Tumor-Targeted Salmonella typhimurium Overexpressing Cytosine Deaminase: A Novel, Tumor-Selective Therapy
The ideal anticancer regimen is one that is specific for cancer cells with limited toxicity to normal tissues. Genetically modified, nonpathogenic Salmonella offer a potential way to induce direct tumoricidal activity or to deliver tumoricidal agents to tumors. An attenuated strain of Salmonella typhimurium, called VNP20009, and its derivative TAPET-CD (which expresses Escherichia coli cytosine deaminase) are highly selective for tumor tissue and can deliver therapeutic proteins preferentially to tumors in preclinical models. Both VNP20009 and TAPET-CD have been investigated successfully in Phase 1 clinical trials in cancer patients.
Key Wordscytosine deaminase 5-fluorocytosine 5-fluorouracil Salmonella TAPET-CD tumor VNP20009
The authors thank Brooks Low, Samuel Miller, and John Pawelek for helpful suggestions and Kimberly Troy, Jeremy Pike, and Caroline Clairmont for technical assistance. This work was supported by Vion Pharmaceuticals, New Haven, CT.
- 3.Murray, S. R., Suwwan de Felipe, K., Obuchowski, P. L., Pike, J., Bermudes, D. and Low, K. B. (2004) Hot spot for a large deletion in the 18- to 19-centisome region confers a multiple phenotype in Salmonella enterica Serovar Typhimurium strain ATCC 14028. J Bacteriol. 186, 8516–8523.PubMedCrossRefGoogle Scholar
- 4.Zheng, L., Luo, X., Feng, M., Li, Z., Le, T., Ittensohn, M. et al. (2000) Tumor amplified protein expression therapy: Salmonella as a tumor-selective protein delivery vector. Oncology Res. 12, 127–135.Google Scholar
- 5.Bermudes, D., Zheng, L., and King, I. C. (2002) Live bacteria as anticancer agents and tumor-selective protein delivery vectors. Curr Opin Drug Discover Develop. 5, 194–199.Google Scholar
- 8.King, I., Bermudes, D., Lin, S., Belcourt, M., Pike, J., Troy, K., et al. Tumor-targeted Salmonella expressing cytosine deaminase as an anticancer agent. Human Gene Therapy 13, 1225–1233.Google Scholar
- 11.Low, K.B., Ittensohn, M., Le, T., Platt, J., Sodi, S., Amoss, M., et al. (1999) Lipid A mutant Salmonella with suppressed virulence and TNFα induction retain tumor-targeting in vivo. Nature Biotechnol. 17, 37–41.Google Scholar
- 12.Davis, R. W., Botstein, D., and Roth, J. R. (1980) Advanced Bacterial Genetics. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York.Google Scholar
- 13.Low, K.B., Ittensohn, M., Luo, X., Zheng, L., King, I., Pawelek, J.M., et al. (2003) Construction of VNP20009. Methods in Molecular Med. 90, 47–59.Google Scholar
- 14.Sambrook, J., Fritsch, E.F., and Maniatis, T. (1989) Molecular Cloning: A Laboratory Manual, 2nd Ed., Cold Spring Harbor Press, Cold Spring Harbor, NY.Google Scholar
- 15.Austin, E. A. and Huber, B. E. (1993) A first step in the development of gene therapy for colorectal carcinoma: cloning, sequencing and expression of Escherichia coli cytosine deaminase. Molecular Pharmacol. 43, 380–387.Google Scholar