Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
Urology. 2011 Oct;78(4):968.e7-11. doi: 10.1016/j.urology.2011.07.1384.
To determine if cellular interleukin-6 production predicts response to tyrosine kinase inhibitors (TKIs). As clinical experience using TKIs in patients with castration-resistant prostate cancer (CRPC) matures, Phase II trials show a heterogeneous response to sunitinib in CRPC patients. Change in serum prostate-specific antigen (PSA) level has proven unreliable for prediction of CRPC response to TKIs. Interleukin-6 (IL-6), a critical mediator of prostate cancer pathogenesis, has been shown to rise in patients with disease progression. As such, 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 reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Apoptosis was examined using the terminal dUTP nick-end labeling assay. For in vivo studies, a CRPC xenograft model in C.B17/Icr-scid mice was used.
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 tumor necrosis factor-alpha, 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.
确定细胞白细胞介素-6（IL-6）的产生是否可以预测酪氨酸激酶抑制剂（TKI）的反应。随着临床应用 TKI 治疗去势抵抗性前列腺癌（CRPC）经验的成熟，II 期临床试验显示，舒尼替尼在 CRPC 患者中的反应存在异质性。血清前列腺特异性抗原（PSA）水平的变化已被证明不能可靠地预测 TKI 治疗 CRPC 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。因此，我们研究了细胞 IL-6 产生是否可以在体外和体内模型中预测 TKI 反应。
通过逆转录聚合酶链反应和酶联免疫吸附试验分别检测 IL-6 mRNA 水平和蛋白表达。使用末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记法检测细胞凋亡。对于体内研究，使用 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性反应。在 TKI 敏感的 DU-145 细胞中观察到 IL-6 呈剂量依赖性减少。相比之下，TKI 耐药的 PC-3 细胞未能抑制 IL-6 的分泌。相反，在肿瘤坏死因子-α存在的情况下，给予 TKI 后 IL-6 显著升高。体外实验结果在 CRPC 的体内小鼠模型中得到证实。
CRPC 细胞对 TKI 的敏感性存在异质性。这些发现与最近发表的使用舒尼替尼治疗 CRPC 患者的 II 期临床试验结果一致。在耐药的 PC-3 细胞中，TKI 存在时，无论是在体外还是体内，IL-6 均显著升高，但在 TKI 敏感的 DU-145 细胞中则不会。这些发现表明，IL-6 可能是 CRPC 患者 TKI 耐药的生物标志物。
