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

doi:10.1016/S0022-3468(97)90198-6

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

Surgery

Research output: Contribution to journal › Article › peer-review

53 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 language	English (US)
Pages (from-to)	301-306
Number of pages	6
Journal	Journal of Pediatric Surgery
Volume	32
Issue number	2
DOIs	https://doi.org/10.1016/S0022-3468(97)90198-6
State	Published - Feb 1997

Bibliographical note

Funding Information:
From the Departments of Surgery and Pediatrtcs, Universtty of Minnesota, Minneapolis, MN; MEGAN Animal Health, St Lows. MO: Department of Biology, Washington University, St Louis, MO; and Department of Pediatrics and Adolescent Medzcme. My\)0 Clime, Rochester; MN. Presented at the 27th Annual Meetmg oj. the Amencan Pediatric Surgical Associatron, San Diego, California, May 20-23, 1996. These studtes bvere supported by grants from Concern II Foundation, Chrldren S Cancer Research Fund, The Elsa U. Pardee Foundation. The Arnold S. Leonard Cancer Research Fund, and the Mmnesota Medical Foundation Dr Heise received the Margaret Mltchell Medical Student Award from the American Cancer Socrety and Dr Saltzman is a recipient oj a NIH NRSA Award. Address reprint requests to Dame1 A. Saltzman. MD, Box 195 UMHC, Department of Surgery, Universrty of Minnesota, 516 Delaware St SE, Minneapolis, MN 55455. Copyright o 1997 by WB. Saunders Company 0022-3468/97/3202-0030$03.00/O

Keywords

Avirulent salmonella
biotherapy
hepatic malignancy
interleukin-2

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10.1016/S0022-3468(97)90198-6

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

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.",

keywords = "Avirulent salmonella, biotherapy, hepatic malignancy, interleukin-2",

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

note = "Funding Information: From the Departments of Surgery and Pediatrtcs, Universtty of Minnesota, Minneapolis, MN; MEGAN Animal Health, St Lows. MO: Department of Biology, Washington University, St Louis, MO; and Department of Pediatrics and Adolescent Medzcme. My\)0 Clime, Rochester; MN. Presented at the 27th Annual Meetmg oj. the Amencan Pediatric Surgical Associatron, San Diego, California, May 20-23, 1996. These studtes bvere supported by grants from Concern II Foundation, Chrldren S Cancer Research Fund, The Elsa U. Pardee Foundation. The Arnold S. Leonard Cancer Research Fund, and the Mmnesota Medical Foundation Dr Heise received the Margaret Mltchell Medical Student Award from the American Cancer Socrety and Dr Saltzman is a recipient oj a NIH NRSA Award. Address reprint requests to Dame1 A. Saltzman. MD, Box 195 UMHC, Department of Surgery, Universrty of Minnesota, 516 Delaware St SE, Minneapolis, MN 55455. Copyright o 1997 by WB. Saunders Company 0022-3468/97/3202-0030$03.00/O",

year = "1997",

month = feb,

doi = "10.1016/S0022-3468(97)90198-6",

language = "English (US)",

volume = "32",

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journal = "Journal of Pediatric Surgery",

issn = "0022-3468",

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T1 - Antitumor mechanisms of attenuated Salmonella typhimurium containing the gene for human interleukin-2

T2 - A novel antitumor agent?

AU - Saltzman, Daniel A.

AU - Katsanis, Emmanuel

AU - Heise, Charles P.

AU - Hasz, Diane E.

AU - Vigdorovich, Vladimir

AU - Kelly, Sandra M.

AU - Curtiss, Roy

AU - Leonard, Arnold S.

AU - Anderson, Peter M.

N1 - Funding Information: From the Departments of Surgery and Pediatrtcs, Universtty of Minnesota, Minneapolis, MN; MEGAN Animal Health, St Lows. MO: Department of Biology, Washington University, St Louis, MO; and Department of Pediatrics and Adolescent Medzcme. My\)0 Clime, Rochester; MN. Presented at the 27th Annual Meetmg oj. the Amencan Pediatric Surgical Associatron, San Diego, California, May 20-23, 1996. These studtes bvere supported by grants from Concern II Foundation, Chrldren S Cancer Research Fund, The Elsa U. Pardee Foundation. The Arnold S. Leonard Cancer Research Fund, and the Mmnesota Medical Foundation Dr Heise received the Margaret Mltchell Medical Student Award from the American Cancer Socrety and Dr Saltzman is a recipient oj a NIH NRSA Award. Address reprint requests to Dame1 A. Saltzman. MD, Box 195 UMHC, Department of Surgery, Universrty of Minnesota, 516 Delaware St SE, Minneapolis, MN 55455. Copyright o 1997 by WB. Saunders Company 0022-3468/97/3202-0030$03.00/O

PY - 1997/2

Y1 - 1997/2

N2 - 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.

AB - 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.

KW - Avirulent salmonella

KW - biotherapy

KW - hepatic malignancy

KW - interleukin-2

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

Abstract

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Keywords

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