Synergistic Effect Of UV Photoelectron And Cisplatin On DNA Damage And Its Mechanism

Cancer is a major public health problem, causing one in 4 deaths of all lethal diseases. The basic treatments for both primary tumors and metastases involve surgery, chemotherapy, radiotherapy and targeted biomolecules as well as combinations of these methods. Combined chemotherapy and radiotherapy, called chemoradiation therapy (CRT), is presently a standard treatment option for many types of solid tumors. However, current CRT protocols are clearly not optimal. The concomitant treatment with both modalities was superadditive, i.e., the chemotherapeutic agents acted as radiosensitizers so that tumor regression was accelerated relative to non-synchronized protocols, has not been achieved. Low energy electrons (LEE) are the most abundant species produced by high-energy ionizing radiation and play important role in radiotherapy. The goal of the present thesis is to determine the mechanisms of synergy between chemotherapeutic drug, cisplatin, and LEE on the interaction of the genome, in order to optimize the benefit of CRT with classic Pt-agents and develop novel radiosensitizers.Since the production of LEE out of ultra-high vacuum is technically difficult, the studies of the interaction of LEE with biomolecules under the similar cellular environment are greatly impeded. Herein, we apply the principle of UV-induction of photoelectrons on metal surface, to produce LE (-0 eV) photoelectrons on tantalum surface under atmospheric pressure; plasmid DNA and cisplatin-DNA complexes were deposited on different substrates and lyophilized to form 5ML films; in a homemade sealed setup the films were illumination by Xenon or Hg lamp; from the exposure-response curves on different substracts, while that of the quartz as the photo absorption indications, the effective yields of DNA damages induced by UV photoelectrons, including C-L, SSB and LS are obtained; the ratios of cisplatin is also studied as important parameter; the bond transformation in cisPt-DNA complexes during irradiation was characterized by XPS.The results show:1) UV induces DNA damages of greatly different degrees on the quartz and Ta substrate. The photoelectrons effectively induce the DNA damages, mainly leading to the loss of supercoiled to SSB formation.2) The introduction of cisplatin furthermore enhances the DNA damage, with EF of SSB and LS ranging from 3.7-8.0 and 3.6-9.5, respectively.3) The below 4:1, initial addition of cisplatin causes highly increasing rate of DNA damage compared to higher ratios.4) XPS characterization shows that the effective rate constants of the corresponding phosphodiester and glycosidic bond cleavages for cisplatin-DNA complexes are 1.8 and 1.9 folds larger than DNA, indicating that DNA radio sensization by cisplatin results not only from the sensitization of DNA to the action of LEE, but also from an increase the production of LEE at the site of binding of the cisplatin.5) The possible mechanism of DNA damages induced by cisplatin and LEE is the synergistic effect of covalently binding as well as DNA distortion by cisplatin and the attachment of LEE, i.e., cisplatin acts simultaneously as effective radiosensitizer, causing the maximum DNA damages. The results provide important insights into the mechanisms of CRT modality, which could also be helpful in the design of new cisplatin-based antitumor drugs.