Interleukin-6: a potential biomarker of resistance to multitargeted receptor tyrosine kinase inhibitors in castration-resistant prostate cancer.
Interleukin-6: a potential biomarker of resistance to multitargeted receptor tyrosine kinase inhibitors in castration-resistant prostate cancer.
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白介素-6：对耐castration耐药的前列腺癌中多核受体酪氨酸激酶抑制剂抗性的潜在生物标志物。
DOI：
10.1016/j.urology.2011.07.1384
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发表时间：
2011-10
期刊：
影响因子：
2.1
通讯作者：
Kolenko VM
中科院分区：
文献类型：
--
作者：
Kutikov A;Makhov P;Golovine K;Canter DJ;Sirohi M;Street R;Simhan J;Uzzo RG;Kolenko VM
在去势抵抗性前列腺癌（CRPC）患者中使用酪氨酸激酶抑制剂（TKIs）的临床经验开始成熟。在II期试验中，已注意到对舒尼替尼的非均匀反应。血清PSA水平的变化已被证明是不可靠的预测CRPC对TKIs的反应。IL-6是前列腺癌发病机制的关键介质，已被证明在疾病进展的患者中升高。我们研究了细胞IL-6的产生是否可以在体外和体内模型中预测TKI反应。分别采用RT-PCR和ELISA检测各组IL-6 mRNA水平和蛋白表达。TUNEL法检测细胞凋亡。在体内研究中，采用C.B17/Icr-scid小鼠的CRPC异种移植模型。PC-3和DU-145 CRPC细胞系对舒尼替尼和帕唑帕尼表现出异质反应。在tki敏感的DU-145细胞中观察到IL-6的剂量依赖性降低。相比之下，耐tki的PC-3细胞未能抑制IL-6的分泌。相反，在TNF-α存在的情况下，给予TKIs后IL-6显著升高。体外实验结果在CRPC小鼠体内模型中得到证实。CRPC细胞对TKIs的敏感性是不均匀的。这些发现与最近发表的使用舒尼替治疗CRPC患者的II期临床试验结果一致。在体外和体内实验中，耐药PC-3细胞中存在tki时，IL-6均显著升高，但在tki敏感的DU-145细胞中没有。这些发现表明，IL-6可能是CRPC患者TKI耐药的生物标志物。
Clinical experience using tyrosine kinase inhibitors (TKIs) in patients with castration-resistant prostate cancer (CRPC) is starting to mature. In Phase II trials, a heterogeneous response to sunitinib has been noted. Change in serum PSA level has proven unreliable for prediction of CRPC response to TKIs. IL-6, a critical mediator of prostate cancer pathogenesis, has been shown to rise in patients with disease progression. We investigated whether cellular IL-6 production can predict TKI response in both in-vitro and in-vivo models. IL-6 mRNA levels and protein expression were examined by RT-PCR and ELISA, respectively. Apoptosis was examined using the TUNEL assay. For in-vivo studies, a CRPC xenograft model in C.B17/Icr-scid mice was employed. PC-3 and DU-145 CRPC cell lines exhibited a heterogeneous response to sunitinib and pazopanib. Dose dependent reduction of IL-6 was observed in TKI-sensitive DU-145 cells. In contrast, the TKI-resistant PC-3 cells failed to suppress IL-6 secretion. Instead, in the presence of TNF-α, IL-6 rose significantly upon administration of TKIs. Findings of in-vitro experiments were confirmed in an in-vivo mouse model of CRPC. Sensitivity of CRPC cells to TKIs is heterogeneous. These findings are consistent with results of recently-published Phase II clinical trials using sunitinib in patients with CRPC. A substantial rise in IL-6 occurs both in-vitro and in-vivo in the presence of TKIs in resistant PC-3 cells but not in TKI-sensitive DU-145 cells. These findings suggest that IL-6 may represent a biomarker for TKI resistance in patients with CRPC.
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影响因子：
254.7
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Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
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