Preclinical evaluation of sunitinib, a multi-tyrosine kinase inhibitor, as a radiosensitizer for human prostate cancer.
Preclinical evaluation of sunitinib, a multi-tyrosine kinase inhibitor, as a radiosensitizer for human prostate cancer.
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DOI：
10.1186/1748-717x-7-154
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发表时间：
2012-09-11
期刊：
影响因子：
--
通讯作者：
Meyn R
中科院分区：
文献类型：
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作者：
Brooks C;Sheu T;Bridges K;Mason K;Kuban D;Mathew P;Meyn R
许多前列腺癌表现出生长因子受体如血管内皮生长因子受体(VEGFR)和血小板衍生生长因子受体(PDGFR)的表达增加，这与其他肿瘤对放射治疗的抵抗力增加和预后不良有关。因此，使用这些异常激活的通路的抑制剂可能会改善对辐射的反应。我们研究了舒尼替尼对人前列腺癌细胞的放射增敏作用，舒尼替尼是一种有效的VEGFR和PDGFR受体的多酪氨酸激酶抑制剂。用克隆形成法检测了舒尼替尼对人前列腺癌DU145、PC3和LNCaP细胞的放射增敏作用。免疫印迹法检测舒尼替尼抑制其关键靶点活性的能力。在裸鼠体内生长的人肿瘤移植瘤上测试了舒尼替尼的放射增敏作用，通过肿瘤生长延迟来评估反应。DU145和PC3细胞克隆存活曲线分析显示，100 nM的舒尼替尼作用24小时后，DU145和PC3细胞的存活分数分别从对照组的0.70和0.52降低到0.44和0.38。Sonitinib对LNCaP细胞无放射增敏作用。舒尼替尼对DU145和PC3细胞的VEGFR和PDGFR活性也有剂量依赖性的抑制作用。我们评估了舒尼替尼对生长在裸鼠后肢的PC3移植瘤的放射增敏能力。在放疗的同时给予舒尼替尼并未延长肿瘤生长延迟。然而，当动物在分割放疗完成后第二天开始接受舒尼替尼治疗时，与单独放疗相比，肿瘤生长延迟增强。根据体内实验结果，我们得出结论，在体内，舒尼替尼和辐射并不像在体外那样直接相互作用来增加PC3肿瘤细胞的放射增敏作用。放射治疗结束后给予舒尼替尼后，肿瘤生长延缓增强的事实表明，舒尼替尼可能作用于受照射的肿瘤间质，并抑制其维持受照射肿瘤再生的能力。基于这些临床前研究结果，我们建议联合应用舒尼替尼和放射治疗前列腺癌值得进一步发展。
Many prostate cancers demonstrate an increased expression of growth factor receptors such as vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR) which have been correlated with increased resistance to radiotherapy and poor prognosis in other tumors. Therefore, response to radiation could potentially be improved by using inhibitors of these abnormally activated pathways. We have investigated the radiosensitizing effects of sunitinib, a potent, multi-tyrosine kinase inhibitor of the VEGFR and PDGFR receptors, on human prostate cancer cells. The radiosensitizing effects of sunitinib were assessed on human prostate cancer cell lines DU145, PC3 and LNCaP by clonogenic assay. Sunitinib’s ability to inhibit the activities of its key targets was determined by immunoblot analysis. The radiosensitizing effects of sunitinib in vivo were tested on human tumor xenografts growing in nude mice where response was assessed by tumor growth delay. Clonogenic survival curve assays for both DU145 and PC3 cells showed that the surviving fraction at 2 Gy was reduced from 0.70 and 0.52 in controls to 0.44 and 0.38, respectively, by a 24 hr pretreatment with 100 nM sunitinib. LNCaP cells were not radiosensitized by sunitinib. Dose dependent decreases in VEGFR and PDGFR activation were also observed following sunitinib in both DU145 and PC3 cells. We assessed the ability of sunitinib to radiosensitize PC3 xenograft tumors growing in the hind limb of nude mice. Sunitinib given concurrently with radiation did not prolong tumor growth delay. However, when animals were treated with sunitinib commencing the day after fractionated radiation was complete, tumor growth delay was enhanced compared to radiation alone. We conclude, based on the in vivo results, that sunitinib and radiation do not interact directly to radiosensitize the PC3 tumor cells in vivo as they did in vitro. The fact that tumor growth delay was enhanced when sunitinib was given after radiotherapy was completed suggests that sunitinib may be acting on the irradiated tumor stroma and suppressing its ability to sustain regrowth of the irradiated tumor. Based on these preclinical findings, we suggest that the combination of sunitinib and radiation for the treatment of prostate cancer deserves further development.