高剂量的PET显像剂18F-FDG对小鼠大肠癌肿瘤模型治疗效果的实验研究
|
摘要
目的:大肠癌是目前发病率最高肿瘤中之一,在男性和女性中大肠癌的发生率和死亡率都很高。现在有很多种放射性核素已应用到大肠癌的综合辅助治疗中,但是应用正电子药物来治疗大肠肿癌的研究至今还没有。理论上来说,正电子也可以像负电子一样杀死肿瘤细胞。本研究就是应用正电子药物~(18)F-FDG来治疗小鼠的大肠癌肿瘤模型并监测治疗效果。
方法:在12只裸鼠上建立大肠肿癌模型,把建好肿癌模型的裸鼠随机分成4组,其中一组为对照组不予任何治疗,另外三组分别给1.5mCi、3.0mCi、6.0mCi的~(18)F-FDG治疗。治疗后每周用~(18)F-FDG microPET监测治疗效果,并测量肿瘤的生长率。最后用免疫组化染色检测肿瘤、大脑、心脏、和肾脏葡萄糖转运体和VEGF的表达,用TUNEL方法检测肿瘤、大脑、心脏、和肾脏细胞的凋亡情况。
结果:所有治疗组裸鼠肿瘤生长率以及FDG标准摄取都显著低于对照组(p＜0.05)。虽然在三个治疗组之间肿瘤生长率以及FDG标准摄取没有显著区别,但是还是可以看到治疗剂量越高,疗效越好。免疫组化染色显示肿瘤组织较大脑、心脏、和肾脏表达更高的葡萄糖转运体和VEGF。治疗组肿瘤细胞凋亡数量显著高于对照组(p＜0.05)。
结论:本研究表明来源于显像剂~(18)F-FDG的正电子对小鼠大肠癌肿瘤模有一定的治疗效果,提示高剂量的~(18)F-FDG释放出来的正电子可以用于大肠癌以及其它肿瘤的放射治疗。
Purpose: Colorectal cancer is the third most common cancer in the world, andremains a major cause of cancer death in men and women. Several radionuclides havebeen tried for the treatment of colorectal cancer, but the therapeutic potential ofpositrons has remained unexplored in this type of cancer. Theoretically, positronsshould kill cancer cells as electrons. This study assessed the therapeutic potential ofPET agent [~(18)F] labeled 2-deoxy-2-fluoro-D-glucose (~(18)F-FDG) in a colon cancermouse model.
Methods: Colonic adenocarcinoma cells were inoculated in nude mice forestablishing tumor model. Twelve tumor-bearing mice were divided into four groups.Three groups were treated with 1.5 mCi, 3.0 mCi and 6.0 mCi of ~(18)F-FDG, respectively.Control group has not received any treatment. Mice were imaged by microPET with~(18)F-FDG before and after treatment weekly and the tumor growth rate was calculated.Tumor, brain, heart and kidney of mice were analyzed for expression of glucosetransporters and VEGF by immunofluorescent staining, and the presences of apoptosiswere detected by TUNEL method.
Results: All three treated groups showed significant ~(18)F-FDG reduction comparedwith the control group (p＜0.05). The higher treatment dose, the better treatmentresponse was observed, though there were no significant differences between the threetreated groups. The tumor growth rate of all three treated groups was also significantlydecreased after treatment (p＜0.05). There was no significant difference of FDG tumoruptake and growth rate of tumor between treated groups (p＞0.05).Immunohistochemistry showed that tumors expressed more glucose transporters thanin brain, heart and kidney. The ~(18)F-FDG treatment of mice resulted in apoptotic celldeath in all three treated groups, which showed significant higher apoptotic cells thancontrol group (p＜0.05).
Conclusion: The study suggested that positrons delivered by ~(18)F-FDG have atherapuetic effect in colonic cancer animal model, which indicated the potential for thedevelopment of positron emitted therapy with ~(18)F-FDG for colonic cancer and othercancers.
