Procaspase 3 activator compounds combined with X-ray irradiation

我们已经从伊利诺伊大学的合作者那里获得了两种procaspase 3激活剂（PAC-1和PAC-1），并获得了一组细胞系，用于在x射线照射和不照射的情况下测试化合物。对许多癌细胞系进行的实验表明，S-PAC-1在所有被测试的细胞系中都是一种有效的辐射致敏剂。最有效的辐射致敏作用是在乳腺癌细胞系中，当S-PAC-1添加到细胞中时，辐射剂量增加了30%。我们已经证明，这些效应与处理细胞中双链DNA断裂的增加有关，并且这些断裂的修复速度较慢。关于死亡机制的实验表明，在S-PAC-1和电离辐射处理后，细胞实际上并不以凋亡为主死亡。事实上，细胞在有丝分裂灾难中死亡的数量确实更高，这是典型的辐射诱导细胞死亡。确定S-PAC-1如何通过辐射影响更大的细胞杀伤的实验表明，S-PAC-1具有先前未知的抑制DNA修复机制的作用。验证性实验正在进行中。S-PAC-1对辐射的影响也在小鼠异种移植肿瘤模型中进行了测试。我们已经开始准备发表这些结果。

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.