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J. L. Flowers, R. M. Hoffman, T. A. Driscoll, M. E. Wall, M. C. Wani, G. Manikumar, H. S. Friedman, M. Dewhirst, O. M. Colvin and D. J. Adams, “The Activity of Camptothecin Analogues Is Enhanced in Histocultures of Human Tumors and Human Tumor Xenografts by Modulation of Extracellular pH,” Cancer Chemotherapy and Pharmacology, Vol. 52, No. 3, 2003, pp. 253-261. doi:10.1007/s00280-003-0635-7

has been cited by the following article:

• TITLE: Bicarbonate Attenuates Irinotecan-Induced Cytotoxicity through Regulation of Both Extracellular and Intracellular pHs in Intestine Cell Line

  AUTHORS: Teruo Miyazaki, Tadashi Ikegami, Yoshiaki Nagai, Amy Nguyen, Yasushi Matsuzaki, Kunihiko Kobayashi, Susan Ceryak

  KEYWORDS: Bicarbonate; SN-38; CPT-11; pHi; Anti-Cancer Drug; Intestine

  JOURNAL NAME: Journal of Cancer Therapy, Vol.4 No.5, June 28, 2013

  ABSTRACT: The anti-cancer therapy of irinotecan (CPT-11) is often limited due to severe late-onset diarrhea. Because the higher toxic form of CPT-11/its active metabolite (SN-38) is produced at acidification, the usefulness of oral sodium bicarbonate treatment against the CPT-11/SN-38-induced intestinal injuries and diarrhea has been confirmed. However, the roles of bicarbonate have been suggested to affect not only intestinal pH environment but also intracellular pH and CPT-11/SN-38 dynamics. The present study proposed to clarify the hypothesis in CPT-11/SN-38-exposed colon cell line in various pH conditions adjusted by bicarbonate. HT29 cell pre-exposed to ~1.0 μM SN-38 lactone or carboxylate forms was incubated at different pH adjusted by either bicarbonate or HCl/NaOH. The degrees of SN-38-induced cell injury depended on the higher proportion of the toxic form (lactone) of SN-38 rather than mere pH condition of medium. Apoptosis and cell injury induced by SN-38 were significantly inhibited by bicarbonate in a dose-dependent manner. Intercellular pH acidification induced by SN-38 was significantly prevented by 30 mM bicarbonate. Cell cytotoxicity of SN-38 depended on not only extracellular but also intracellular pH that converts the SN-38 form, while the intracellular acidification was prevented by bicarbonate. The multiple regulations of bicarbonate on both exracellular and intracellular pH would be essential mechanism against intestinal cell injury by CPT-11/SN-38.