方法:在12只裸鼠上建立大肠肿癌模型,把建好肿癌模型的裸鼠随机分成4组,其中一组为对照组不予任何治疗,另外三组分别给1.5mCi、3.0mCi、6.0mCi的~(18)F-FDG治疗。治疗后每周用~(18)F-FDG microPET监测治疗效果,并测量肿瘤的生长率。最后用免疫组化染色检测肿瘤、大脑、心脏、和肾脏葡萄糖转运体和VEGF的表达,用TUNEL方法检测肿瘤、大脑、心脏、和肾脏细胞的凋亡情况。
结果:所有治疗组裸鼠肿瘤生长率以及FDG标准摄取都显著低于对照组(p＜0.05)。虽然在三个治疗组之间肿瘤生长率以及FDG标准摄取没有显著区别,但是还是可以看到治疗剂量越高,疗效越好。免疫组化染色显示肿瘤组织较大脑、心脏、和肾脏表达更高的葡萄糖转运体和VEGF。治疗组肿瘤细胞凋亡数量显著高于对照组(p＜0.05)。
结论:本研究表明来源于显像剂~(18)F-FDG的正电子对小鼠大肠癌肿瘤模有一定的治疗效果,提示高剂量的~(18)F-FDG释放出来的正电子可以用于大肠癌以及其它肿瘤的放射治疗。
Purpose: Colorectal cancer is the third most common cancer in the world, andremains a major cause of cancer death in men and women. Several radionuclides havebeen tried for the treatment of colorectal cancer, but the therapeutic potential ofpositrons has remained unexplored in this type of cancer. Theoretically, positronsshould kill cancer cells as electrons. This study assessed the therapeutic potential ofPET agent [~(18)F] labeled 2-deoxy-2-fluoro-D-glucose (~(18)F-FDG) in a colon cancermouse model.
Methods: Colonic adenocarcinoma cells were inoculated in nude mice forestablishing tumor model. Twelve tumor-bearing mice were divided into four groups.Three groups were treated with 1.5 mCi, 3.0 mCi and 6.0 mCi of ~(18)F-FDG, respectively.Control group has not received any treatment. Mice were imaged by microPET with~(18)F-FDG before and after treatment weekly and the tumor growth rate was calculated.Tumor, brain, heart and kidney of mice were analyzed for expression of glucosetransporters and VEGF by immunofluorescent staining, and the presences of apoptosiswere detected by TUNEL method.
Results: All three treated groups showed significant ~(18)F-FDG reduction comparedwith the control group (p＜0.05). The higher treatment dose, the better treatmentresponse was observed, though there were no significant differences between the threetreated groups. The tumor growth rate of all three treated groups was also significantlydecreased after treatment (p＜0.05). There was no significant difference of FDG tumoruptake and growth rate of tumor between treated groups (p＞0.05).Immunohistochemistry showed that tumors expressed more glucose transporters thanin brain, heart and kidney. The ~(18)F-FDG treatment of mice resulted in apoptotic celldeath in all three treated groups, which showed significant higher apoptotic cells thancontrol group (p＜0.05).
Conclusion: The study suggested that positrons delivered by ~(18)F-FDG have atherapuetic effect in colonic cancer animal model, which indicated the potential for thedevelopment of positron emitted therapy with ~(18)F-FDG for colonic cancer and othercancers.
引文
[1] Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol.2001;2:533-43.
[2] Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin.2008;58:71-96.
[3] Chan TA. Nonsteroidal anti-inflammatory drugs, apoptosis, and colon-cancerchemoprevention. Lancet Oncol. 2002 ;3:166-74.
[4] Caridad V, Arsenak M, Abad MJ, et al. Effective radiotherapy of primary tumorsand metastasis with 18F-2-deoxy-2-fluoro-D-glucose in C57BL/6 mice. CancerBiother Radiopharm. 2008;23:371-5.
[5] Rohren EM, Turkington TG, Coleman RE. Clinical applications of PET inoncology. Radiology. 2004;231:305-32.
[6] Gallagher BM, Fowler JS, Gutterson NI, MacGregor RR, Wan CN, Wolf AP.Metabolic trapping as a principle of oradiopharmaceutical design: some factorsresposible for the biodistribution of [18F] 2-deoxy-2-fluoro-D-glucose. J NuclMed. 1978;19:1154-61.
