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Departments of ¹ Microbiology and Immunology and ² Pediatrics and Molecular Imaging Program, Stanford University School of Medicine, Stanford, California

Requests for reprints: A. Matin, Department of Microbiology and Immunology, Stanford University School of Medicine, Sherman Fairchild Science Building, 299 Campus Drive, Stanford, CA 94305. Phone: 650-725-4745; Fax: 650-725-6757. E-mail: a.matin{at}stanford.edu

Reductive prodrugs, mitomycin C and 5-aziridinyl-2,4-dinitrobenzamide (CB 1954), are nontoxic in their native form but become highly toxic upon reduction. Their effectiveness in cancer chemotherapy can be enhanced by delivering to tumors enzymes with improved prodrug reduction kinetics. We report the discovery of a new prodrug-reducing enzyme, YieF, from Escherichia coli, and the improvement of its kinetics for reducing mitomycin C and CB 1954. A YieF-derived enzyme, Y6, killed HeLa spinner cells with 5-fold efficiency than the wild-type enzymes, YieF and NfsA, at a variety of drug and enzyme concentrations and incubation times. With adhered HeLa cells and Salmonella typhimurium SL 7838 bacteria as enzyme delivery vehicle, at least an order of magnitude less of Y6-producing bacteria were required to kill >90% of tumor cells compared with bacteria expressing the wild-type enzymes, which at a comparable level killed <5% of the cells. Thus, Y6 is a promising enzyme for use in cancer chemotherapy, and Salmonella strain SL 7838, which specifically targets tumors, may be used to deliver the prodrug-activating enzymes to tumors. [Mol Cancer Ther 2006;5(1):97–103]

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³ Y. Barak, D.F. Ackerley, B. Lal, A. Matin, unpublished data.

⁴ S.H. Thorne, J. Hardy, B. Stoker, C.H. Contag, D.H. Kirn, unpublished data.

⁵ http://www.ncbi.nlm.nih.gov/sutils/genom_table.cgi.

⁶ http://searchlauncher.bcm.tmc.edu/multi-align/multi-align.html.

⁷ Y. Barak, Y. Nov, A. Matin, unpublished data.

⁸ Y. Barak, S. Jaiswal, J. Rao, A. Matin, unpublished data.

Received 9/12/05; revised 10/13/05; accepted 10/25/05.

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