TY - JOUR
T1 - A Hydrogen Peroxide Activatable Gemcitabine Prodrug for the Selective Treatment of Pancreatic Ductal Adenocarcinoma
AU - Matsushita, Katsunori
AU - Okuda, Takumi
AU - Mori, Shohei
AU - Konno, Masamitsu
AU - Eguchi, Hidetoshi
AU - Asai, Ayumu
AU - Koseki, Jun
AU - Iwagami, Yoshifumi
AU - Yamada, Daisaku
AU - Akita, Hirofumi
AU - Asaoka, Tadafumi
AU - Noda, Takehiro
AU - Kawamoto, Koichi
AU - Gotoh, Kunihito
AU - Kobayashi, Shogo
AU - Kasahara, Yuuya
AU - Morihiro, Kunihiko
AU - Satoh, Taroh
AU - Doki, Yuichiro
AU - Mori, Masaki
AU - Ishii, Hideshi
AU - Obika, Satoshi
N1 - Funding Information:
This work received financial support from grants-in-aid for Scientific Research from the Japan Agency for Medical Research and Development (AMED) (18ck0106372h0002 (to M. Mori)); from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), and the Japan Society for the Promotion of Science (JSPS) (KAKENHI grant nos. 17H04282 (to H. Ishii), 17K19698 (to H. Ishii), 16K15615 (to M. Konno), and 15H05791 (to M. Mori)); from the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research) (BINDS) from the AMED (JP18am0101084), and the Basic Science and Platform Technology Program for Innovative Biological Medicine from the AMED (JP18am0301004) (to S. Obika). S. Mori is grateful for a Research Fellowship for Young Scientists from JSPS. Institutional endowments were received by Y.D., M.M., and H.I. from Taiho Pharmaceutical Co. Ltd., Unitech Co. Ltd. (Chiba, Japan), IDEA Consultants Inc. (Tokyo, Japan), and Kinshu-kai Medical Corporation (Osaka, Japan), and by Y.D., M.M., T.S. from Chugai Co. Ltd., Yakult Honsha Co. Ltd., and Merck Co. Ltd. Sponsors had no role in the study design or performance, data collection, management, or interpretation, or article preparation and approval.
Publisher Copyright:
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2019/8/6
Y1 - 2019/8/6
N2 - The main concern in the use of anticancer chemotherapeutic drugs is host toxicity. Patients need to interrupt or change chemotherapy due to adverse effects. In this study, we aimed to decrease adverse events with gemcitabine (GEM) in the treatment of pancreatic ductal adenocarcinoma and focused on the difference of hydrogen peroxide levels in normal versus cancer cells. We designed and synthesized a novel boronate-ester-caged prodrug that is activated by the high H2O2 concentrations found in cancer cells to release GEM. An H2O2-activatable GEM (A-GEM) has higher selectivity for H2O2 over other reactive oxygen species (ROS) and cytotoxic effects corresponding to the H2O2 concentration in vitro. A xenograft model of immunodeficient mice indicated that the effect of A-GEM was not inferior to that of GEM when administered in vivo. In particular, myelosuppression was significantly decreased following A-GEM treatment compared with that following GEM treatment.
AB - The main concern in the use of anticancer chemotherapeutic drugs is host toxicity. Patients need to interrupt or change chemotherapy due to adverse effects. In this study, we aimed to decrease adverse events with gemcitabine (GEM) in the treatment of pancreatic ductal adenocarcinoma and focused on the difference of hydrogen peroxide levels in normal versus cancer cells. We designed and synthesized a novel boronate-ester-caged prodrug that is activated by the high H2O2 concentrations found in cancer cells to release GEM. An H2O2-activatable GEM (A-GEM) has higher selectivity for H2O2 over other reactive oxygen species (ROS) and cytotoxic effects corresponding to the H2O2 concentration in vitro. A xenograft model of immunodeficient mice indicated that the effect of A-GEM was not inferior to that of GEM when administered in vivo. In particular, myelosuppression was significantly decreased following A-GEM treatment compared with that following GEM treatment.
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U2 - 10.1002/cmdc.201900324
DO - 10.1002/cmdc.201900324
M3 - Article
C2 - 31207139
AN - SCOPUS:85068526695
SN - 1860-7179
VL - 14
SP - 1384
EP - 1391
JO - ChemMedChem
JF - ChemMedChem
IS - 15
ER -
