Antitumor mechanisms of attenuated Salmonella typhimurium containing the gene for human interleukin-2: A novel antitumor agent?

Daniel A. Saltzman, Emmanuel Katsanis, Charles P. Heise, Diane E. Hasz, Vladimir Vigdorovich, Sandra M. Kelly, Roy Curtiss, Arnold S. Leonard, Peter M. Anderson

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37 Scopus citations

Abstract

Currently, there is no long-term effective treatment for unresectable hepatic malignancies. Salmonella species are known to naturally track to the liver during active infection. To develop a biological vector for delivery of interleukin-2 (IL-2) to the fiver for antitumor purposes, the (χ)4550 attenuated strain of Salmonella typhimurium was used as a vector for IL-2. The gene for human IL-2 was cloned into plasmid pYA292 and inserted into the attenuated S typhimurium and renamed [(χ)4550(pIL-2)]. MCA-38 murine adenocarcinoma cells were injected intrasplenically into C57BL/6 mice to produce hepatic metastases that were subsequently enumerated after 12 days. We previously have demonstrated that the (χ)4550(pIL-2) produces biologically active IL-2 and that a single gavage feeding of 107 (χ)4550(pIL-2) significantly reduced the number of hepatic metastases when compared with animals fed salmonella lacking the IL-2 gene or non-treated controls. The aims of the current studies were to determine which host effector cell populations were responsible for the antitumor effect seen with (χ)4550(pIL-2) by depletion of natural killer (NK), cytotoxic T lymphocytes (CD8+), T helper (CD4+) cells, and Kupffer cells. Multiple experiments were conducted for each host effector cell population depleted. We found a consistent reduction in the mean number of hepatic metastases in animals fed (χ)4550(pIL-2) (55.6 metastases; n = 54) when compared with controls (162.3 metastases; n = 53) (P < .0001). Depletion of NK cells and CD8+ T cells significantly inhibited the antitumor effect of (χ)4550(pIL-2) (analysis of variance [ANOVA], P < .01). Elimination of CD4+ T cells and Kupffer cells had no significant impact on the antitumor effect of χ4550(pIL-2) (ANOVA, P value was not significant). Salmonella IL-2 may represent a novel form of in vivo biotherapy for unresectable hepatic malignancies that employs the oral route of administration. Furthermore, both NK cells or CD8+ cells are required for the antitumor effect seen while CD4+ T cells and Kupffer cells do not appear to be as essential.

Original languageEnglish (US)
Pages (from-to)301-306
Number of pages6
JournalJournal of Pediatric Surgery
Volume32
Issue number2
DOIs
StatePublished - Feb 1997

Keywords

  • Avirulent salmonella
  • biotherapy
  • hepatic malignancy
  • interleukin-2

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    Saltzman, D. A., Katsanis, E., Heise, C. P., Hasz, D. E., Vigdorovich, V., Kelly, S. M., Curtiss, R., Leonard, A. S., & Anderson, P. M. (1997). Antitumor mechanisms of attenuated Salmonella typhimurium containing the gene for human interleukin-2: A novel antitumor agent? Journal of Pediatric Surgery, 32(2), 301-306. https://doi.org/10.1016/S0022-3468(97)90198-6