Anti-tumor effect of alkylating pyrrole-imidazole polyamide targeting rhabdomyosarcoma specific fusion gene PAX3-FOXO1

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K10930
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatric surgery
• Research Institution: Nihon University
• Principal Investigator: FURUYA Takeshi 日本大学, 医学部, 助教 (20568539)
• Co-Investigator(Kenkyū-buntansha): 杉藤 公信 日本大学, 医学部, 研究医員 (10328750) ; 藤原 恭子 日本大学, 医学部, 助教 (40595708) ; 越永 從道 日本大学, 医学部, 教授 (70205376) ; 植草 省太 日本大学, 医学部, 専修医 (70746338)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 医学 / 臨床外科学 / 小児腫瘍学 / 横紋筋肉腫 / ピロール・イミダゾール・ポリアミド / CBI

Outline of Final Research Achievements

Alveolar rhabdomyosarcoma (ARMS) is one of the typical subtypes of rhabdomyosarcoma (RMS), and is characterized by a frequent chromosomal translocation. This translocation results in the formation of fusion gene including PAX3-FOXO1, which possess tumor promoting functions. In the present study, we have synthesized pyrrole-imidazole polyamides (PIP) recognizing PAX3-FOXO1 fusion site and conjugated them with alkylating agent chlorambucil. That molecule (Rhab-ChB1) could specifically bind to DNA with PAX3-FOXO1 fusion site sequence, but not to negative control DNA. Rhab-ChB1 showed strong growth suppressing effect, not only on fusion gene positive cells, but also on fusion gene negative cells. Flow cytometry analysis elucidated that the treatment with Rhab-ChB 1 provoked G2/M arrest. Since the effective concentration of Rhab-ChB1 was almost 100 times lower than that of ChB itself, Rhab-ChB1 may be developed as a new effective alkylating agent.

Free Research Field

医歯薬学