惡性腫瘤放射增敏機制及藥物研究進展_West China Medical Journal

Authors：

 張佳惠 ,  李平

四川大學華西醫院腫瘤中心（成都 610041）;

Corresponding?author：

李平, Email: lipinglunwen@163.com

Keywords：

惡性腫瘤; 放射治療; 放射增敏劑; 靶向藥物; 乏氧

DOI：

10.7507/1002-0179.20150453

Video：

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Abstract Full text Figures/Tables Video References Cited by

放射治療是惡性腫瘤治療的有效方式之一，幾乎超過50%的惡性腫瘤患者在抗癌過程中接受過放射治療。但是高能量的放射線在殺死腫瘤細胞的同時，不可避免會損傷腫瘤周圍正常組織。所以控制腫瘤放射劑量，使腫瘤放射“局部化”，是腫瘤科醫生共同的追求。放射增敏劑的使用助于獲得相對低量高效的放射劑量，有效增加腫瘤局部控制率，降低放射對腫瘤周圍正常組織的傷害。但是目前臨床上使用的放射增敏劑，大多數存在藥物自身細胞毒性大、選擇性低、價格昂貴等特點，限制了臨床廣泛使用。所以尋找安全經濟且可區分腫瘤組織和正常組織的“智能型”放射增敏物質十分迫切且必要。這篇綜述主要對腫瘤放射增敏機制及相關藥物研究進展進行了總結分析，并介紹一些新興的放射增敏措施，為臨床上放射增敏劑的使用和進一步研發提供方向。

Citation： 張佳惠, 李平. 惡性腫瘤放射增敏機制及藥物研究進展. 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, 錢曉萍, 劉寶瑞. 惡性腫瘤放射增敏劑研究進展[J]. 現代腫瘤學, 2014, 22(1):226-228.
8. 巴桑卓瑪. 細胞凋亡與腫瘤[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. 況里杉, 王宇亮, 周向東. 堿基切除修復與抗腫瘤藥物耐藥[J]. 腫瘤, 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. 劉小艷, 許新華. 乏氧微環境與腫瘤治療抗拒[J]. 廣東醫學, 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, L?ser 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. 余長順, 歐陽洪貴, 胡斌, 等. 低氧激活的抗腫瘤藥物及其研究近況[J]. 藥學進展, 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. 雷永鳳. GLUT1在子宮內膜腺癌中的表達與臨床意義[J]. 現代腫瘤雜志, 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. 放療與免疫治療聯合應用的相關機制及研究進展[J]. 中國腫瘤臨床, 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. 張立煌, 王青青. 惡性腫瘤免疫治療的現狀及展望[J]. 浙江大學學報:醫學版, 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. Wers?ll 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.
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