A Hydrogen Peroxide Activatable Gemcitabine Prodrug for the Selective Treatment of Pancreatic Ductal Adenocarcinoma

Katsunori Matsushita, Takumi Okuda, Shohei Mori, Masamitsu Konno, Hidetoshi Eguchi, Ayumu Asai, Jun Koseki, Yoshifumi Iwagami, Daisaku Yamada, Hirofumi Akita, Tadafumi Asaoka, Takehiro Noda, Koichi Kawamoto, Kunihito Gotoh, Shogo Kobayashi, Yuuya Kasahara, Kunihiko Morihiro, Taroh Satoh, Yuichiro Doki, Masaki MoriHideshi Ishii, Satoshi Obika

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1384-1391
Number of pages8
JournalChemMedChem
Volume14
Issue number15
DOIs
Publication statusPublished - 2019

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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