1、BIOLOGICAL EFFECTS OF IONIZING RADIATION AT MOLECULAR AND CELLULAR LEVELS,Module VIII-a,Module Medical VIII.,- 2,Historical background,Module Medical VIII.,- 3,Wilhelm Conrad Roentgen,Discovery of X rays (1895),Module Medical VIII.,- 4,Antoine Henri Becquerel,Marie Curie,Discovery of uraniums natura
2、l radioactivity,Module Medical VIII.,- 5,First radiation-induced skin cancer reportedin 1902 First radiation-induced leukemia described in 1911,First reports on harmful effects of radiation,1920s: bone cancer among radium dial painters1930s: liver cancer and leukemia due to Throtrast administration1
3、940s: excess leukemia among first radiologists,Module Medical VIII.,- 6,Studies of Japanese A-bomb survivors,Module Medical VIII.,- 7,Effects of radiation on cells at atomic level,Ionization,Excitation,Module Medical VIII.,- 8,Mechananisms of damage at molecular level,Module Medical VIII.,- 9,Direct
4、 action,Ionizing radiation + RH R- + H+,OHI R C = NH imidol (enol),OII R C = NH2 amide (ketol),Tautomeric Shifts,Bond breaks,Module Medical VIII.,- 10,e-,X ray ray,P+,O,H,H,OH-,H+,Ho,OHo,Indirect action,Module Medical VIII.,- 11,Radiolysis of H2O molecule,Shared electron,Shared electron,H-O-H H+ + O
5、H- (ionization) H-O-H H0+OH0 (free radicals),Module Medical VIII.,- 12,Reactions with free radicals,H0 + OH0 HOH (recombination) H0 + H0 H2 (dimer) OH0 + OH0 H2O2 (hydrogen peroxide) OH0+RH R0+HOH (radical transfer),Module Medical VIII.,- 13,Effects of oxygen on free radical formation,Oxygen can mod
6、ify the reaction by enabling creation of other free radical species with greater stability and longer lifetimesH0+O2 HO20 (hydroperoxy free radical)R0+O2 RO20 (organic peroxy free radical),Module Medical VIII.,- 14,Lifetimes of free radicals,3nm,Because short life of simple free radicals (10-10sec),
7、 only those formed in water column of 2-3 nm around DNA are able to participate in indirect effect,Ho,OHo,Ho,OHo,HO2o,RO2o,Module Medical VIII.,- 15,Relation between LET and action type,Direct action is predominant with high LET radiation, e.g. alpha particles and neutrons Indirect action is predomi
8、nant with low LET radiation, e.g. X and gamma rays,Module Medical VIII.,- 16,Biochemical reactions with ionizing radiation,DNA is primary target for cell damage from ionizing radiation,Module Medical VIII.,- 17,Types of radiation induced lesions in DNA,Single-strand breaks,Double strand breaks,Base
9、damage,Module Medical VIII.,- 18,Mechanisms of DNA repair,Module Medical VIII.,- 19,DNA restoration failure,Unrejoined DNA double strand breaks,Incorrect repair of DNA damage,Cytotoxic effect,Mutations,Module Medical VIII.,- 20,Chromosomes,Module Medical VIII.,- 21,DNA lesions and chromosome aberrat
10、ions,DNA SİNGLESTRAND BREAK,DNA DOUBLESTRAND BREAK,Module Medical VIII.,- 22,Radiation induced chromosomal aberrations,Module Medical VIII.,- 23,Effect of radiation on cell Cell kinetics,Module Medical VIII.,- 24,Radiosensitivity of cell in cell cycle,Relative Survivability,G1 S G2 G1,M,Relative sur
11、vivability of cells irradiated in different phases of the cell cycle. Synchronised cells in late G2 and in mitosis (M) showed greatest sensitivity to cell killing.,Module Medical VIII.,- 25,NORMAL,IRRADIATED,Mitotic death,Module Medical VIII.,- 26,The most radiosensitive cells are actively prolifera
12、ting/dividing at the time of exposureundifferentiated (non-specialized in structure and function),Bergoni and Tribondeaus law (1906),Module Medical VIII.,- 27,Interphase death,Why are peripheral blood lymphocytes highly sensitive to radiation, although well differentiated?,Module Medical VIII.,- 28,
13、Radiation induced membrane damage,Module Medical VIII.,- 29,Dose rate and fractionation Radiation quality Temperature Chemical modification Oxygen Radiosensitizing agents Radioprotective agents,Modification of radiation injury,Module Medical VIII.,- 30,Dose rate and fractionation,Prolonged exposure
14、with lower dose rate,Acute exposure with high dose rate,Fractionated dose,Acute dose,Time,Time,Module Medical VIII.,- 31,Radiation quality,Module Medical VIII.,- 32,Survival curve for mammalian cells exposed to high- (A) and low-LET (B) radiation,A,B,Dq,n,D0,D0,1-1/e,1-1/e,037,Module Medical VIII.,-
15、 33,Temperature,For cell kiling effects, tissues are more radiosensitive at higher temperatures Chromosome aberrations increase at lower temperatures (suppression of repair process),Module Medical VIII.,- 34,Chemical modification: oxygen,OER =,Dose required to cause effect with oxygen,Dose required
16、to cause effect without oxygen,Dissolved oxygen in tissues increases stability and toxicity of free radicals Oxygen enhancement ratio (OER) is determined by:The OER has a maximum value of 3.0,Module Medical VIII.,- 35,Radiosensitizing agents,Halogenated and substituted analoges of DNA bases: 5-bromo
17、-uracil and 6-thio-guanine Electroaffinic compounds:Nitroimidazoles (misonidazole, nitroimidazole, and nitrofuran) sensitization enhancement ratio (SER) of 1.2 to 1.4,Module Medical VIII.,- 36,Radioprotective agents,Thiols (cysteine, 2-mercaptoethylamine, cystamine and thiourea). Thiols have dose re
18、duction factor (DRF) ratio of 1.4 to 2.0 They are thought to protect cells by scavenging free radicals producing hypoxia temporarily inhibiting DNA synthesis, allowing time for the repair enzymes to complete repair of sublethal damage forming disulphide bonds in proteins, thereby strengthening them,
