Triple-Methyl Blockade with Recombinant Methioninase, Cycloleucine, and Azacitidine Arrests a Pancreatic Cancer Patient-Derived Orthotopic Xenograft Model

Norihiko Sugisawa, Jun Yamamoto, Qinghong Han, Yuying Tan, Yoshihiko Tashiro, Hiroto Nishino, Sachiko Inubushi, Kazuyuki Hamada, Kei Kawaguchi, Michiaki Unno, Michael Bouvet, Robert M. Hoffman

研究成果: Article査読

4 被引用数 (Scopus)

抄録

Objectives Methionine addiction is a fundamental and general hallmark of cancer caused by enhanced methyl flux. In the present study, we effected a novel methionine-methylation blockade to target a patient-derived orthotopic xenograft model of pancreatic cancer. Methods The pancreatic cancer patient-derived orthotopic xenograft mouse models were randomized into 6 groups of 8 mice each and treated for 2 weeks: untreated control; azacitidine; oral recombinant methioninase (o-rMETase); o-rMETase plus cycloleucine; o-rMETase plus cycloleucine plus azacitidine (triple-methyl blockade therapy); and gemcitabine (positive control). Results Triple-methyl blockade therapy arrested tumor growth (mean relative tumor volume, 1.03 [standard deviation, 0.36]) and was significantly more effective compared with azacitidine (P = 0.0001); o-rMETase (P = 0.007); or o-rMETase plus cycloleucine (P = 0.04). Gemcitabine alone also inhibited but did not arrest tumor growth (mean relative tumor volume, 1.50 [standard deviation, 0.30]). The percentage of cancer cells that were negative for 5-methylcytosine staining in immunohistochemistry, indicating reduction of DNA methylation, increased with triple-methyl blockade therapy (37.5%), compared with gemcitabine (1.8%); o-rMETase (2.8%); azacitidine (9.0%); or o-rMETase plus cycloleucine (10.6%). Conclusions This new concept of triple-methyl blockade therapy has clinical potential for pancreatic cancer, which is currently a recalcitrant disease.

本文言語English
ページ(範囲)93-98
ページ数6
ジャーナルPancreas
50
1
DOI
出版ステータスPublished - 2021

ASJC Scopus subject areas

  • 内科学
  • 内分泌学、糖尿病および代謝内科学
  • 肝臓学
  • 内分泌学

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