Noriyuki Hayashi1, Hiromi Kataoka2, Shigenobu Yano3,4, Jun-Ichi Kikuchi3, Mamoru Tanaka1, Hirotada Nishie1, Yuma Kinoshita5, Miki Hatano5, Akihiro Nomoto5, Akiya Ogawa5, Masahiro Inoue6, Tsutomu Mizoshita1, Takaya Shimura1, Yoshinori Mori1, Eiji Kubota1, Satoshi Tanida1, Takashi Joh1. 1. Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. 2. Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan hkataoka@med.nagoya-cu.ac.jp. 3. Graduate School of Materials Science, Nara Institute of Science and Technology, Nara, Japan. 4. Office of Society-Academia Collaboration for Innovation, Kyoto University, Kyoto, Japan. 5. Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, Osaka, Japan. 6. Department of Biochemistry, Osaka Medical Centre for Cancer and Cardiovascular Diseases, Osaka, Japan.
Abstract
BACKGROUND/AIM: Resistance against cisplatin is a problem for the success of gastric cancer chemotherapy. Herein, we evaluated the antitumor effect of a new aminosugar-conjugated, mono-functional platinum complex (Pt-Oqn), which forms a single covalent bond with DNA. MATERIALS AND METHODS: We compared the cytotoxicity of Pt-Oqn to that of cisplatin (CDDP), oxaliplatin (L-OHP) and carboplatin (CBDCA). We also compared Pt-Oqn and cisplatin for DNA double-strand breaks based on phosphorylated histone H2AX levels in cancer cells and antitumor effects in xenograft models. RESULTS: The resistance factor (RF) for Pt-Oqn was low among the four drugs, indicating the potential of Pt-Oqn for overcoming CDDP-induced resistance. In MKN45-R cells, γ-H2AX protein increased following treatment with Pt-Oqn, but not with cisplatin. Finally, Pt-Oqn, but not cisplatin, showed significant antitumor effects in MKN45-R xenografts. CONCLUSION: This new aminosugar-conjugated platinum complex is a promising candidate agent for overcoming the drug resistance of cisplatin-resistant stomach cancer. Copyright
BACKGROUND/AIM: Resistance against cisplatin is a problem for the success of gastric cancer chemotherapy. Herein, we evaluated the antitumor effect of a new aminosugar-conjugated, mono-functional platinum complex (Pt-Oqn), which forms a single covalent bond with DNA. MATERIALS AND METHODS: We compared the cytotoxicity of Pt-Oqn to that of cisplatin (CDDP), oxaliplatin (L-OHP) and carboplatin (CBDCA). We also compared Pt-Oqn and cisplatin for DNA double-strand breaks based on phosphorylated histone H2AX levels in cancer cells and antitumor effects in xenograft models. RESULTS: The resistance factor (RF) for Pt-Oqn was low among the four drugs, indicating the potential of Pt-Oqn for overcoming CDDP-induced resistance. In MKN45-R cells, γ-H2AX protein increased following treatment with Pt-Oqn, but not with cisplatin. Finally, Pt-Oqn, but not cisplatin, showed significant antitumor effects in MKN45-R xenografts. CONCLUSION: This new aminosugar-conjugated platinum complex is a promising candidate agent for overcoming the drug resistance of cisplatin-resistant stomach cancer. Copyright