Use of an optimised enzyme/prodrug combination for Clostridia directed enzyme prodrug therapy induces a significant growth delay in necrotic tumours
- 8 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cancer Gene Therapy
- Vol. 29 (2), 178-188
- https://doi.org/10.1038/s41417-021-00296-7
Abstract
Necrosis is a typical histological feature of solid tumours that provides a selective environment for growth of the non-pathogenic anaerobic bacterium Clostridium sporogenes. Modest anti-tumour activity as a single agent encouraged the use of C. sporogenes as a vector to express therapeutic genes selectively in tumour tissue, a concept termed Clostridium Directed Enzyme Prodrug Therapy (CDEPT). Here, we examine the ability of a recently identified Neisseria meningitidis type I nitroreductase (NmeNTR) to metabolise the prodrug PR-104A in an in vivo model of CDEPT. Human HCT116 colon cancer cells stably over-expressing NmeNTR demonstrated significant sensitivity to PR-104A, the imaging agent EF5, and several nitro(hetero)cyclic anti-infective compounds. Chemical induction of necrosis in human H1299 xenografts by the vascular disrupting agent vadimezan promoted colonisation by NmeNTR-expressing C. sporogenes, and efficacy studies demonstrated moderate but significant anti-tumour activity of spores when compared to untreated controls. Inclusion of the pre-prodrug PR-104 into the treatment schedule provided significant additional activity, indicating proof-of-principle. Successful preclinical evaluation of a transferable gene that enables metabolism of both PET imaging agents (for vector visualisation) and prodrugs (for conditional enhancement of efficacy) is an important step towards the prospect of CDEPT entering clinical evaluation.Keywords
Funding Information
- Manatu Hauora | Health Research Council of New Zealand (14/289)
- ZonMw (43400009, 43400009)
- KWF Kankerbestrijding (Alpe d’HuZes Unieke Kansen #8025)
This publication has 45 references indexed in Scilit:
- Fiji: an open-source platform for biological-image analysisNature Methods, 2012
- Integration of DNA into bacterial chromosomes from plasmids without a counter-selection markerNucleic Acids Research, 2012
- The ClosTron: Mutagenesis in Clostridium refined and streamlinedJournal of Microbiological Methods, 2010
- A modular system for Clostridium shuttle plasmidsJournal of Microbiological Methods, 2009
- CNOB/ChrR6, a new prodrug enzyme cancer chemotherapyMolecular Cancer Therapeutics, 2009
- Optimized Clostridium-Directed Enzyme Prodrug Therapy Improves the Antitumor Activity of the Novel DNA Cross-Linking Agent PR-104Cancer Research, 2008
- The ClosTron: A universal gene knock-out system for the genus ClostridiumJournal of Microbiological Methods, 2007
- Repeated cycles of Clostridium-directed enzyme prodrug therapy result in sustained antitumour effects in vivoBritish Journal of Cancer, 2006
- New Guidelines to Evaluate the Response to Treatment in Solid TumorsJNCI Journal of the National Cancer Institute, 2000
- The effect of tube feeding of glucose or corn oil on adipose tissue lipoprotein lipase activity and uptake of 14C-labeled palmitic acid of chyle triglycerides in vitroBiochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism, 1967