PT-100, a small molecule dipeptidyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism.

Abstract

The amino boronic dipeptide, PT-100 (Val-boro-Pro), a dipeptidyl peptidase (DPP) inhibitor, has been shown to up-regulate gene expression of certain cytokines in hematopoietic tissue via a high-affinity interaction, which appears to involve fibroblast activation protein. Because fibroblast activation protein is also expressed in stroma of lymphoid tissue and tumors, the effect of PT-100 on tumor growth was studied in mice in vivo. PT-100 has no direct cytotoxic effect on tumors in vitro. Oral administration of PT-100 to mice slowed growth of syngeneic tumors derived from fibrosarcoma, lymphoma, melanoma, and mastocytoma cell lines. In WEHI 164 fibrosarcoma and EL4 and A20/2J lymphoma models, PT-100 caused regression and rejection of tumors. The antitumor effect appeared to involve tumor-specific CTL and protective immunological memory. PT-100 treatment of WEHI 164-inoculated mice increased mRNA expression of cytokines and chemokines known to promote T-cell priming and chemoattraction of T cells and innate effector cells. The role of innate activity was further implicated by observation of significant, although reduced, inhibition of WEHI 164 and A20/2J tumors in immunodeficient mice. PT-100 also demonstrated ability to augment antitumor activity of rituximab and trastuzumab in xenograft models of human CD20(+) B-cell lymphoma and HER-2(+) colon carcinoma where antibody-dependent cytotoxicity can be mediated by innate effector cells responsive to the cytokines and chemokines up-regulated by PT-100. Although CD26/DPP-IV is a potential target for PT-100 in the immune system, it appeared not to be involved because antitumor activity and stimulation of cytokine and chemokine production was undiminished in CD26(-/-) mice.

• Authors: Sharlene Adams, Glenn T Miller, Michael I Jesson, Takeshi Watanabe, Barry Jones, Barbara P Wallner
• Journal: Cancer research (Cancer Res) Vol. 64 Issue 15 Pg. 5471-80 (Aug 01 2004) ISSN: 0008-5472 [Print] United States
• PMID: 15289357 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antibodies, Monoclonal, Murine-Derived
• Antineoplastic Agents
• Boronic Acids
• Chemokines
• Cytokines
• Dipeptides
• Enzyme Inhibitors
• Neoplasm Proteins
• PT-100 dipeptide
• Rituximab
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
• Dipeptidyl Peptidase 4
• Trastuzumab

Topics

• Administration, Oral
• Animals
• Antibodies, Monoclonal (administration & dosage)
• Antibodies, Monoclonal, Humanized
• Antibodies, Monoclonal, Murine-Derived
• Antibody-Dependent Cell Cytotoxicity (immunology)
• Antineoplastic Agents (therapeutic use)
• Boronic Acids (therapeutic use)
• Chemokines (metabolism)
• Colonic Neoplasms (drug therapy, pathology)
• Cytokines (metabolism)
• Dipeptides (therapeutic use)
• Dipeptidyl Peptidase 4 (metabolism)
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases (antagonists & inhibitors)
• Enzyme Inhibitors (pharmacology)
• Fibrosarcoma (drug therapy, pathology)
• Gene Expression Profiling
• Humans
• Lymphoma (drug therapy, pathology)
• Mastocytoma (drug therapy, pathology)
• Melanoma (drug therapy, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Mice, Inbred NOD
• Mice, Knockout
• Neoplasm Proteins (metabolism)
• Neoplasms, Experimental (drug therapy, pathology)
• Oligonucleotide Array Sequence Analysis
• Rituximab
• Transplantation, Heterologous
• Trastuzumab