Enhancement of Th1 type cytokine production and primary T cell activation by PBI-1393

Clin Immunol. 2007 Dec;125(3):318-27. doi: 10.1016/j.clim.2007.07.017. Epub 2007 Sep 12.

Abstract

In previous reports, we have shown that PBI-1393 (formerly BCH-1393), N,N-Dimethylaminopurine pentoxycarbonyl D-arginine, stimulates cytotoxic T-lymphocyte (CTL) responses both in vitro and in vivo in normal immune status and immunosuppressed mice. Additionally, PBI-1393 was tested for anticancer activity in syngeneic mouse experimental tumor models and it displayed significant inhibition of tumor outgrowths when given in combination with sub-therapeutic doses of cytotoxic drugs (cyclophosphamide, 5-fluorouracil, doxorubicin and cis-platinum). However, the mechanism of action of PBI-1393 was still unknown. Here, we report that PBI-1393 enhances IL-2 and IFN-gamma production in human activated T cells by 51% and 46% respectively. PBI-1393 increases also IL-2 and IFN-gamma mRNA expression as shown by RT-PCR. The physiological relevance of IL-2 and IFN-gamma gene modulation by PBI-1393 is illustrated by the advantageous increase of T cell proliferation (39+/-0.3% above control) and human CTL response against prostate (PC-3) cancer cells (42+/-0.03%). The enhancement of human T cell proliferation and CTL activation by PBI-1393 demonstrates that this compound potentiates the immune response and in this regard, it could be used as an alternative approach to IL-2 and/or IFN-gamma therapy against cancer.

MeSH terms

  • Arginine / analogs & derivatives*
  • Arginine / pharmacology
  • Cell Proliferation / drug effects
  • Cytotoxicity, Immunologic
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression / drug effects
  • Genes, fos / drug effects
  • Humans
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / drug effects*
  • Interleukin-2 / biosynthesis*
  • Jurkat Cells
  • Lymphocyte Activation / drug effects*
  • Lymphocyte Activation / immunology
  • Mitogen-Activated Protein Kinase Kinases / drug effects
  • Purines / pharmacology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Th1 Cells / drug effects*
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Transcription Factor AP-1 / drug effects

Substances

  • BCH 1393
  • Interleukin-2
  • Purines
  • Transcription Factor AP-1
  • Interferon-gamma
  • Arginine
  • Mitogen-Activated Protein Kinase Kinases