Enhancement of Th1 type cytokine production and primary T cell activation by PBI-1393.
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.
Allam
Mustapha
M
ProMetic BioSciences Inc., 500 Cartier Blvd. West, Suite 150, Laval, Quebec, Canada H7V 5B7. m.allam@prometic.com
Julien
Nathalie
N
Zacharie
Boulos
B
Penney
Christopher
C
Gagnon
Lyne
L
D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000187:drug effects*; D007376:Interleukin-2 / Q000096:biosynthesis*; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects; D011687:Purines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000187:drug effects