A Study of Farnesyltransferase Inhibitor for the Treatment of Pancreatic Cancer.

法呢基转移酶抑制剂治疗胰腺癌的研究。

• 批准号: 07671290
• 负责人: ASANO Takehide
• 金额: $ 1.54万
• 依托单位: Chiba University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07671290/
• 关键词: Farnesyltransferase inhibitor; Manumycin; Pancreatic cancer; MAPK; Ras; farnesyltransferase inhibitor; manumycin; apoptosis; K-ras

The effects of manumycin, a competitive farnesyltransferase (FTase) inhibitor, on pancreatic cancer cell lines with or without K-ras mutation were studied. Manumycin inhibited the growth of human pancreatic cancer cells (SUIT-2, MIA PaCa-2, AsPC-1, BxPC-3) in a dose-dependent manner. The fifty percent inhibitory concentration (IC_<50>) in cell lines with a mutant K-ras gene (SUIT-2, MIA PaCa-2, AsPC-1) was lower than that in BxPC-3 with a wild-type ras. Both mitogen-activated protein kinase (MAPK) activity after growth stimuli and an ability of chemotactic invasion were markedly inhibited by manumycin in SUIT-2 than in BxPC-3. These results suggest that mutated Ras is more sensitive to manumycin than wild-type. Futhermore, tumor growth and liver metastasis in nude mice inoculated with manumycin-treated SUIT-2 cells were inhibited dose-dependently. Thus, this study provides evidence that Manumycin inhibits growth and invasiveness of human pancreatic cancer cells by inhibition of signal transduction. This result suggests that manumycin is potentially useful for the treatment of pancreatic cancer. Inhibition of Ras activity might be a new anti-cancer strategy in pancreatic cancer in which Ras plays a role.

本文研究了竞争性法尼基转移酶（FTase）抑制剂manumycin对K-ras基因突变的胰腺癌细胞株的作用。Manumycin以剂量依赖性方式抑制人胰腺癌细胞（SUIT-2、MIA PaCa-2、AsPC-1、BxPC-3）的生长。突变<50>型K-ras基因（SUIT-2、MIA PaCa-2、AsPC-1）的半数抑制浓度（IC_（50））低于野生型ras基因的BxPC-3。两个丝裂原活化蛋白激酶（MAPK）的活性后，生长刺激和趋化侵袭的能力显着抑制SUIT-2比BxPC-3的manumycin。这些结果表明突变的Ras比野生型对manumycin更敏感。经manumycin处理的SUIT-2细胞接种裸鼠后，其生长、肝转移和肿瘤生长均受到抑制，并呈剂量依赖性。因此，本研究提供了Manumycin通过抑制信号转导抑制人胰腺癌细胞生长和侵袭的证据。这一结果表明，manumycin是潜在的有用的胰腺癌的治疗。抑制Ras活性可能是一种新的抗胰腺癌策略。

项目成果

Osamu Kainuma, Takehide Asano, Masayuki Hasegawa, and Kaichi Isono: "Growth Inhibition of Human Pancreatic Cancer by Farnesyl Transferase Inhibitor" Jpn J Cancer Chemother. 23. 1657-1659 (1996)

Osamu Kainuma、Takehide Asano、Masayuki Hasekawa 和 Kaichi Isono：“法尼基转移酶抑制剂对人类胰腺癌的生长抑制”Jpn J Cancer Chemother。

貝沼修: "ファルネシア化阻害剤による膵癌治療の可能性" 癌と化学療法. 23. 1657-1659 (1996)

Osamu Kainuma：“用法尼西亚化抑制剂治疗胰腺癌的可能性”《癌症与化疗》23. 1657-1659 (1996)。

貝沼修: "ファルネシル化阻害剤による膵癌治療の可能性" 癌と化学療法. 23. 1657-1659 (1996)

Osamu Kainuma：“用法尼基化抑制剂治疗胰腺癌的可能性”《癌症与化疗》23. 1657-1659 (1996)。