恶性肿瘤放射增敏机制及药物研究进展_West China Medical Journal

Authors：

 张佳惠 ,  李平

四川大学华西医院肿瘤中心（成都 610041）;

Corresponding author：

李平, Email: lipinglunwen@163.com

Keywords：

恶性肿瘤; 放射治疗; 放射增敏剂; 靶向药物; 乏氧

DOI：

10.7507/1002-0179.20150453

Video：

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Abstract Full text Figures/Tables Video References Cited by

放射治疗是恶性肿瘤治疗的有效方式之一，几乎超过50%的恶性肿瘤患者在抗癌过程中接受过放射治疗。但是高能量的放射线在杀死肿瘤细胞的同时，不可避免会损伤肿瘤周围正常组织。所以控制肿瘤放射剂量，使肿瘤放射“局部化”，是肿瘤科医生共同的追求。放射增敏剂的使用助于获得相对低量高效的放射剂量，有效增加肿瘤局部控制率，降低放射对肿瘤周围正常组织的伤害。但是目前临床上使用的放射增敏剂，大多数存在药物自身细胞毒性大、选择性低、价格昂贵等特点，限制了临床广泛使用。所以寻找安全经济且可区分肿瘤组织和正常组织的“智能型”放射增敏物质十分迫切且必要。这篇综述主要对肿瘤放射增敏机制及相关药物研究进展进行了总结分析，并介绍一些新兴的放射增敏措施，为临床上放射增敏剂的使用和进一步研发提供方向。

Citation： 张佳惠, 李平. 恶性肿瘤放射增敏机制及药物研究进展. West China Medical Journal, 2015, 30(8): 1581-1586. doi: 10.7507/1002-0179.20150453 Copy

