TX-1877, a bifunctional hypoxic cell radiosensitizer, enhances anticancer host response: immune cell migration and nitric oxide production.
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.
Oshikawa
Tetsuya
T
Second Department of Oral and Maxillofacial Surgery, Tokushima University School of Dentistry, 3-18-15 Kuramoto-cho, Tokushima, Japan.
Okamoto
Masato
M
Ahmed
Sharif U
SU
Furuichi
Sachiko
S
Tano
Tomoyuki
T
Sasai
Akiko
A
Kan
Shin
S
Kasai
Soko
S
Uto
Yoshihiro
Y
Nagasawa
Hideko
H
Hori
Hitoshi
H
Sato
Mitsunobu
M
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D002294:Carcinoma, Squamous Cell / Q000276:immunology*; D015687:Cell Hypoxia; D002465:Cell Movement; D003713:Dendritic Cells; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis*; D009593:Nitroimidazoles / Q000494:pharmacology*; D011836:Radiation Tolerance; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology*
C115855:2-nitroimidazole acetamide; D009593:Nitroimidazoles; D009569:Nitric Oxide