TX-1877, a bifunctional hypoxic cell radiosensitizer, enhances anticancer host response: immune cell migration and nitric oxide production.

Abstract

We investigated in the current study the effect of TX-1877, a bifunctional hypoxic cell radiosensitizer, in augmenting anticancer host response. In the syngeneic squamous cell carcinoma-bearing mouse model, a single administration of TX-1877 significantly inhibited the primary tumor growth as well as lung metastasis. TX-1877 administration resulted in a significant infiltration of immune cells, such as CD4+T, CD8+T cells, macrophages and dendritic cells (DCs), and an increased expression of chemokines for cytotoxic T lymphocytes (CTLs), helper T-cell 1 (Th1) cells, monocytes/macrophages and DCs, in tumor tissues. Nitric oxide (NO) production and the expression of inducible NO synthase (iNOS) and interferon-gamma, a major Th1 cytokine that plays a major role in anticancer immunity, were also enhanced. Furthermore, neutralization of NO by N-monomethyl-L-arginine acetate resulted in a marked inhibition of the antitumor effect of TX-1877. In tumor-draining lymph nodes, MHC class I-restricted CD8+ memory CTLs specific for inoculated cancer cells were induced by TX-1877. In in vitro experiments, TX-1877 induced chemokines and iNOS/NO in several types of culture cells. These findings strongly suggested that TX-1877 induces migration of CD8+CTLs, CD4+Th1 cells, macrophage/monocytes and dendritic cells into the tumor site, and that this migration is mediated by chemokine induction. In addition, it was suggested that NO produced by several types of cells stimulated by TX-1877 in the tumor sites plays a major role in the anticancer effect of TX-1877. TX-1877 was thus shown to be an effective immunopotentiator as well as a hypoxic cell radiosensitizer.

• Authors: Tetsuya Oshikawa, Masato Okamoto, Sharif U Ahmed, Sachiko Furuichi, Tomoyuki Tano, Akiko Sasai, Shin Kan, Soko Kasai, Yoshihiro Uto, Hideko Nagasawa, Hitoshi Hori, Mitsunobu Sato
• Journal: International journal of cancer. Journal international du cancer (Int J Cancer) Vol. 116 Issue 4 Pg. 571-8 (Sep 10 2005) ISSN: 0020-7136 [Print] United States
• PMID: 15825172 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2005 Wiley-Liss, Inc.

Chemical References

• 2-nitroimidazole acetamide
• Nitroimidazoles
• Nitric Oxide

Topics

• Animals
• CD4-Positive T-Lymphocytes (drug effects, immunology)
• CD8-Positive T-Lymphocytes (drug effects, immunology)
• Carcinoma, Squamous Cell (immunology)
• Cell Hypoxia
• Cell Movement
• Dendritic Cells
• Disease Models, Animal
• Humans
• Mice
• Nitric Oxide (biosynthesis)
• Nitroimidazoles (pharmacology)
• Radiation Tolerance
• T-Lymphocytes, Cytotoxic (drug effects, immunology)