Department of Experimental Radiation Oncology, The University of Texas M, D, Anderson Cancer Center, Houston, TX, USA.
Radiat Oncol. 2012 Sep 11;7:154. doi: 10.1186/1748-717X-7-154.
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.
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，这与其他肿瘤中放射治疗抵抗和预后不良有关。因此，通过使用这些异常激活途径的抑制剂，有可能改善对辐射的反应。我们研究了舒尼替尼（一种有效的 VEGFR 和 PDGFR 受体多酪氨酸激酶抑制剂）对人前列腺癌细胞的放射增敏作用。
通过集落形成试验评估舒尼替尼对人前列腺癌细胞系 DU145、PC3 和 LNCaP 的放射增敏作用。通过免疫印迹分析确定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异种移植物中测试舒尼替尼的放射增敏作用，通过肿瘤生长延迟评估反应。
DU145 和 PC3 细胞的克隆存活曲线分析表明，与对照相比，24 小时 100 nM 舒尼替尼预处理后，2 Gy 时的存活分数分别从 0.70 和 0.52 降低至 0.44 和 0.38。LNCaP 细胞不受舒尼替尼的放射增敏作用。在 DU145 和 PC3 细胞中，也观察到舒尼替尼处理后 VEGFR 和 PDGFR 激活的剂量依赖性降低。我们评估了舒尼替尼在裸鼠后肢生长的 PC3 异种移植肿瘤中放射增敏的能力。舒尼替尼与放射同时给予并未延长肿瘤生长延迟。然而，当动物在分次放射后完成的第一天开始接受舒尼替尼治疗时，与单独放射相比，肿瘤生长延迟得到增强。
基于体内结果，我们得出结论，舒尼替尼和放射在体内没有直接相互作用以放射增敏 PC3 肿瘤细胞，就像它们在体外一样。当放射治疗完成后给予舒尼替尼时肿瘤生长延迟增强的事实表明，舒尼替尼可能作用于辐照的肿瘤基质并抑制其维持辐照肿瘤再生长的能力。基于这些临床前发现，我们建议舒尼替尼和放射联合治疗前列腺癌值得进一步发展。
