Procaspase 3 activator compounds combined with X-ray irradiation

我们已经从我们在伊利诺伊大学的合作者那里获得了两个proaspase 3激活剂(Pac-1和Spc-1)，并获得了一组细胞株，在其上测试化合物在有无X射线照射的情况下。对一些癌细胞的实验表明，S-Pac-1在所有被测试的细胞系中都是一种有效的辐射增敏剂。对乳腺癌细胞的辐射增敏作用最强，当S-PAC-1加入到细胞中时，辐射剂量增加了30%。我们已经证明，这些影响与处理细胞中双链DNA断裂的增加以及这些断裂的修复速度较慢有关。对死亡机制的实验表明，在S-PAC-1和电离辐射处理后，细胞实际上出人意料地没有以凋亡为主。事实上，细胞确实会因有丝分裂灾难而死亡，这是辐射诱导的细胞死亡的典型现象。确定S-PAC-1如何通过辐射影响更大的细胞杀伤率的实验表明，S-PAC-1具有一种以前未知的抑制DNA修复机制的作用。验证性实验正在进行中。S-PAC-1的辐射效应也正在小鼠异种移植瘤模型中进行测试。我们已经开始准备这些结果以供发表。

We have obtained two procaspase 3 activators (PAC-1 and sPAC-1) from our collaborators at the University of Illinois, and have obtained a panel of cell lines on which to test the compounds with and without X-irradiation.Experiments with a number of carcinoma cell lines have shown that S-PAC-1 is a potent radiation sensitizer in all cell lines tested. The most potent radiation sensitization was in breast cancer cell lines, where a 30% enhancement of radiation dose was achieved when S-PAC-1 was added to cells. We have demonstrated that these effects correlate with increased presence of double stranded DNA breaks in treated cells, and with slower repair of these breaks. Experiments on the mechanism of death suggest that cells in fact surprisingly do not die predominantly by apoptosis after treatment with S-PAC-1 and ionizing radition. In fact, cells do die at higher numbers by mitotic catastrophe, as is typical for radiation-induced cell death. Experiments to determine how S-PAC-1 is effecting greater cell killing by radiation suggest that S-PAC-1 has a previously unknown effect inhibiting the DNA repair machinery. Confirmatory experiments are ongoing. The effects of S-PAC-1 with radiation are also being tested in a mouse xenograft tumor model. We have begun preparing these results for publication.