Masitinib combined with standard gemcitabine chemotherapy: in vitro and in vivo studies in human pancreatic tumour cell lines and ectopic mouse model.
Masitinib combined with standard gemcitabine chemotherapy: in vitro and in vivo studies in human pancreatic tumour cell lines and ectopic mouse model.
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DOI：
10.1371/journal.pone.0009430
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发表时间：
2010-03-04
期刊：
影响因子：
3.7
通讯作者：
Dubreuil P
中科院分区：
文献类型：
--
作者：
Humbert M;Castéran N;Letard S;Hanssens K;Iovanna J;Finetti P;Bertucci F;Bader T;Mansfield CD;Moussy A;Hermine O;Dubreuil P
酪氨酸激酶是胰腺癌治疗的有吸引力的靶点，因为几种酪氨酸激酶过度表达，包括PDGFRα/β、FAK、Src和林恩。肥大细胞在胰腺癌的发展中也有重要作用的报道。马赛替尼是一种酪氨酸激酶抑制剂，选择性靶向c-Kit、PDGFRα/β、林恩，并在较小程度上靶向FAK通路，而不抑制已知毒性的激酶。马赛替尼在控制肥大细胞的增殖、分化和脱粒方面特别有效。本研究评估了马赛替尼作为单一药物和与吉西他滨联合治疗胰腺癌的治疗潜力。在体外对人胰腺肿瘤细胞系进行了概念验证研究，然后使用人胰腺癌小鼠模型进行了体内研究。通过基因表达谱研究分子机制。马赛替尼作为单一药剂没有显著的抗增殖活性，而马赛替尼/吉西他滨组合在体外对吉西他滨难治性细胞系Mia Paca 2和Pancl的增殖显示出协同作用，并且在体内对Mia Paca 2细胞肿瘤生长显示出较小程度的协同作用。具体地，10 μM的马赛替尼使Mia Paca 2细胞对吉西他滨强烈敏感（IC 50降低>400倍）;并且使Pancl细胞中度敏感（降低10倍）。转录分析鉴定了Wnt/β-连环蛋白信号传导途径在通过马赛替尼/吉西他滨组合再致敏的细胞系中下调。这些数据建立了马赛替尼可以使吉西他滨难治性胰腺癌细胞系敏感的概念验证，并保证了进一步的体内研究。事实上，最近在接受马赛替尼/吉西他滨组合的胰腺癌患者的2期临床研究中观察到了这种效果。
Tyrosine kinases are attractive targets for pancreatic cancer therapy because several are over-expressed, including PDGFRα/β, FAK, Src and Lyn. A critical role of mast cells in the development of pancreatic cancer has also been reported. Masitinib is a tyrosine kinase inhibitor that selectively targets c-Kit, PDGFRα/β, Lyn, and to a lesser extent the FAK pathway, without inhibiting kinases of known toxicities. Masitinib is particularly efficient in controlling the proliferation, differentiation and degranulation of mast cells. This study evaluates the therapeutic potential of masitinib in pancreatic cancer, as a single agent and in combination with gemcitabine. Proof-of-concept studies were performed in vitro on human pancreatic tumour cell lines and then in vivo using a mouse model of human pancreatic cancer. Molecular mechanisms were investigated via gene expression profiling. Masitinib as a single agent had no significant antiproliferative activity while the masitinib/gemcitabine combination showed synergy in vitro on proliferation of gemcitabine-refractory cell lines Mia Paca2 and Panc1, and to a lesser extent in vivo on Mia Paca2 cell tumour growth. Specifically, masitinib at 10 µM strongly sensitised Mia Paca2 cells to gemcitabine (>400-fold reduction in IC50); and moderately sensitised Panc1 cells (10-fold reduction). Transcriptional analysis identified the Wnt/β-catenin signalling pathway as down-regulated in the cell lines resensitised by the masitinib/gemcitabine combination. These data establish proof-of-concept that masitinib can sensitise gemcitabine-refractory pancreatic cancer cell lines and warrant further in vivo investigation. Indeed, such an effect has been recently observed in a phase 2 clinical study of patients with pancreatic cancer who received a masitinib/gemcitabine combination.
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影响因子：
4.9
作者：
Tebib J;Mariette X;Bourgeois P;Flipo RM;Gaudin P;Le Loët X;Gineste P;Guy L;Mansfield CD;Moussy A;Dubreuil P;Hermine O;Sibilia J
通讯作者：
Sibilia J
影响因子：
3.4
作者：
Esposito, I;Menicagli, M;Campani, D
通讯作者：
Campani, D
影响因子：
45.3
作者：
Moore, Malcolm J.;Goldstein, David;Parulekar, Wendy
通讯作者：
Parulekar, Wendy
影响因子：
2.1
作者：
Irizarry, RA;Hobbs, B;Speed, TP
通讯作者：
Speed, TP
系统的综述，包括荟萃分析，使用辐射/组合式疗法对局部晚期胰腺癌进行管理。
影响因子：
8.8
作者：
Sultana, A.;Smith, C. Tudur;Cunningham, D.;Starling, N.;Tait, D.;Neoptolemos, J. P.;Ghaneh, P.
通讯作者：
Ghaneh, P.