[7] Tian M, Zhang H, Oriuchi N, Higuchi T, Endo K. Comparison of HC-cholinePET and FDG PET for the differential diagnosis of malignant tumors. Eur J NuclMed Mol Imaging. 2004;31:1064-72.
[8] Haddad F, Ferrer L, Guertin A, et al. ARRONAX, a high-energy andhigh-intensity cyclotron for nuclear medicine. Eur J Nucl Med Mol Imaging.2008;35:1377-87.
[9] Moadel RM, Weldon RH, Katz EB, et al. Positherapy: targeted nuclear therapyof breast cancer with 18F-2-deoxy-2-fluoro-D-glucose. Cancer Res.2005;65:698-702.
[10] Seidlin SM, Marinelli LD, Oshry E. Radioactive iodine therapy. JAMA.1946;132:838-47.
[11] Alavi A, Dann R, Chawluk J, Alavi J, Kushner M, Reivich M. Positron emissiontomography imaging of regional cerebral glucose metabolism. Semin Nucl Med.1986;16:2-34.
[12] Moadel RM, Nguyen AV, Lin EY, et al. Positron emission tomography agent2-deoxy-2-[18F]fluoro-D-glucose has a therapeutic potential in breast cancer.Breast Cancer Res. 2003;5:R199-205.
[13] Knoess C, Siegel S, Smith A, et al. Performance evaluation of the microPET R4PET scanner for rodents. Eur J Nucl Med Mol Imaging. 2003;30:737-47.
[14] Weber S, Bauer A. Small animal PET: aspects of performance assessment. Eur JNucl Med Mol Imaging. 2004;31:1545-55.
[15] 李建,吴志芳.最大后验概率重建算法在发射CT中的应用.CT理论与应用研究.2005:14:10-5.
[16] Sutherland BM, Bennett PV, Saparbaev M, Sutherland JC, Laval J. ClusteredDNA damages as dosemeters for ionising radiation exposure and biologicalresponses. Radiat Prot Dosimetry. 2001 ;97:33-8.
[17] Buchholz TA. Radiation therapy for early-stage breast cancer afterbreast-conserving surgery. N Engl J Med. 2009;360:63-70.
[18] Tuteja N, Tuteja R. Unraveling DNA repair in human: molecular mechanismsand consequences of repair defect. Crit Rev Biochem Mol Biol. 2001;36:261-90.
[19] Hays MT, Segall GM. A mathematical model for the distribution offluorodeoxyglucose in humans. J Nucl Med. 1999;40:1358-66.
[20] Barrington SF, Maisey MN. Skeletal muscle uptake of fluorine-18-FDG: effectof oral diazepam. J Nucl Med. 1996;37:1127-9.
[21] Moran JK, Lee HB, Blaufox MD. Optimization of urinary FDG excretion duringPET imaging. J Nucl Med. 1999;40:1352-7.
[22] Bruccoleri A, Pennypacker KR, Harry GJ. Effect of dexamethasone on elevatedcytokine mRNA levels in chemical-induced hippocampal injury. J Neurosci Res.1999;57:916-26.
[23] Macheda ML, Rogers S, Best JD. Molecular and cellular regulation of glucosetransporter (GLUT) proteins in cancer. J Cell Physiol. 2005;202:654-62.
[24] Mueckler M. Facilitative glucose transporters. Eur J Biochem. 1994;219:713-25.
[25] Bell GI, Kayano T, Buse JB, et al. Molecular biology of mammalian glucosetransporters. Diabetes Care. 1990;l3:198-208.
[26] Wincewicz A, Sulkowska M, Koda M, Sulkowski S. Clinicopathologicalsignificance and linkage of the distribution of HIF-1 alpha and GLUT-1 in humanprimary colorectal cancer. Pathol Oncol Res. 2007;13:15-20.
[27] Ito T, Noguchi Y, Udaka N, Kitamura H, Satoh S. Glucose transporter expressionin developing fetal lungs and lung neoplasms. Histol Histopathol.1999;14:895-904.
