The Synergy Mechanism Of Typical Platinum-based Chemotherapy Drugs With Radiation

Combined chemotherapy and radiotherapy,called chemoradiation therapy(CRT),is a most frequent and standard treatment option for many types of solid tumors,including colon,head and neck,gastric,cervical,bladder and lung.Cisplatin and its platinum(Pt)-based analogues are the most widely used drugs in CRT and have been shown to sensitize cells to radiation.Concomitant treatment with both modalities was sometimes superadditive;i.e.the chemotherapeutic agents acted as radiosensitizers so that tumor regression was accelerated relative to non-synchronized protocols.However,the current protocols are far from optimal and not based on a clear understanding of the mechanism of synergy between cisplatin and radiation.The goal of the present thesis is to determine the mechanisms of synergy between cisplatin and radiation,and the relative importance of each mechanism in radiosensitization,in order to optimize the benefit of CRT with these agents.In our experiments,thin DNA films are irradiated with low-energy electrons(LEE)of 5 and 10 eV,which are produced abundantly by any types of ionizing radiation and play an important role in damage to the genome.Our strategy involves two parallel administrations of cisplatin and LEE radiation to plasmid DNA as biological target:1)the LEE bombardment of DNA and subsequently reaction with cisplatin;2)the reaction with cisplatin followed by the LEE bombardment.The different forms of DNA damages including loss of supercoiled,SSB and DSB were analyzed by agarose gel electrophoresis.Base modification was revealed by treating the samples with E.coli base excision repair endonuclease(Nth and Fpg).The effective yields of various lesions were obtained from the respective dose-response curves.The results show that administration of cisplatin followed by LEE radiation consistently yields more DNA damages compared that of the reverse order.The yields of LS and SSB increase to 3 folds and DSB more than 5 folds.Strikingly,after enzyme treatment the yields of DSB rise by factors of 5.3-15.4,indicating there are large amounts of base modifications occurring within 10 nucleotide base pairs during the CRT,which should essentially translate into lethal DSB in cells.The synergy mechanism suggests that prior chemical sensitization of DNA could facilitate the highly reactive LEE to produce optimal DNA damages.The timing between the administration of chemotherapeutic agents and radiation must be synchronized with a well-defined time delay to optimize any superadditive effect in CRT.This study provides a fundamental understanding of the mechanisms of synergy between Pt-drugs and radiation,and hence,has potential for the development of more effective CRT protocols in the clinic,via optimization of primary DNA damages to cancer cells,while dramatically reducing the toxicity of Pt-chemotherapeutic agents.