Colorectal Cancer Research Today is a free monthly online journal that collates and summarizes the latest research about Colorectal Cancer, including details on symptoms, genetics, screening, treatment, information. | ||||||||
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Repeated cycles of Clostridium-directed enzyme prodrug therapy result in sustained antitumour effects in vivo.Theys J, Pennington O, Dubois L, Anlezark G, Vaughan T, Mengesha A, Landuyt W, Anné J, Burke PJ, Dûrre P, Wouters BG, Minton NP, Lambin P Department of Radiation Oncology (Maastro Lab), GROW Research Institute, University of Maastricht, UNS 50/23, PO Box 616, Maastricht 6200 MD, The Netherlands. The unique properties of the tumour microenvironment can be exploited by using recombinant anaerobic clostridial spores as highly selective gene delivery vectors. Although several recombinant Clostridium species have been generated during the past decade, their efficacy has been limited. Our goal was to substantially improve the prospects of clostridia as a gene delivery vector. Therefore, we have assessed a series of nitroreductase (NTR) enzymes for their capacity to convert the innocuous CB1954 prodrug to its toxic derivative. Among the enzymes tested, one showed superior prodrug turnover characteristics. In addition, we established an efficient gene transfer procedure, based on conjugation, which allows for the first time genetic engineering of Clostridium strains with superior tumour colonisation properties with high success rates. This conjugation procedure was subsequently used to create a recombinant C. sporogenes overexpressing the isolated NTR enzyme. Finally, analogous to a clinical setting situation, we have tested the effect of multiple consecutive treatment cycles, with antibiotic bacterial clearance between cycles. Importantly, this regimen demonstrated that intravenously administered spores of NTR-recombinant C. sporogenes produced significant antitumour efficacy when combined with prodrug administration. Published 1 November 2006 in Br J Cancer, 95(9): 1212-9.
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