The combination of ONYX-411 NTR with PR-104 was efficacious against HCT116 xenografts, whilst neither prodrug nor virus were active as single agents. This work highlights the potential for future clinical development of NTR-armed oncolytic viruses in combination with bioreductive prodrugs.
(© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)
(© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)