- 著者
- Hidenori Ando Sherif E. Emam Yoshino Kawaguchi Taro Shimizu Yu Ishima Kiyoshi Eshima Tatsuhiro Ishida
- 出版者
- The Pharmaceutical Society of Japan
- 雑誌
- Biological and Pharmaceutical Bulletin (ISSN:09186158)
- 巻号頁・発行日
- vol.44, no.6, pp.844-852, 2021-06-01 (Released:2021-06-01)
- 参考文献数
- 45
- 被引用文献数
- 10
Acidic extracellular pH (pHe) is characteristic of the tumor microenvironment. Several reports suggest that increasing pHe improves the response of immune checkpoint inhibitors in murine models. To increase pHe, either sodium bicarbonate (NaHCO3) or citric acid/potassium-sodium citrate (KNa-cit) was chronically administered to mice. It is hypothesized that bicarbonate ions (HCO3−), produced from these alkalinizing agents in vivo, increased pHe in the tumor, and excess HCO3− eliminated into urine increased urinary pH values. However, there is little published information on the effect of changing serum HCO3− concentrations, urinary HCO3− concentrations and urinary pH values on the therapeutic outcomes of immunotherapy. In this study, we report that oral administration of either NaHCO3 or KNa-cit increased responses to anti-programmed cell death-1 (PD-1) antibody, an immune checkpoint inhibitor, in a murine B16 melanoma model. In addition, we report that daily oral administration of an alkalinizing agent increased blood HCO3− concentrations, corresponding to increasing the tumor pHe. Serum HCO3− concentrations also correlated with urinary HCO3− concentrations and urinary pH values. There was a clear relationship between urinary pH values and the antitumor effects of immunotherapy with anti-PD-1 antibody. Our results imply that blood HCO3− concentrations, corresponding to tumor pHe and urinary pH values, may be important factors that predict the clinical outcomes of an immunotherapeutic agent, when combined with alkalinizing agents such as NaHCO3 and KNa-cit.
- 著者
- Hidenori Ando Kiyoshi Eshima Tatsuhiro Ishida
- 出版者
- The Pharmaceutical Society of Japan
- 雑誌
- Biological and Pharmaceutical Bulletin (ISSN:09186158)
- 巻号頁・発行日
- vol.44, no.2, pp.266-270, 2021-02-01 (Released:2021-02-01)
- 参考文献数
- 29
- 被引用文献数
- 13
Extracellular pH (pHe) of tumor cells is characteristic of tumor microenvironment (TME). Acidic TME impairs the responses of tumors to some anti-cancer chemotherapies. In this study, we showed that daily oral dosing of sodium potassium citrate (K/Na citrate) increased blood HCO3− concentrations, corresponding to increase of HCO3− concentrations and pHs in urine, and neutralized the tumor pHe. Neutralization of acidic TME by alkaline substance like HCO3−, an active metabolite of K/Na citrate, well potentiated the therapeutic effect of anticancer agent TS-1®, an orally active 5-fuluoro-uracil derivative, in Panc-1 pancreatic cancer-xenograft murine model. Neutralization of acidic TME by using an alkaline K/Na citrate is a smart approach for enhancement of the therapeutic effects of anticancer agents for pancreatic cancer in the end stage.