Attenuated Salmonella typhimurium containing interleukin-2 decreases MC-38 hepatic metastases: A novel anti-tumor agent

Daniel A. Saltzman, Charles P. Heise, Diane E. Hasz, Marcela Zebede, Sandra M. Kelly, Roy Curtiss, Arnold S. Leonard, Peter M. Anderson

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Currently, there is no long-term effective treatment for unresectable hepatic malignancies. Salmonella sp. 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 liver for anti-tumor purposes, the avirulent and highly immunogenic χ4550 strain of Salmonella typhimurium was used as a vector for IL-2. The gene for human IL-2 was cloned into plasmid pYA292 (renamed pIL-2) and inserted into the attenuated Salmonella typhimurium and renamed [χ4550 (pIL-2)]. This transformant was found to produced biologically active IL-2 demonstrated by NK cell activation in a 4 hour chromium release cytotoxicity assay. To determine anti-tumor potential, MCA-38 munne adenocarcinoma cells were injected intrasplenically into C51BL/6 mice to produce hepatic metastases and metastases were subsequently enumerated after 12 days. Statistical significance was determined by ANOVA with Fisher's test for significance. Hepatic metastases enumerated by blinded observers revealed that the mean number of metastases was 106.4 in control mice, 103.7 in mice gavage fed attenuated salmonella without IL-2 [χ4550(pYA292)], and 44.3 in mice fed the χ4550(pIL2); (ANOVA: p<0.01). Culture of livers and spleens in mice administered a single gavage dose of salmonella demonstrated persistent colonization for up to 4 weeks. No observable toxicity was seen 10 either IL-2 or salmonella. These studies demonstrate that the χ4550(pIL2) is a novel form of in vivo biotherapy which produces biologically active IL-2 and employs the oral route of administration to stimulate an immune response against malignancy in the liver.

Original languageEnglish (US)
Pages (from-to)145-153
Number of pages9
JournalCancer Biotherapy and Radiopharmaceuticals
Volume11
Issue number2
StatePublished - Apr 1996
Externally publishedYes

Fingerprint

Salmonella typhimurium
Interleukin-2
Neoplasm Metastasis
Liver
Salmonella
Neoplasms
Analysis of Variance
Biological Therapy
Chromium
Natural Killer Cells
Oral Administration
Adenocarcinoma
Plasmids
Spleen
Infection
Genes

Keywords

  • Attenuated salmonella typhimurium
  • Interleukin-2
  • Metastases

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology

Cite this

Saltzman, D. A., Heise, C. P., Hasz, D. E., Zebede, M., Kelly, S. M., Curtiss, R., ... Anderson, P. M. (1996). Attenuated Salmonella typhimurium containing interleukin-2 decreases MC-38 hepatic metastases: A novel anti-tumor agent. Cancer Biotherapy and Radiopharmaceuticals, 11(2), 145-153.

Attenuated Salmonella typhimurium containing interleukin-2 decreases MC-38 hepatic metastases : A novel anti-tumor agent. / Saltzman, Daniel A.; Heise, Charles P.; Hasz, Diane E.; Zebede, Marcela; Kelly, Sandra M.; Curtiss, Roy; Leonard, Arnold S.; Anderson, Peter M.

In: Cancer Biotherapy and Radiopharmaceuticals, Vol. 11, No. 2, 04.1996, p. 145-153.

Research output: Contribution to journalArticle

Saltzman, DA, Heise, CP, Hasz, DE, Zebede, M, Kelly, SM, Curtiss, R, Leonard, AS & Anderson, PM 1996, 'Attenuated Salmonella typhimurium containing interleukin-2 decreases MC-38 hepatic metastases: A novel anti-tumor agent', Cancer Biotherapy and Radiopharmaceuticals, vol. 11, no. 2, pp. 145-153.
Saltzman, Daniel A. ; Heise, Charles P. ; Hasz, Diane E. ; Zebede, Marcela ; Kelly, Sandra M. ; Curtiss, Roy ; Leonard, Arnold S. ; Anderson, Peter M. / Attenuated Salmonella typhimurium containing interleukin-2 decreases MC-38 hepatic metastases : A novel anti-tumor agent. In: Cancer Biotherapy and Radiopharmaceuticals. 1996 ; Vol. 11, No. 2. pp. 145-153.
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