第五章 细胞存活曲线201Xppt课件

1、.基础放射医学系,第五章 细胞存活曲线,北京大学医学部放射医学系 李载权,.基础放射医学系,.基础放射医学系,参考文献,Eric J. Hall, Amato J. Giaccia. Chapter 3. Cell Survival Curves; Chapter 4. Radiosensitivity and Cell Age in the Mitotic Cycle; Chapter 5. Fractionated Radiation and the Dose-Rate Effect; Chapter 6. Oxygen Effect and Reoxygenation; Chapter

2、7. Linear Energy Transfer and Relative Biologic Effectiveness. In: Radiobiology for the radiologist, 6th ed. Philadelphia, PA: Lippincott Williams B, E. coli; C, E. coli B/r; D, yeast; E, phage staph E; F, B. megatherium; G, potato virus; H, Micrococcus radiodurans.,不同细胞的辐射敏感性 有丝分裂细胞 2G 干细胞 1G 成熟功能细

3、胞 100G 微球菌 2000G 肿瘤干细胞 80G（细胞含大量的自由基清除剂等） 肿瘤细胞 50G,.基础放射医学系,3、肿瘤细胞,肿瘤细胞的异化,.基础放射医学系,细胞死亡丢失率（cell loss factor, LF，f ） 增殖期细胞增殖份数（growth fraction, GF） 细胞标记指数（LI）与分裂指数（MI） 肿瘤体积实际倍增时间(Td) 肿瘤潜在增殖倍增时间(Tpot),肿瘤细胞有生有死？,.基础放射医学系,.基础放射医学系,Summary of D0 values for cells of human origin grown and irradiated in v

4、itro. Cells from human tumors tend to have a wide range of radiosensitivities, which brackets the radiosensitivity of normal human fibroblasts. In general, squamous cell carcinoma cells （鳞状细胞癌） are more resistant than sarcoma cells（肉瘤细胞） , but the spectra of radiosensitivities are broad and overlap.

5、 (Courtesy of Dr. Ralph Wechselbaum.),鳞状细胞癌与肉瘤细胞,.基础放射医学系,A: Compilation of survival curves for asynchronous cultures of a number of cell lines of human and rodent origin. Note the wide range of radiosensitivity (most notably the size of the shoulder) between mouse EMT6 cells, the most resistant, an

6、d two neuroblastoma cell lines of human origin (the most sensitive). The cell survival curve for mitotic cells is very steep, and there is little difference in radiosensitivity for cell lines that are very different in asynchronous culture. B：18 hours after irradiation with 10 Gy (1,000 rad) and ele

7、ctrophoresed for 90 minutes at 6 V/cm. Note the broad variation in the amount of laddering which is characteristic of an apoptotic death. In this form of death, double-strand breaks occur in the linker regions between nucleosomes, producing DNA fragments that are multiples of about 185 base pairs. N

8、ote that cell lines that show prominent laddering are radiosensitive.,凋亡的肿瘤细胞,.基础放射医学系,细胞衰老或坏死而死亡的部分通过干细胞及时补充，这就是细胞增殖动力学,.基础放射医学系,第五节,影响细胞存活曲线 的其他因素,第五节 曲线影响因素,.基础放射医学系,影响细胞存活曲线的主要因素,辐射能量剂量的空间密度-LET. 指标用RBE 氧效应-氧含量. 指标用OER 化学分子-放射防护剂与辐射增敏剂. 指标用DMF和SER 剂量分割-小剂量多次照射. 指标用Dc 辐射剂量的时间密度-剂量率. 指标用DDREF,.基础放

9、射医学系,1、LET对细胞存活曲线的影响,Sparsely Ionizing (10 keV/mm) 2.5 MeV a-particles (166 keV/mm) 2-GeV Fe ions (1,000 keV/mm),.基础放射医学系,辐射能量剂量的空间密度-LET. 指标用RBE,.基础放射医学系,LET, low LET to high LET,.基础放射医学系,LET, low LET to high LET,.基础放射医学系,.基础放射医学系,The upper three curves represent fluctuations in the survival of jej

10、unal crypt cells exposed to X - rays or neutrons as they pass through the cell cycle after synchronization with hydroxyurea (H-U). The doses were 11 Gy (1,100 rad) of X -rays; 7 Gy (700 rad) of neutrons generated by 50 MeV d+ Be; and 6 Gy (600 rad) of neutrons generated by 16 MeV d+ Be. The lower cu

11、rve represents the uptake of tritiated thymidine (expressed as counts per minute) per wet weight of jejunum as a function of time after the last injection of (H-U). The first wave indicates crypt stem cells passing through S phase after synchronization at G1-S phase by (H-U). (From Withers HR, Mason