[28] Sakashita M, Aoyama N, Minami R, et al. Glutl expression in Tl and T2 stagecolorectal carcinomas: its relationship to clinicopathological features. Eur JCancer. 2001 ;37:204-9.
[29] Parente P, Coli A, Massi G, Mangoni A, Fabrizi MM, Bigotti G.Immunohistochemical expression of the glucose transporters Glut-1 and Glut-3in human malignant melanomas and benign melanocytic lesions. J Exp ClinCancer Res. 2008;27:34.
[30] Loges S, Roncal C, Carmeliet P. Development of targeted angiogenic medicine.J Thromb Haemost. 2009;7:21-33.
[31] Gorski DH, Beckett MA, Jaskowiak NT, et al. Blockage of the vascularendothelial growth factor stress response increases the antitumor effects ofionizing radiation. Cancer Res. 1999;59:3374-8.
[32] O'Reilly MS. The interaction of radiation therapy and antiangiogenic therapy.Cancer J. 2008;14:207-13.
[1] Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol. 2001;2:533-43.
[2] Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71-96.
[3] Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225-49.
[4] Zoller F, Eisenhut M, Haberkorn U, Mier W. Endoradiotherapy in cancer treatment-basic concepts and future trends. Eur J Pharmacol. 2009;625:55-62.
[5] Haberkorn U, Eisenhut M, Altmann A, Mier W. Endoradiotherapy with peptides - status and future development. Curr Med Chem. 2008;15:219-34.
[6] Wangler C, Buchmann I, Eisenhut M, Haberkorn U, Mier W. Radiolabeled peptides and proteins in cancer therapy. Protein Pept Lett. 2007;14:273-9.
[7] Ting G, Chang CH, Wang HE. Cancer nanotargeted radiopharmaceuticals for tumor imaging and therapy. Anticancer Res. 2009;29:4107-18.
[8] Ishihara S, Watanabe T. [Significance of chemo-radiotherapy of rectal neoplasms]. Gan To Kagaku Ryoho. 2009;36:1822-5.
[9] Yeung AH, Sughrue ME, Kane AJ, Tihan T, Cheung SW, Parsa AT. Radiobiology of vestibular schwannomas: mechanisms of radioresistance and potential targets for therapeutic sensitization. Neurosurg Focus. 2009;27:E2.
[10] Colangelo JE, Johnston J, Killion JB, Wright DL. Radiation biology and protection. Radiol Technol. 2009;80:421-41.
[11] Powers WE. Radiation biological contributions to radiation therapy. Proc Can Cancer Conf. 1967;7:405-32.
[12] 王荣福.核医学. 林景辉,王荣福.放射性核素治疗.北京:北京大学医学出版社；2004:190-1.
[13] Malone JF. The radiation biology of the thyroid. Curr Top Radiat Res Q. 1975;10:263-368.
[14] 黄建敏,曲雁,王荣福.恶性肿瘤骨转移骨痛的核素诊治现状与进展.中国医学影像技术杂志.2004;20:480-3.
[15] Clark JC, Dass CR, Choong PF. Current and future treatments of bone metastases. Expert Opin Emerg Drugs. 2008;13:609-27.
[16] 欧阳巧洪,田嘉禾,滕小梅,刘加昌,张瑾,文志道.153Sm-EDTMP治疗癌性骨痛的影响因素研究.感染、炎症、修复.2001;2:120-3.
[17] 冯真贵.153Sm-EDTMP治疗骨转移瘤前后骨摄取比变化及与镇痛效果比较.实用肿瘤杂志2002;17:98-101.
[18] Lessig MK. The role of 131I-MIBG in high-risk neuroblastoma treatment. J Pediatr Oncol Nurs. 2009;26:208-16.
[19] Vlcek P, Michalova K, Taborska K, Sykorova P. [Radionuclide screening in endocrinology]. Vnitr Lek. 2006;52:969-72.
[20] Loh KC, Fitzgerald PA, Matthay KK, Yeo PP, Price DC. The treatment of malignant pheochromocytoma with iodine-131 metaiodobenzylguanidine (131I-MEBG): a comprehensive review of 116 reported patients. J Endocrinol Invest. 1997;20:648-58.
