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Project Leaders
Translational Therapeutics Main Page
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.
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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.
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)
