A novel approach in the treatment of neuroendocrine gastrointestinal tumors: Additive antiproliferative effects of interferon-γ and meta-iodobenzylguanidine
A novel approach in the treatment of neuroendocrine gastrointestinal tumors: Additive antiproliferative effects of interferon-γ and meta-iodobenzylguanidine
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治疗神经内分泌胃肠道肿瘤的新方法：干扰素-γ和间碘苄胍的叠加抗增殖作用
作者：
M. Höpfner;A. Sutter;A. Huether;G. Ahnert;H. Scherübl
背景有效抑制神经内分泌胃肠肿瘤生长和扩散的治疗选择仍然有限。由于间碘苄胍（MIBG）和干扰素-γ（IFNγ）都会对神经内分泌胃肠道肿瘤细胞产生抗肿瘤作用，我们研究了IFNγ和非放射性标记的MIBG联合对神经内分泌肠道STC-1和胰腺类癌BON肿瘤细胞的抗增殖作用。方法和结果两种模型中均表达IFNγ受体。 IFNγ剂量和时间依赖性地抑制STC-1和BON肿瘤细胞的生长，IC50值分别为95±15U/ml和135±10U/ml。超过 10 U/ml 的 IFNγ 在任一细胞系中以时间依赖性方式诱导凋亡特异性 caspase-3 活性，并引起细胞周期 S 期的剂量依赖性停滞。此外，IFNγ在NE肿瘤细胞中诱导细胞毒作用。NE肿瘤靶向药物MIBG通过去甲肾上腺素转运蛋白选择性摄取，从而特异性抑制NE肿瘤细胞的生长。有趣的是，通过半定量 RT-PCR 测定，IFNγ 治疗诱导神经内分泌肿瘤细胞中去甲肾上腺素转运蛋白表达上调。联合使用亚IC50浓度的IFNγ和MIBG会产生附加的生长抑制作用，这主要是由于细胞毒性增加和细胞周期S期阻滞。结论我们的数据表明，IFNγ通过诱导细胞周期阻滞、细胞凋亡和细胞毒性对神经内分泌胃肠道肿瘤细胞发挥抗增殖作用。 IFNγ 与 NE 肿瘤靶向药物 MIBG 的组合可在减少任一药物剂量的情况下有效控制生长。因此，单独使用 IFNγ，尤其是与 MIBG 联合使用，是治疗神经内分泌胃肠肿瘤的一种有前途的新方法。
BackgroundTherapeutic options to effectively inhibit growth and spread of neuroendocrine gastrointestinal tumors are still limited. As both meta-iodobenzylguanidine (MIBG) and interferon-γ (IFNγ) cause antineoplastic effects in neuroendocrine gastrointestinal tumor cells, we investigated the antiproliferative effects of the combination of IFNγ and non-radiolabeled MIBG in neuroendocrine gut STC-1 and pancreatic carcinoid BON tumor cells.Methods and resultsIFNγ receptors were expressed in both models. IFNγ dose- and time-dependently inhibited the growth of both STC-1 and of BON tumor cells with IC50-values of 95 ± 15 U/ml and 135 ± 10 U/ml, respectively. Above 10 U/ml IFNγ induced apoptosis-specific caspase-3 activity in a time-dependent manner in either cell line and caused a dose-dependent arrest in the S-phase of the cell cycle. Furthermore, IFNγ induced cytotoxic effects in NE tumor cells.The NE tumor-targeted drug MIBG is selectively taken up via norepinephrine transporters, thereby specifically inhibiting growth in NE tumor cells. Intriguingly, IFNγ treatment induced an upregulation of norepinephrine transporter expression in neuroendocrine tumors cells, as determined by semi-quantitative RT-PCR. Co-application of sub-IC50 concentrations of IFNγ and MIBG led to additive growth inhibitory effects, which were mainly due to increased cytotoxicity and S-phase arrest of the cell cycle.ConclusionOur data show that IFNγ exerts antiproliferative effects on neuroendocrine gastrointestinal tumor cells by inducing cell cycle arrest, apoptosis and cytotoxicity. The combination of IFNγ with the NE tumor-targeted agent MIBG leads to effective growth control at reduced doses of either drug. Thus, the administration of IFNγ alone and more so, in combination with MIBG, is a promising novel approach in the treatment of neuroendocrine gastrointestinal tumors.
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影响因子：
8.3
作者：
Horiuchi, M;Yamada, H;Dzau, VJ
通讯作者：
Dzau, VJ
干扰素治疗对 14 种人结直肠癌细胞系的影响：体外生长和癌胚抗原分泌。
DOI：
10.1089/jir.1990.10.579
发表时间：
1990
期刊：
Journal of interferon research
影响因子：
--
作者：
Toth,CA;Thomas,P
通讯作者：
Thomas,P
影响因子：
2.3
作者：
Yim, JH;Ro, SH;Doherty, GM
通讯作者：
Doherty, GM
人类同种异体反应性 CTL 与神经胶质瘤和那些因外源 IFN-γ 或 IFN-γ 基因修饰而上调 HLA 表达的细胞相互作用。
DOI：
10.1089/107999003322226032
发表时间：
2003
期刊：
Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research
影响因子：
--
作者：
Read,SusanaB;Kulprathipanja,NishaV;Gomez,GermanG;Paul,DavidB;Winston,KenR;Robbins,JoanM;Kruse,CarolA
通讯作者：
Kruse,CarolA