Development Of Radio- And Chemo- Sensitizer And Mechanism Study ——Research On The Correspondence Between Intracellular Biological Molecular And Tumour Cells Sensitivity To Irradiation And Antineoplastic Drugs

Cancer is still a lethiferous disease and the majority of cancers show a steep increase in incidence with age and the proportion of elderly people is increasing, due to the wide availability of birth control methods and because of our success in treating other diseases such as infections and cardiovascular disease. The conventional therapy of solid tumour involves the use of surgery, radiotherapy and chemotherapy as major treatment modalities. Nowadays, approximately 70% of cancer patients are treated with radiotherapy and chemotherapy. However, for most common tumours, there has been little change in overall cure rates for over 40 years. The major obstacle impeding the success of radio- and chemo- therapy is tumour cells show intrinsically or acquire resistance to irradiation or anticancer drugs.In order to increase tumour cells sensitivity to irradiation and anticancer drugs, since 1963 Adams pioneered the concept of the efficiency of radiosensitisation was directly related to electron affinity of compounds, a number of drugs radiosensitizers were synthesized and some of them have reached clinical evalution. Moreover, as a branch of antineoplastic agents, cancer sensitizer has beyonded the original concept of radiosensitizer, chemical agents that mimic oxygen and directly and preferentially sensitize the resistant hypoxic tumour cell population to radiation, today more and more cancer sensilizers are developed and effect by overcoming a certain cause of resistance. It's equal important to screen noval senstilizer and clearify the mechanism of those compounds, In this thesis, we determined the cytotoxicity effect of several MMC-based compounds and analysis the mechanism of an prospect radiosensitizer—AQ4N, all of them are belong to bioreductive drugs, an noval type of sensitizer, which requiring metabolic reduction to generate cytotoxic metabolites and showed preferentially enhanced toxicity to solide tumours based on its appropriate reductases and lower oxygen conditions to normal tissures. On the other side, we analyzed the correspondence between biological low-molecular (glutathione ) and hypoxic low-molecular ( nitrogen monoxide) and cells sensitivity to irradiation and anticancer drugs, hope to exploit new intracellular target for designing new antieoplastic drugs, evaluating the possibility of BSO to overcome MDR caused by overexpressing MRP.ObjectiveNowadays, more and more people die of cancer, the large majority from metastatic spread. This highlights the urgent need for major improvements in systemic chemotherapy and radiotherapy, which may be possible through innovative approaches to rational drug development. The work in this thesis has focused on one branch of anticancer agents —radio- and chemo- sensitizers and attempted to educidated the mechanism of the sensitization of these agents. Therefore, the overall goals of the work were as follows:1)To observe the correspondence between the intracellular low-molecular glutathione(GSH), nitrogen monoxide(NO ) and cells sensitivity to irradiation and antineoplastic drugs, and estimate the possibility of enhancing tumour cells sensitivity to radio- and chemo- therapy by some agents which can influence the synthesis of above biological molecular.2)To determine whether BSO ,a gluthathione synthesis inhibitor, can be used to overcome the multidrug resistance(MDR) caused by over-expressing multidrug resistance associated protein(MRP), analyze the rationship among MRP, GSH and GSH-related enzymes(GST, GSH-Px) in the occurance of MDR.3)To evaluate the feasibility of monitoring patients sensitivity to radio- and chemo- therapy by determining the GSH content in peripheral monocyto( PMN). 4)To determine the cytotoxicity of a series of MMC- based noval bioreductive drugs(RH1,629,630,629AC,630AC), and observe whether NO synthase(NOS) and NO, provide realistic targets or take part in the metabolisation of those agents5)To clarify the role of NOS in the metabolism of AQ4N, a prospect bioreductive radiosensitizer, discuss the possible mechanism of the bioactivati...