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

Research output: Contribution to journalArticle

34 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Salmonella typhimurium
Antineoplastic Agents
Interleukin-2
Kupffer Cells
Neoplasm Metastasis
Liver
Salmonella
Genes
T-Lymphocytes
Natural Killer Cells
Analysis of Variance
Biological Therapy
Cytotoxic T-Lymphocytes
Helper-Inducer T-Lymphocytes
Inbred C57BL Mouse
Population
Oral Administration
Neoplasms
Adenocarcinoma
Plasmids

Keywords

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

ASJC Scopus subject areas

  • Surgery

Cite this

Antitumor mechanisms of attenuated Salmonella typhimurium containing the gene for human interleukin-2 : A novel antitumor agent? / Saltzman, Daniel A.; Katsanis, Emmanuel; Heise, Charles P.; Hasz, Diane E.; Vigdorovich, Vladimir; Kelly, Sandra M.; Curtiss, Roy; Leonard, Arnold S.; Anderson, Peter M.

In: Journal of Pediatric Surgery, Vol. 32, No. 2, 02.1997, p. 301-306.

Research output: Contribution to journalArticle

Saltzman, DA, Katsanis, E, Heise, CP, Hasz, DE, Vigdorovich, V, Kelly, SM, Curtiss, R, Leonard, AS & Anderson, PM 1997, 'Antitumor mechanisms of attenuated Salmonella typhimurium containing the gene for human interleukin-2: A novel antitumor agent?', Journal of Pediatric Surgery, vol. 32, no. 2, pp. 301-306. https://doi.org/10.1016/S0022-3468(97)90198-6
Saltzman, Daniel A. ; Katsanis, Emmanuel ; Heise, Charles P. ; Hasz, Diane E. ; Vigdorovich, Vladimir ; Kelly, Sandra M. ; Curtiss, Roy ; Leonard, Arnold S. ; Anderson, Peter M. / Antitumor mechanisms of attenuated Salmonella typhimurium containing the gene for human interleukin-2 : A novel antitumor agent?. In: Journal of Pediatric Surgery. 1997 ; Vol. 32, No. 2. pp. 301-306.
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