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1. Delaney G, Jacob S, Featherstone C, et al. The role of radiotherapy in cancer treatment:estimating optimal utilization from a review of evidence-based clinical guidelines[J]. Cancer, 2005, 104(6):1129-1137.
2. Giusti AM, Raimondi M, Ravagnan G, et al. Human cell membrane oxidative damage induced by single and fractionated doses of ionizing radiation:a fluorescence spectroscopy study[J]. Int J Radiat Biol, 1998, 74(5):595-605.
3. Maisin JR, Van Gorp U, De Saint-Georges L. The ultrastructure of the lung after exposure to ionizing radiation as seen by transmission and scanning electron microscopy[J]. Scan Electron Microsc, 1982(Pt 1):403-412.
4. Azzam EI, De Toledo SM, Little JB. Expression of CONNEXIN43 is highly sensitive to ionizing radiation and other environmental stresses[J]. Cancer Res, 2003, 63(21):7128-7135.
5. Dayal D, Martin SM, Owens KM, et al. Mitochondrial complex Ⅱ dysfunction can contribute significantly to genomic instability after exposure to ionizing radiation[J]. Radiat Res, 2009, 172(6):737-745.
6. Bhide SA, Nutting CM. Recent advances in radiotherapy[J]. BMC Med, 2010, 8:25.
7. 江曼, 钱晓萍, 刘宝瑞. 恶性肿瘤放射增敏剂研究进展[J]. 现代肿瘤学, 2014, 22(1):226-228.
8. 巴桑卓玛. 细胞凋亡与肿瘤[J]. 西藏科技, 2004, 12:47-50.
9. Milas L, Hunter NR, Mason KA, et al. Role of reoxygenation in induction of enhancement of tumor radioresponse by paclitaxel[J]. Cancer Res, 1995, 55(16):3564-3568.
10. Berdis AJ. Current and emerging strategies to increase the efficacy of ionizing radiation in the treatment of cancer[J]. Expert Opin Drug Discov, 2014, 9(2):167-181.
11. 况里杉, 王宇亮, 周向东. 碱基切除修复与抗肿瘤药物耐药[J]. 肿瘤, 2013, 33(3):294-296.
12. Bartek J, Lukas J. Chk1 and Chk2 kinases in checkpoint control and cancer[J]. Cancer Cell, 2003, 3(5):421-429.
13. Rockwell S, Dobrucki IT, Kim EY, et al. Hypoxia and radiation therapy:past history, ongoing research, and future promise[J]. Curr Mol Med, 2009, 9(4):442-458.
14. Ghattass K, Assah R, El-Sabban M, et al. Targeting hypoxia for sensitization of tumors to radio-and chemotherapy[J]. Curr Cancer Drug Targets, 2013, 13(6):670-685.
15. 刘小艳, 许新华. 乏氧微环境与肿瘤治疗抗拒[J]. 广东医学, 2013, 34(23):3667-3669.
16. Hay MP, Hicks KO, Wang J. Hypoxia-directed drug strategies to target the tumor microenvironment[J]. Adv Exp Biol, 2014(772):111-145.
17. Wilson WR, Hay MP. Targeting hypoxia in cancer therapy[J]. Nat Rev Cancer, 2011, 11(6):393-410.
18. Ahmad S. Platinum-DNA interactions and subsequent cellular processes controlling sensitivity to anticancer Platinum complexes[J]. Chem Biodivers, 2010, 7(3):543-566.
19. Rezaee M, Hunting DJ, Sanche L. New insights into the mechanism underlying the synergistic action of ionizing radiation with Platinum chemotherapeutic drugs:the role of low-energy electrons[J]. Int J Radiat Oncol Biol Phys, 2013, 87(4):847-853.
20. Khalaj A, Abdi K, Ostad SN, et al. Synthesis, in vitro cytotoxicity and radiosensitizing activity of novel 3-[(2,4-dinitrophenylamino)alkyl] derivatives of 5-fluorouracil[J]. Chem Biol Drug Des, 2014, 83(2):183-190.
21. Abraham RT. PI 3-kinase related kinases:‘big’ players in stress-induced signaling pathways[J]. DNA Repair (Amst), 2004, 3(8/9):883-887.
22. Deorukhkar A, Shentu S, Park HC, et al. Inhibition of radiation-induced DNA repair and prosurvival pathways contributes to vorinostat-mediated radiosensitization of pancreatic cancer cells[J]. Pancreas, 2010, 39(8):1277-1283.
23. Mueller S, Yang X, Sottero TL, et al. Cooperation of the HDAC inhibitor vorinostat and radiation in metastatic neuroblastoma:efficacy and underlying mechanisms[J]. Cancer Lett, 2011, 306(2):223-229.
24. Palmieri D, Lockman PR, Thomas FC, et al. Vorinostat inhibits brain metastatic colonization in a model of triple-negative breast cancer and induces DNA double-strand breaks[J]. Clin Cancer Res, 2009, 15(19):6148-6157.
25. Oike T, Ogiwara H, Torikai K, et al. Garcinol, a histone acetyltransferase inhibitor, radiosensitizes cancer cells by inhibiting non-homologous end joining[J]. Int J Radiat Oncol Biol Phys, 2012, 84(3):815-821.
26. Sandur SK, Deorukhkar A, Pandey MK, et al. Curcumin modulates the radiosensitivity of colorectal cancer cells by suppressing constitutive and inducible NF-kappaB activity[J]. Int J Radiat Oncol Biol Phys, 2009, 75(2):534-542.
27. Sun YL, Jiang XF, Chen SJ, et al. Inhibition of histone acetyltransferase activity by anacardic acid sensitizes tumor cells to ionizing radiation[J]. FEBS Lett, 2006, 580(18):4353-4356.
28. Oike T, Komachi M, Ogiwara H, et al. C646, a selective small molecule inhibitor of histone acetyltransferase p300, radiosensitizes lung cancer cells by enhancing mitotic catastrophe[J]. Radiother Oncol, 2014, 111(2):222-227.
29. Mitchell J, Smith GC, Curtin NJ. Poly(ADP-Ribose) polymerase-1 and DNA-dependent protein kinase have equivalent roles in double Strand break repair following ionizing radiation[J]. Int J Radiat Oncol Biol Phys, 2009, 75(5):1520-1527.
