Faculty of Medical and Health Sciences


'Armed' tumour-tropic replicating vectors

Project Leaders


Most modern cancer chemotherapy regimes have dose-limiting toxicities that often leave little room for inclusion of new therapies. Consequently novel cancer treatments with unique toxicity profiles and fundamentally different ways for killing cancer cells (mechanisms of action) are required to augment established therapies. A radically new strategy with considerable promise is to use biological entities (viruses or bacteria) capable of replicating in tumours as cytolytic agents.

Treatment_graph

One approach to this 'microbiological warfare' against cancer utilises oncolytic viruses as therapeutic agents (virus directed enzyme prodrug therapy or VDEPT) whilst another utilises obligate anaerobic bacteria (clostridium-dependent enzyme prodrug therapy or CDEPT). We have developed an 'armed' tumour tropic adenovirus (ONYX-411NTR) that replicates conditionally in cells with a defective retinoblastoma pathway (>90% of human tumours) and concurrently spreads a bacterial nitroreductase (NTR) enzyme which is able to activate prodrugs.

SN29884

In collaboration with Dr Jeff Smaill we have also developed a library of fluorogenic NTR probes to track the behaviour of NTR-armed replicating vectors in vitro. UV, purple, blue, green, yellow, red and far-red probes have been generated, some with specificity for certain nitroreductases. These small molecule probes are valuable tools for real-time monitoring of NTR-engineered therapeutic vector phenotypes.

Collaborators: Dr David Ackerley

Keywords: Chemotherapy, Oncolytic viruses, CDEPT

Related publications


Singleton, D.C., Li, D., Bai, S.Y., Syddall, S.P., Smaill, J.B., Shen, Y., Denny, W.A., Wilson, W.R., Patterson, A.V. The nitroreductase prodrug SN28343 enhances the potency of the systemically administered armed oncolytic adenovirus ONYX-411NTR. Cancer Gene Therapy 2007; 14: 953-967. (PMID:17975564)

Liu, S.C., Ahn, G.O., Kioi, M., Dorie, M.J., Patterson, A.V., Brown, J.M. Optimised Clostridium-directed enzyme prodrug therapy improves the antitumour activity of the novel DNA crosslinking agent PR-104. Cancer Research 2008; 68: 7995-8003. (PMID:18829557)

Prosser, G.A., Copp, J.N., Syddall, S.P., Williams, E.M., Smaill, J.B., Wilson, W.R., Patterson, A.V., Ackerley, D.F. Discovery and evaluation of Escherichia coli nitroreductases that activate the anti-cancer prodrug CB1954. Biochemical Pharmacology 2010; 79: 678-687. (PMID:19852945)

Prosser, G.A., Patterson, A.V., Ackerley, D.F. uvrB deletion enhances SOS chromatest sensitivity from nitroreductases that preferentially generate the 4-hydroxylamine metabolite of the anti-cancer dru CB1954. Journal of Biotechnology 2010; 150 (1): 150-154. (PMID:20727918)