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 journalArticle

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
JournalChemMedChem
DOIs
Publication statusPublished - Jan 1 2019

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gemcitabine
Prodrugs
Hydrogen Peroxide
Adenocarcinoma
Air cushion vehicles
Cells
Therapeutics
Chemotherapy
Heterografts
Antineoplastic Agents
Toxicity
Reactive Oxygen Species
Neoplasms
Esters
Drug Therapy

All Science Journal Classification (ASJC) codes

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

Cite this

A Hydrogen Peroxide Activatable Gemcitabine Prodrug for the Selective Treatment of Pancreatic Ductal Adenocarcinoma. / Matsushita, Katsunori; Okuda, Takumi; Mori, Shohei; Konno, Masamitsu; Eguchi, Hidetoshi; Asai, Ayumu; Koseki, Jun; Iwagami, Yoshifumi; Yamada, Daisaku; Akita, Hirofumi; Asaoka, Tadafumi; Noda, Takehiro; Kawamoto, Koichi; Gotoh, Kunihito; Kobayashi, Shogo; Kasahara, Yuuya; Morihiro, Kunihiko; Satoh, Taroh; Doki, Yuichiro; Mori, Masaki; Ishii, Hideshi; Obika, Satoshi.

In: ChemMedChem, 01.01.2019.

Research output: Contribution to journalArticle

Matsushita, K, Okuda, T, Mori, S, Konno, M, Eguchi, H, Asai, A, Koseki, J, Iwagami, Y, Yamada, D, Akita, H, Asaoka, T, Noda, T, Kawamoto, K, Gotoh, K, Kobayashi, S, Kasahara, Y, Morihiro, K, Satoh, T, Doki, Y, Mori, M, Ishii, H & Obika, S 2019, 'A Hydrogen Peroxide Activatable Gemcitabine Prodrug for the Selective Treatment of Pancreatic Ductal Adenocarcinoma', ChemMedChem. https://doi.org/10.1002/cmdc.201900324
Matsushita, Katsunori ; Okuda, Takumi ; Mori, Shohei ; Konno, Masamitsu ; Eguchi, Hidetoshi ; Asai, Ayumu ; Koseki, Jun ; Iwagami, Yoshifumi ; Yamada, Daisaku ; Akita, Hirofumi ; Asaoka, Tadafumi ; Noda, Takehiro ; Kawamoto, Koichi ; Gotoh, Kunihito ; Kobayashi, Shogo ; Kasahara, Yuuya ; Morihiro, Kunihiko ; Satoh, Taroh ; Doki, Yuichiro ; Mori, Masaki ; Ishii, Hideshi ; Obika, Satoshi. / A Hydrogen Peroxide Activatable Gemcitabine Prodrug for the Selective Treatment of Pancreatic Ductal Adenocarcinoma. In: ChemMedChem. 2019.
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AU - Satoh, Taroh

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