30. Dungey FA, Löser DA, Chalmers AJ. Replication-dependent radiosensitization of human glioma cells by inhibition of poly(ADP-Ribose) polymerase:mechanisms and therapeutic potential[J]. Int J Radiat Oncol Biol Phys, 2008, 72(4):1188-1197.
31. Senra JM, Telfer BA, Cherry KE, et al. Inhibition of PARP-1 by olaparib (AZD2281) increases the radiosensitivity of a lung tumor xenograft[J]. Mol Cancer Ther, 2011, 10(10):1949-1958.
32. Wang L, Mason KA, Ang KK, et al. MK-4827, a PARP-1/-2 inhibitor, strongly enhances response of human lung and breast cancer xenografts to radiation[J]. Invest New Drugs, 2012, 30(6):2113-2120.
33. Rouse J, Jackson SP. Interfaces between the detection, signaling, and repair of DNA damage[J]. Science, 2002, 297(5581):547-551.
34. Liu XD, Ma SM, Liu Y, et al. Short hairpin RNA and retroviral vector-mediated silencing of p53 in mammalian cells[J]. Biochem Biophys Res Commun, 2004, 324(4):1173-1178.
35. Baulcombe DC. Fast forward genetics based on virus-induced gene silencing[J]. Curr Opin Plant Biol, 1999, 2(2):109-113.
36. Wargelius A, Ellingsen S, Fjose A. Double-stranded RNA induces specific developmental defects in zebrafish embryos[J]. Biochem Biophys Res Commun, 1999, 263(1):156-161.
37. Wu J, Lai G, Wan F, et al. Knockdown of checkpoint kinase 1 is associated with the increased radiosensitivity of glioblastoma stem-like cells[J]. Tohoku J Exp Med, 2012, 226(4):267-274.
38. Ma Z, Yao G, Zhou B, et al. The Chk1 inhibitor AZD7762 sensitises p53 mutant breast cancer cells to radiation in vitro and in vivo[J]. Mol Med Rep, 2012, 6(4):897-903.
39. Reddy SB, Williamson SK. Tirapazamine:a novel agent targeting hypoxic tumor cells[J]. Expert Opin Investig Drugs, 2009, 18(1): 77-87.
40. 余长顺, 欧阳洪贵, 胡斌, 等. 低氧激活的抗肿瘤药物及其研究近况[J]. 药学进展, 2012, 36(2):65-72.
41. Sun JD, Liu Q, Wang J, et al. Selective tumor hypoxia targeting by hypoxia-activated prodrug TH-302 inhibits tumor growth in preclinical models of cancer[J]. Clin Cancer Res, 2012, 18(3):758-770.
42. Lohse I, Rasowski J, Cao PJ, et al. Targeting tumor hypoxia in patient-derived pancreatic xenografts using TH-302[J]. Cancer Res, 2012, 72(14 Supple):A43.
43. Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism[J]. Nat Rev Cancer, 2011, 11(2):85-95.
44. Kurtoglu M, Gao N, Shang J, et al. Under normoxia, 2-deoxy-D-glucose elicits cell death in select tumor types not by inhibition of glycolysis but by interfering with N-linked glycosylation[J]. Mol Cancer Ther, 2007, 6(11):3049-3058.
45. 雷永凤. GLUT1在子宫内膜腺癌中的表达与临床意义[J]. 现代肿瘤杂志, 2014, 22(3):632-634.
46. Anderson P, Aguilera D, Pearson M, et al. Outpatient chemotherapy plus radiotherapy in sarcomas:improving cancer control with radiosensitizing agents[J]. Cancer Control, 2008, 15(1):38-46.
47. 于金明, 滕菲菲. 放疗与免疫治疗联合应用的相关机制及研究进展[J]. 中国肿瘤临床, 2014, 41(9):547-550.
48. Chakraborty M, Gelbard A, Carrasquillo J, et al. Systemic radioimmunotherapy in synergy with vaccine renders antitumor effects in a preclinical model[M]. AACR Annual Proceedings, 2006:1165.
49. 张立煌, 王青青. 恶性肿瘤免疫治疗的现状及展望[J]. 浙江大学学报:医学版, 2010, 39(4):339-344.
50. Demaria S, Formenti SC. Sensors of ionizing radiation effects on the immunological microenvironment of cancer[J]. Int J Radiat Biol, 2008, 83(11/12):819-825.
51. Demaria S, Bhardwaj N, McBride WH, et al. Combining radiotherapy and immunotherapy:a revived partnership[J]. Int J Radiat Oncol Biol Phys, 2005, 63(3):655-666.
52. Tesniere A, Panaretakis T, Kepp O, et al. Molecular characteristics of immunogenic cancer cell death[J]. Cell Death Differ, 2008, 15(1):3-12.
53. Ferrara TA, Hodge JW, Gulley JL. Combining radiation and immunotherapy for synergistic antitumor therapy[J]. Curr Opin Mol Ther, 2009, 11(1):37-42.
54. Wersäll PJ, Blomgren H, Pisa P, et al. Regression of non-irradiated metastases after extracranial stereotactic radiotherapy in metastatic renal cell carcinoma[J]. Acta Oncol, 2006, 45(4):493-497.
55. Nesslinger NJ, Sahota RA, Stone B, et al. Standard treatments induce antigen-specific immune responses in prostate cancer[J]. Clin Cancer Res, 2007, 13(5):1493-1502.
56. Okawa T, Kita M, Arai T, et al. Phase Ⅱ randomized clinical trial of LC9018 concurrently used with radiation in the treatment of carcinoma of the uterine cervix. Its effect on tumor reduction and histology[J]. Cancer, 1989, 64(9):1769-1776.
57. Gulley JL, Arlen PM, Bastian A, et al. Combining a recombinant cancer vaccine with standard definitive radiotherapy in patients with localized prostate cancer[J]. Clin Cancer Res, 2005, 11(9):3353-3362.
58. Chi KH, Liu SJ, Li CP, et al. Combination of conformal radiotherapy and intratumoral injection of adoptive dendritic cell immunotherapy in refractory hepatoma[J]. J Immunother, 2005, 28(2):129-135.
59. Cmielová J, Havelek R, Jiroutová A, et al. DNA damage caused by ionizing radiation in embryonic diploid fibroblasts WI-38 induces both apoptosis and senescence[J]. Physiol Res, 2011, 60(4):667.
60. Kim VN. MicroRNA biogenesis:coordinated cropping and dicing[J]. Nat Rev Mol Cell Biol, 2005, 6(5):376-385.
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