Advertisement

Tumor-Targeted Salmonella

Highly Selective Delivery Vectors
  • David Bermudes
  • Brooks Low
  • John Pawelek
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 465)

Summary

Genetically engineered Salmonella offer an intriguing new approach to selectively target solid tumors, including melanoma, lung, colon, breast, kidney and liver. These bacteria target tumors after systemic administration and selectively replicate within them. Specificity for tumors is often more than 1,000 times greater than for any other tissue. Auxotrophic mutations make these bacteria highly safe and form the basis for maintaining tumor specificity. An altered lipid greatly reduces the potential for septic shock yet also retains the antitumor properties of these bacteria. These bacteria have innate antitumor activity towards both primary and metastatic tumors and the ability to deliver proteins capable of activating chemotherapeutic agents directly within tumors. The delay in tumor growth results in mice that survive up to twice as long. These bacteria are susceptible to a wide range of antibiotics, allowing external control of the vector after administration. The combination of these features within a single vector seems especially surprising considering their unlikely source.

Keywords

Thymidine Kinase Cancer Gene Therapy Inhibit Tumor Metastasis Stealth Liposome Amino Acid Auxotrophy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Allen, T.M., Hansen, C.B., and Zalipsky, S. 1995. Antibody-targeted stealth liposomes. In: Stealth Liposomes, D.D. Lasic (ed), CRC Press, Boca Raton, pp. 233–244.Google Scholar
  2. Bacon, G.A., Burrows, T.W., and Yates, M. 1950. The effects of biochemical mutation on the virulence of bacterium typhosum: The virulence of mutants. Br. J. Exp. Path. 31:714–724.Google Scholar
  3. Bacon G.A., Burrows T.W., and Yates M. 1951. The effects of biochemical mutation on the virulence of bacterium typhosum: The loss of virulence of certain mutants. Br. J. Exp. Path. 32:85–96.Google Scholar
  4. Baselga, J., Norton, L., Albanell, J., Kim, Y.-M., and Mendelsohn, J. 1998. Recombinant humanized anti-HER2 antibody (HerceptinTM) enhances the antitumor activity of paclitaxol and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res. 58:2825–2831.PubMedGoogle Scholar
  5. Bischoff, J.R., Kirn, D.H., Williams, A., Heise, C., Horn, S., Muna, M., Ng, L., Nye, J.A., Sampson-Johannes, A., Fattaey, A., and McCormick, F. 1996. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 274:373–376.PubMedCrossRefGoogle Scholar
  6. Boucher, Y., Leunig, M., and Jain, R.K. 1996. Tumor angiogenesis and interstitial hypertension. Cancer Res. 56:4264–4266.PubMedGoogle Scholar
  7. Carey, R.W., Holland, J.F., Whang, H.Y., Neter, E., and Bryant, B. 1967. Clostridial oncolysis in man. Eur. J. Cancer 3:37–46.Google Scholar
  8. Carter, P.B., and Collins, F.M. 1974. The route of enteric infection in normal mice. J. Exp. Med. 139:1189–1203.PubMedCrossRefGoogle Scholar
  9. Fox, M.E., Lemmon, J.J., Mauchline, M.L., Davis, T.O., Giaccia, A.J., Minton, N.P., and Brown, J.M 1996. Anaerobic bacteria as a delivery system for cancer gene therapy: in vitro activation of 5-fluorocytosine by genetically engineered clostridia. Gene Therapy 3:173–178.PubMedGoogle Scholar
  10. Friedman, P.N., McAndrew, S.J., Gawlak, S.L., Trail, P.A., Brown, J.P., and Siegall, C.B. 1993. BR96 sFv-PE40, a potent single-chain immunotoxin that selectively kills carcinoma cells. Cancer Res. 53:334–339.PubMedGoogle Scholar
  11. Garapin A.C., Colbère-Garapin, F., Cohen-Solal, Horondniceanu, F., and Kourilsky, P. 1981. Expression of herpes simples virus type I thymidine kinase gene in Escherichia coli. Proc. Natl. Acad. Sci. USA 78:815–819.PubMedGoogle Scholar
