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Tumor suppression after tumor-cell targeted tumor-necrosis-factor-alpha gene-transfer

Academic Article
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Overview

authors

  • Blankenstein, T.
  • Qin, Z. H.
  • Uberla, K.
  • Muller, W.
  • Rosen, Hugh
  • Volk, H. D.
  • Diamantstein, T.

publication date

  • May 1991

journal

  • Journal of Experimental Medicine  Journal

abstract

  • The tumor necrosis factor alpha (TNF-alpha) gene was introduced by retroviral gene transfer into the TNF-alpha-insensitive tumor cell line J558L. Production of 40 pg/ml TNF-alpha by clone J2T12 consistently did not change the growth rate in vitro, but drastically suppressed tumor growth when injected into syngeneic BALB/c mice. Within 2 wk, 90% of the mice inoculated with J558L cells developed a tumor, but none of the mice injected with J2T12 did so. Within the observation period (greater than 3 mo), 60% of the mice inoculated with J2T12 did not develop a tumor. In the other 40% of the mice, tumor manifestation was significantly delayed. Mice injected simultaneously with J2T12 cells and an anti-TNF-alpha monoclonal antibody developed tumors similar to parental J558L cells. Similarly, the tumor-suppressive effects of TNF-alpha were abolished, e.g., by injection of an anti-type 3 complement receptor (CR3) monoclonal antibody that is known to prevent migration of inflammatory cells. These results and the observation of tumor-infiltrating macrophages suggest that lack of tumorigenicity of J2T12 cells is due to the TNF-alpha secretion by the tumor cells and that TNF-alpha acts indirectly by a mechanism that involves chemotactic recruitment and activation of cells, predominantly of macrophages. In contrast, the tumor growth was not affected when, instead of TNF-alpha, interleukin 6 was expressed by J558L cells. Together, our results support the concept of tumor cell-targeted cytokine gene transfer as a tool for cancer treatment, and particularly demonstrate that extremely low doses of TNF-alpha produced by tumor cells are sufficient to inhibit tumor growth without detectable side effects.

subject areas

  • Alkaline Phosphatase
  • Animals
  • Antibodies, Monoclonal
  • Cell Movement
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor
  • Immunohistochemistry
  • Interleukin-6
  • Macrophage-1 Antigen
  • Macrophages
  • Mice
  • Mice, Inbred BALB C
  • Multiple Myeloma
  • Phenotype
  • Plasmacytoma
  • Retroviridae
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha
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Identity

International Standard Serial Number (ISSN)

  • 0022-1007

Digital Object Identifier (DOI)

  • 10.1084/jem.173.5.1047

PubMed ID

  • 2022919
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Additional Document Info

start page

  • 1047

end page

  • 1052

volume

  • 173

issue

  • 5

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