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Bystander or No Bystander for Gene Directed Enzyme Prodrug Therapy
Angiogenesis and Cancer Research Group, University of Otago, Christchurch, PO Box 4345, Christchurch 8140, New Zealand
Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
* Author to whom correspondence should be addressed.
Received: 10 October 2009; in revised form: 3 November 2009 / Accepted: 5 November 2009 / Published: 10 November 2009
(This article belongs to the Special Issue Prodrugs
Abstract: Gene directed enzyme prodrug therapy (GDEPT) of cancer aims to improve the selectivity of chemotherapy by gene transfer, thus enabling target cells to convert nontoxic prodrugs to cytotoxic drugs. A zone of cell kill around gene-modified cells due to transfer of toxic metabolites, known as the bystander effect, leads to tumour regression. Here we discuss the implications of either striving for a strong bystander effect to overcome poor gene transfer, or avoiding the bystander effect to reduce potential systemic effects, with the aid of three successful GDEPT systems. This review concentrates on bystander effects and drug development with regard to these enzyme prodrug combinations, namely herpes simplex virus thymidine kinase (HSV-TK) with ganciclovir (GCV), cytosine deaminase (CD) from bacteria or yeast with 5-fluorocytodine (5-FC), and bacterial nitroreductase (NfsB) with 5-(azaridin-1-yl)-2,4-dinitrobenzamide (CB1954), and their respective derivatives.
Keywords: nitroreductase; thymidine kinase; cytosine deaminase; alkylating agents; chemotherapy
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Dachs, G.U.; Hunt, M.A.; Syddall, S.; Singleton, D.C.; Patterson, A.V. Bystander or No Bystander for Gene Directed Enzyme Prodrug Therapy. Molecules 2009, 14, 4517-4545.
Dachs GU, Hunt MA, Syddall S, Singleton DC, Patterson AV. Bystander or No Bystander for Gene Directed Enzyme Prodrug Therapy. Molecules. 2009; 14(11):4517-4545.
Dachs, Gabi U.; Hunt, Michelle A.; Syddall, Sophie; Singleton, Dean C.; Patterson, Adam V. 2009. "Bystander or No Bystander for Gene Directed Enzyme Prodrug Therapy." Molecules 14, no. 11: 4517-4545.