Involvement of nitric oxide in anti-tumor effects of OK-432, a streptococcal anti-tumor immunotherapeutic agent.
We examined the role of nitric oxide (NO) induced by OK-432, a streptococcal immunotherapeutic agent, in anti-tumor effects of the OK-432 by in vitro and in vivo experiments using an NO synthase inhibitor, N-monomethyl-l-arginine acetate (NMA). The in vitro treatment of mouse splenocytes with OK-432 increased the expression of inducible NO synthase (iNOS) gene and NO production in a dose-dependent manner. Although it is well known that OK-432 induces cytokines such as interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha, both of which are known to be potent NO inducers, we observed only a partial reduction of OK-432-induced NO production with the addition of anti-IFN-gamma and/or anti-TNF-alpha neutralizing antibodies. The cytotoxicity of the splenocytes increased by in vitro OK-432 stimulation was almost completely inhibited by the treatment with NMA. OK-432 administration resulted in a marked prolongation of survival and a significant inhibition of tumor growth in syngeneic tumor-bearing mice, whereas NMA significantly inhibited the anti-tumor effects of OK-432. Although the increased cytotoxicity of adherent splenocytes derived from OK-432-treated tumor-bearing mice was almost completely inhibited by NMA, only partial inhibition by NMA was observed in the cytotoxicity of the nonadherent splenocytes. These findings strongly suggest that the iNOS/NO induced by OK-432 is intimately involved in the anti-tumor effects of OK-432.
Oshikawa
Tetsuya
T
Second Department of Oral and Maxillofacial Surgery, Tokushima University School of Dentistry, Tokushima, 7708504, Japan.
Okamoto
Masato
M
Tano
Tomoyuki
T
Uddin Ahmed
Sharif
S
Sasai
Akiko
A
Kan
Shin
S
Moriya
Yoichiro
Y
Ryoma
Yoshiki
Y
Saito
Motoo
M
Sato
Mitsunobu
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007114:Immunization; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010844:Picibanil / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013297:Streptococcus pyogenes; D019323:omega-N-Methylarginine
D000970:Antineoplastic Agents; D001120:Arginine; D009566:Nitrates; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites; D010844:Picibanil; D012333:RNA, Messenger; C092506:N(G)-monomethylarginine acetate; D019323:omega-N-Methylarginine