从物理学出发探讨癌症治疗新途径：反铂与顺铂联合应用的研究

Cancer is a leading cause of population death in China and worldwide since 2012. Genome instability and defective DNA repair are crucial signatures of cancerous tissue. Cisplatin is the “golden standard” among chemotherapy drugs in clinic. Cisplatin cures testicular cancers successfully. However, due to emerging drug resistance, other types of cancer cannot be cured by cisplatin so far. We previously discovered that cisplatin and transplatin successively linked to DNA to form complex DNA lesions which were reluctant for tumour cells to repair, by single molecular methods to reveal the dynamic process of platinum drugs interacting with DNA molecules. Cisplatin and transplatin co-treatment increased significantly the anti-tumour effect but leaved normal cells largely intact. The co-treatment of cisplatin and transplatin displays similar function profiles as cisplatin curing testicular cancer. Based on these results, we plan to investigate thoroughly the possibility and feasibility of cisplatin and transplatin coordination in animals to cure growing tumours other than testicular tumour and the safety of this method to normal tissues. The molecular mechanisms that tumour cells were killed and normal cells survived safely, as well as the mechanism of lack of drug resistance by co-treatment to enhance cisplatin clinical efficacy, will also be studied in details by combining single molecular methods, cellular biochemistry and medical animal experimental methods. The present study aims to develop a new method and strategy to cancer therapy, which would provide new insights into intervention of genome instability of cancer and functions of DNA repair systems in killing tumour cells. The single molecular, cellular and animal pre-clinical findings from this program would provide new clues for both basic research and clinical applications in cancer chemotherapy.

癌症是目前造成我国和世界人类死亡的首要因素。基因组不稳定性和DNA损伤修复能力下降是癌症发生的重要原因。顺铂是临床上使用最广泛的化疗药物，能成功治愈睾丸癌；但是由于抗药性产生，尚不能治愈其他类型癌症。我们先前通过DNA与铂类药物的单分子动态作用规律研究，发现顺铂和反铂共同作用有效形成DNA复杂铰链，明显增强顺铂的抗癌效果，超越癌细胞修复能力，并且对机体正常细胞没有明显毒性作用。这些现象与“顺铂治愈睾丸癌”机理相似。在此基础上，本项目致力于综合运用单分子、细胞生化和医学实验动物学等研究方法，全面详细研究顺铂反铂联合应用在动物机体内的安全性和杀灭体内肿瘤的有效性，以及对癌细胞杀伤和克服顺铂耐药性的分子机理和正常细胞耐受的修复代谢机理。本研究探讨癌症治疗新方法和策略，对理解癌症基因组不稳定性的可干预性和DNA损伤修复功能在癌症治疗过程中的作用机制等，具有基础研究和临床应用研究的重要参考意义。