  12. Gotoh, A., Ko, S.C., Shirakawa, T., Cheon, J., Kao, C., Miyamoto, T., Gardner, T.A., Ho, L.J., Cleutjens, C.B., Trapman, J., Graham, F.L., and Chung, L.W. 1998. Development of prostate-specific antigen promoterbased gene therapy for androgen-independent human prostate cancer. J. Urol. 160:220–229.PubMedGoogle Scholar
  13. Groisman, E.A., and Saier, M.H. Jr. 1990. Salmonella virulence: new clues to intramacrophage survival. Trends Biochem. Sci. 15:30–33.PubMedCrossRefGoogle Scholar
  14. Hoiseth, S.K.J., and Stocker, B.A.D. 1981. Aromatic-dependent Salmonella typhimurium are non-virulent and effective as live vaccines. Nature 291:238–239.PubMedCrossRefGoogle Scholar
  15. Jain, R.K. 1994. Barriers to drug delivery in solid tumors. Scientific American 271(July):58–65.Google Scholar
  16. Joiner, K.A. 1988. Complement evasion by bacteria and parasites. Ann. Rev. Microbiol. 42:201–230.CrossRefGoogle Scholar
  17. Khan, S.A., Everest, P., Servos, S., Foxwell, N., Zähringer, U., Brade, H., Rietschel, E. Th., Dougan, G., Charles, I.G., and Maskell, D.J. 1998. A lethal role for lipid A in Salmonella infections. Mol. Mircobiol. 29:571–579.Google Scholar
  18. King, I., Feng, M, Luo, X., Lin, S., Bermudes, D., and Zheng, L.-M. 1998. Tumor-targeted Salmonella expressing cytosine deaminase converted 5-fluorocytosine to 5-fluorouracil and inhibited tumor growth in vivo. Proc. Amer. Asoc. Can. Res. 39, p. 512, Abstract 3484.Google Scholar
  19. Kops, S.K., Luo, X., Fischer, J., Le, T., Bermudes, D., Bolognia, J.L., Carmichael, E., Key-Yen, A., King, I., Low, K.B., Pawelek, J.M., Sodi. S.S., and Zheng, L.-M. Salmonella typhimurium as an anti-cancer vector: Localization within solid tumors. Proc. Amer. Asoc. Can. Res. 38, p. 7, Abstract 46.Google Scholar
  20. Lemmon, M.J., van Zijl, P., Fox, M.E., Mauchline, M.L., Giaccia, A.J., Minton, N.P., and Brown, J.M. 1997. Anaerobic bacteria as a gene delivery system that is controlled by the tumor microenvironment. Gene Therapy 4:791–796.PubMedCrossRefGoogle Scholar
  21. Low, K.B., Ittensohn, M., Le, T., Platt, J., Sodi, S., Amoss, M., Ash, O., Carmichael, E., Chakraborty, A., Fischer, J., Lin, S.L., Luo, X., Miller, S.I., Zheng, L.-M., King, I., Pawelek, J.M., and Bermudes, D. 1998. Disruption of the Salmonella msbB gene suppresses virulence and TNFα induction yet retain tumor-targeting in vivo. Proc. Amer. Asoc. Can. Res. 39, p. 60, Abstract 409.Google Scholar
  22. Möse, J.R., and Möse, G. 1964. Oncolysis by Clostridia. I. Activity of Clostridium butyricum (M-55) and other nonpathogenic clostridia against the Ehrlich carcinoma. Cancer Res. 24:212–216.Google Scholar
  23. Parker, R.C., Plummer, H.C., Siebenmann, C.O., and Chapman, M.G. 1967. Effect of histollyticus infection and toxin on transplantable mouse tumors. Proc. Soc. Exp. Biol. Med. 66:461–467.Google Scholar
  24. Pawelek, J., Low, K.B., and Bermudes, D. 1997. Tumor-targeted Salmonella as a novel anti-cancer vector. Cancer Research 57:4537–4544.PubMedGoogle Scholar
  25. Siegall, C.B. 1995. Targeted therapy of carcinomas using BR96 sFv-PE40, a single-chain immunotoxin that binds to the Le(y) antigen. Semin Cancer Biol. 6:289–295.PubMedCrossRefGoogle Scholar
  26. Trail, P.A., Willner, D., Lasch, S.J., Henderson, A.J., Hostead, S., Casazaza, A.M., Firestone, R.A., Hellström, I., and Hellström, K.E. 1993. Cure of xenografted human carcinomas by BR96-doxorubicin immunoconjugates. Science 261:212–215.PubMedGoogle Scholar
  27. Zheng, L.-M., Luo, X., Fischer, J., Le, T., Bermudes, D., Low, B., Pawelek, J.M., and King, I. 1997. Attenuated Salmonella typhimurium inhibited tumor metastasis in vivo. Proc. Amer. Asoc. Can. Res. 38, p. 9, Abstract 60.Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • David Bermudes
    • 1
  • Brooks Low
    • 2
  • John Pawelek
    • 3
  1. 1.Vion Pharmaceuticals, Inc.New HavenUSA
  2. 2.Department of Therapeutic RadiologyYale University School of MedicineNew HavenUSA
  3. 3.Department of Therapeutic DermatologyYale University School of MedicineNew HavenUSA

Personalised recommendations