Genistein与IGF1R抑制剂在前列腺癌中的协同放疗增敏效应及相关机理研究

Radiosensitization is now one of the hot points of prostate cancer(PC) research. Discovery and utilization of synergism of different radiosensitizors is now the new hotpoint of PC therapy. Previously we found that A, inhibition of Insulin-like growth factor receptor(IGF1R) could radiosensitize PC cells to gamma irradiation via inhibition of ATM phosphorylation and thus inhibit DNA damage repair process. B, there is synergism in radiosensitization of genistein and IGF1R inhibitor. It is hypothesized that it is related with the inhibitive effect of DNA topoisomerase by genistein and inhibitive effect of Rad51 foci formation by IGF1R inhibitor. In this project, we planned to expose PC cells to genistein and/or IGF1R inhibitors treatment in vitro and in vivo, and then induce DNA damage by gamma irradiation. After that, we planned to observe whether genistein could act synergistically with IGF1R inhibitors in inhibition of homologous recombination repair of DNA damage, and explore its molecular mechanism from multiple levels, such as IGF1R signal transduction, DNA damage repair process, etc. Our project is expected to provide theoretic foundation for synergistic radiosensitization of genistein and IGF1R inhibitor clinically.

放疗增敏治疗是目前前列腺癌（PC）研究热点之一。利用不同放疗增敏剂的协同效应是肿瘤放疗的新热点。前期研究发现，1、抑制IGF1R可以通过抑制ATM而抑制DNA损伤修复，从而对放疗增敏；但同时将激活其他受体信号途径，减弱其对DNA损伤修复的抑制，增敏效果受到限制。2、Genistein与IGF1R抑制剂在抑制DNA修复方面存在协同效应，我们推测与Genistein对DNA拓扑异构酶的抑制和IGF1R对Rad51的局部富集相关。本研究拟在PC细胞中单独或同时加入genistein和IGF1R抑制剂，而后通过放射介导DNA损伤，研究与单独阻断IGF1R相比，genistein是否可以与IGF1R抑制剂协同抑制DNA损伤修复，增加对放疗的增敏效应。并从IGF1R信号通路、DNA损伤修复过程等多个不同层次阐明此种协同相关机制，从而为临床联合应用genistein和IGF1R抑制剂为PC放疗奠定基础。

放疗增敏治疗是目前前列腺癌（PC）研究热点之一。利用不同放疗增敏剂的协同效应是肿瘤放疗的新热点。前期研究发现，1、抑制IGF1R可以通过抑制ATM而抑制DNA损伤修复，从而对.放疗增敏；但同时将激活其他受体信号途径，减弱其对DNA损伤修复的抑制，增敏效果受到限制。2、Genistein与IGF1R抑制剂在抑制DNA修复方面存在协同效应，我们推测与Genistein对DNA拓扑异构酶的抑制和IGF1R对Rad51的局部富集相关。本研究拟在PC细胞中单独或同时加入genistein和IGF1R抑制剂，而后通过放射介导DNA损伤，研究与单独阻断IGF1R相比，genistein是否可以与IGF1R抑制剂协同抑制DNA损伤修复，增加对放疗的增敏效应。并从IGF1R信号通路、DNA损伤修复过程等多个不同层次阐明此种协同相关机制，从而为临床联合应用genistein和IGF1R抑制剂为PC放疗奠定基础。