[21] Rose B, Matthay KK, Price D, et al. High-dose 131I-metaiodobenzylguanidine therapy for 12 patients with malignant pheochromocytoma. Cancer. 2003;98:239-48.
[22] Lam MG, Lips CJ, Jager PL, et al. Repeated [131I]metaiodobenzylguanidine therapy in two patients with malignant pheochromocytoma. J Clin Endocrinol Metab. 2005;90:5888-95.
[23] Ciezki JP, Klein EA. Brachytherapy or surgery? A composite view. Oncology (Williston Park). 2009;23:960-4.
[24] Sandier HM, Mirhadi AJ. Radical radiotherapy for prostate cancer is the 'only way to go'. Oncology (Williston Park). 2009;23:840-3.
[25] Winterhalder RC. [Prostate cancer: a review of therapeutic strategies]. Praxis (Bern 1994). 2009;98:1149-53.
[26] Bagshaw MA, Kaplan ED, Cox RC. Prostate cancer. Radiation therapy for localized disease. Cancer. 1993;71:939-52.
[27] Ray GR, Bagshaw MA. The role of radiation therapy in the definitive treatment of adenocarcinoma of the prostate. Annu Rev Med. 1975;26:567-88.
[28] Del Regato JA. Radiotherapy in the conservative treatment of operable and locally inoperable carcinoma of the prostate. Radiology. 1967;88:761-6.
[29] del Regato JA, Trailins AH, Pittman DD. Twenty years follow-up of patients with inoperable cancer of the prostate (stage C) treated by radiotherapy: report of a national cooperative study.Int J Radiat Oncol Biol Phys. 1993;26:197-201.
[30] Bennett JE. Treatment of carcinoma of the prostate by cobalt-beam therapy. Radiology. 1968;90:532-5.
[31] Estrada PC, Scardino PL. Total perineal prostatectomy after cobalt 60 therapy: report of a case. J Urol. 1971;106:100-1.
[32] Davis WH, Scardino PL, Carlton FE. Radical perineal prostatectomy: a 20-year overview. J Urol. 1972;108:604-8.
[33] Scardino PT, Frankel JM, Wheeler TM, et al. The prognostic significance of post-irradiation biopsy results in patients with prostatic cancer. J Urol. 1986;135:510-6.
[34] Parker WR, Montgomery JS, Wood DP, Jr. Quality of life outcomes following treatment for localized prostate cancer: is there a clear winner? Curr Opin Urol. 2009;19:303-8.
[35] Parmentier C, Gardet P. The use of 32 phosphorus (32P) in the treatment of polycythemia vera. Nouv Rev Fr Hematol. 1994;36:189-92.
[36] Najean Y, Rain JD, Dresch C, et al. Risk of leukaemia, carcinoma, and myelofibrosis in 32P- or chemotherapy-treated patients with polycythaemia vera: a prospective analysis of 682 cases. The "French Cooperative Group for the Study of Polycythaemias". Leuk Lymphoma. 1996;22 Suppl 1:111-9.
[37] Berlin NI. Treatment of the myeloproliferative disorders with 32P. Eur J Haematol. 2000;65:1-7.
[38] Tefferi A, Silverstein MN. Treatment of polycythaemia vera and essential thrombocythaemia. Baillieres Clin Haematol. 1998;11:769-85.
[39] 梁培炎,李群,张伟光,杨小春,钱剑杨,张林.放射性核素磷近距离治疗小儿皮肤血管瘤的近期疗效.新医学.2002;33:67-71.
[40] Keezer MR, Del Maestro R. Radiation-induced cavernous hemangiomas: case report and literature review. Can J Neurol Sci. 2009;36:303-10.
[41] 邓敬兰.131I-MG7在胃癌患者体内的动态分布观察.中华核医学杂志.1997;17:114-6.
[42] Li Y, Tan T, Mo T, et al. [Pharmacokinetics of injection of iodine-131 labelling MEI-TUO-XI monoclonal antibody in human body]. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2007;24:857-61.
[43] Gold DV, Cardillo T, Goldenberg DM, Sharkey RM. Localization of pancreatic cancer with radiolabeled monoclonal antibody PAM4. Crit Rev Oncol Hematol. 2001;39:147-54.
