Department of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599, USA.
Radiother Oncol. 2011 Mar;98(3):394-9. doi: 10.1016/j.radonc.2010.12.017. Epub 2011 Feb 4.
To assess the relative radiosensitivities of a large collection of melanoma cell lines and to determine whether pharmacologic inhibition of mutant B-RAF with PLX-4032 can radiosensitize B-Raf+ melanoma cells.
A large collection of melanoma cell lines (n=37) were treated with 0-8Gy IR and clonogenic survival assays used to generate survival curves to rank relative radiosensitivities among the cell lines. The ability of a B-RAF inhibitor, PLX-4032, to radiosensitize highly radioresistant B-Raf+ cells was also assessed by clonogenic cell survival and spheroid invasion assays and the effects of treatment on the cell cycle assessed by FACS.
Melanoma cell lines displayed a very large, heterogeneous range of SF2 values (1.002-0.053) with a mean of 0.51. Cell lines with surviving fractions of 0.29 or less at SF2 and SF4 were observed at a high frequency of 18.9% and 70.2%, respectively. Treatment of B-Raf+ cells with the B-RAF inhibitor PLX-4032 in combination with radiation provided enhanced inhibition of both colony formation and invasion, and radiosensitized cells through an increase in G(1) arrest.
Our data suggest that melanomas are not uniformly radioresistant with a significant subset displaying inherent radiosensitivity. Pharmacologic inhibition of B-RAF with PLX-4032 effectively radiosensitized B-Raf+ melanoma cells suggesting that this combination approach could provide improved radiotherapeutic response in B-Raf+ melanoma patients.
评估大量黑素瘤细胞系的相对放射敏感性，并确定抑制突变型 B-RAF 的药理学抑制剂 PLX-4032 是否能增敏 B-Raf+黑素瘤细胞的放射敏感性。
用 0-8GyIR 处理了一组大的黑素瘤细胞系（n=37），并用克隆形成存活实验来生成存活曲线，以对细胞系之间的相对放射敏感性进行排序。还通过克隆形成细胞存活和球体侵袭实验评估了 B-RAF 抑制剂 PLX-4032 增敏高度耐辐射的 B-Raf+细胞的能力，并通过 FACS 评估了处理对细胞周期的影响。
黑素瘤细胞系显示出非常大的、异质性的 SF2 值范围（1.002-0.053），平均值为 0.51。SF2 和 SF4 存活分数为 0.29 或更低的细胞系的频率分别为 18.9%和 70.2%。用 B-RAF 抑制剂 PLX-4032 联合辐射处理 B-Raf+细胞，可同时增强对集落形成和侵袭的抑制作用，并通过增加 G1 期阻滞来增敏细胞。
我们的数据表明，黑素瘤并不是均匀的耐辐射，相当一部分显示出固有放射敏感性。用 PLX-4032 抑制 B-RAF 的药理学作用可有效地增敏 B-Raf+黑素瘤细胞，这表明这种联合治疗方法可能会改善 B-Raf+黑素瘤患者的放射治疗反应。