12、 K, Reid BO, et al.: Response of mouse intestine to neutrons and gamma rays in relation to dose fractionation and division cycle. Cancer 34:39-47, 1974, with permission.),不同时相不同LET射线对细胞存活的影响,.基础放射医学系,.基础放射医学系,2、氧对细胞存活曲线的影响,有氧条件下不同辐射剂量对细胞存活分数的影响,OER是以一定水平细胞存活分数为基准，基础固定的含氧水平下所需剂量之间的比值,.基础放射医学系,不同氧剂量水平

13、对细胞OER的影响,.基础放射医学系,.基础放射医学系,有氧条件下不同LET射线对细胞存活分数的影响,.基础放射医学系,高LET射线OER效应最低，或氧含量水平对高LET射线作用最低，即没有氧效应现象,.基础放射医学系,LET, low LET to high LET,.基础放射医学系,.基础放射医学系,.基础放射医学系,DMF =,Chemical agents that reduce or enhance cell response to radiation are called radio-protectors or radio-sensitizers. The examples of

14、formers are WR-2721or MEA, while those of latters are halogenated pyrimidines and hypoxic cell radiosensitizers.,The dose modifying factor (DMF) is defined as follows:,Dose to produce an effect with radiioprotector,Dose to produce the same effect without radiioprotector,3、化学分子,.基础放射医学系,放射防护剂,.基础放射医学

15、系,Effect of Adding a Phosphate-Covering Function on the Free Sulfhydryl of Mercaptoethylamine (MEA),放射防护剂氨磷汀（amifostine, WR2721）,.基础放射医学系,.基础放射医学系,Amifostine （氨磷汀）有可能减少辐射对正常组织的损伤,.基础放射医学系,放射增敏剂,.基础放射医学系,.基础放射医学系,.基础放射医学系,.基础放射医学系,4、剂量分割,剂量分割式照射中与一次性照射相比，二次打击的有效剂量-存活曲线(the effective dose-survival cur

16、ve)细胞存活率更多；细胞存活率随辐射打击二次之间的时间延长而增加；2小时之后细胞存活率将不再增加。,分割时间长短对存活分数的影响,.基础放射医学系,剂量分割式照射中有效剂量-存活曲线(the effective dose-survival curve)细胞存活率除与间隔时间有关外，还与重复打击的次数（n）有关。,分割时间足够情况下，不同分割次数对细胞存活分数的影响,.基础放射医学系,The concept of an effective survival curve for a multifraction regimen is illustrated. If the radiation do

17、se is delivered in a series of equal fractions separated by time intervals sufficiently long for the repair of sublethal damage to be complete between fractions, the shoulder of the survival curve is repeated many times. The effective dose-survival curve is an exponential function of dose, that is,

18、a straight line from the origin through a point on the single-dose survival curve corresponding to the daily dose fraction (e.g., 2 Gy, or 200 rad). The dose resulting in one decade of cell killing (D10) is related to the D0 by the expression D10 = 2.3 D0.,.基础放射医学系,剂量分割式照射中有效剂量-存活曲线(the effective do

19、se-survival curve)的细胞存活率还与LET有关，但是只有低LET射线才有更强的存活效率。,高LET射线的分割对细胞存活影响最小,.基础放射医学系,辐射剂量率(dose rate, DR)系指单位时间内照射剂量，剂量率单位伦琴/秒或拉德/分钟，实际上低剂量率LDR时具有较高的分割次数。,5、剂量率的影响,按辐射剂量率分类,.基础放射医学系,条件：总剂量一样、不同分割照射之间有足够间隔时间，分割剂量越低，结果分割次数越多，即相当于LDR射线。,.基础放射医学系,辐射剂量率与细胞存活率之间的关系,.基础放射医学系,相对高剂量率(HDR)射线而言，低剂量率(LDR)射线由于射线粒子照射打击时间间隔大，因此为LDR电离射线所损伤的细胞提供了更多修复机会，结果使得细胞更容易存活。,辐射剂量率定律原理,剂量率(DR)是影响细胞存活效率的时间密度性物理参数。一般而言，同种射线和同样剂量条件下，细胞对高剂量率(high dose rate, HDR)的射线比低剂量率(low dose rate, LDR) 的射线更加敏感，这被称为 剂量率定律。,.基础放射医学系,.基础放射医学系,当物理学吸收总剂量一样时，分割剂量越低，分割的次数就会越多。结果HDR和LDR不同射线之间，实际产生的有效作用剂量是不同的，一般而言HDR射线生物效应比LDR