[44] Alduaij W, Illidge TM. Radioimmunotherapy: strategies for the future in indolent and aggressive lymphoma. Curr Oncol Rep. 2009;11:363-70.
[45] Sharkey RM, Goldenberg DM. Novel radioimmunopharmaceuticals for cancer imaging and therapy. Curr Opin Investig Drugs. 2008;9:1302-16.
[46] Ansquer C, Kraeber-Bodere F, Chatal JF. Current status and perspectives in peptide receptor radiation therapy. Curr Pharm Des. 2009;15:2453-62.
[47] Zaccaro L, Del Gatto A, Pedone C, Saviano M. Peptides for tumour therapy and diagnosis: current status and future directions. Curr Med Chem. 2009;16:780-95.
[48] Hubalewska-Dydejczyk A, Trofimiuk M, Sowa-Staszczak A, et al. [Somatostatin receptors expression (SSTR1-SSTR5) in pheochromocytomas]. Przegl Lek. 2008;65:405-7.
[49] Volante M, Rosas R, Allia E, et al. Somatostatin, cortistatin and their receptors in tumours. Mol Cell Endocrinol. 2008;286:219-29.
[50] Waldherr C, Pless M, Maecke HR, Haldemann A, Mueller-Brand J. The clinical value of [90Y-DOTA]-D-Phel-Tyr3-octreotide (90Y-DOTATOC) in the treatment of neuroendocrine tumours: a clinical phase II study. Ann Oncol. 2001;12:941-5.
[51] Forrer F, Waldherr C, Maecke HR, Mueller-Brand J. Targeted radionuclide therapy with 90Y-DOTATOC in patients with neuroendocrine tumors. Anticancer Res. 2006;26:703-7.
[52] Schumacher T, Hofer S, Eichhorn K, et al. Local injection of the 90Y-labelled peptidic vector DOTATOC to control gliomas of WHO grades Ⅱ and Ⅲ: an extended pilot study. Eur J Nucl Med Mol Imaging. 2002;29:486-93.
[53] Raty JK, Pikkarainen JT, Wirth T, Yla-Herttuala S. Gene therapy: the first approved gene-based medicines, molecular mechanisms and clinical indications. Curr Mol Pharmacol. 2008;1:13-23.
[54] Boland A, Ricard M, Opolon P, et al. Adenovirus-mediated transfer of the thyroid sodium/iodide symporter gene into tumors for a targeted radiotherapy. Cancer Res. 2000;60:3484-92.
[55] Rogers BE, Rosenfeld ME, Khazaeli MB, et al. Localization of iodine-125-mIP-Des-Metl4-bombesin (7-13)NH2 in ovarian carcinoma induced to express the gastrin releasing peptide receptor by adenoviral vector-mediated gene transfer. J Nucl Med. 1997;38:1221-9.
[56] Germann C, Shields AF, Grierson JR, Morr I, Haberkorn U. 5-Fluoro-1-(2'-deoxy-2'-fluoro-beta-D-ribofuranosyl) uracil trapping in Morris hepatoma cells expressing the herpes simplex virus thymidine kinase gene. J Nucl Med. 1998;39:1418-23.
[57] Lammering G, Hewit TH, Hawkins WT, et al. Epidermal growth factor receptor as a genetic therapy target for carcinoma cell radiosensitization. J Natl Cancer Inst. 2001;93:921-9.
[58] Ou XH, Tan TZ, Li YC. [Preparation and biodistribution of VIP-125I-ASON]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2005;36:713-6.
[59] Sedelnikova OA, Panyutin IG, Luu AN, et al. Targeting the human mdr1 gene by 125I-labeled triplex-forming oligonucleotides. Antisense Nucleic Acid Drug Dev. 2000;10:443-52.
[60] Gaidamakova EK, Neumann RD, Panyutin IG. Antisense radiotherapy: targeting full-size mdrl mRNA with 125I-labelled oligonucleotides. Int J Radiat Biol. 2004;80:889-93.
[61] Kairemo KJ, Tenhunen M, Jekunen AP. Gene therapy using antisense oligodeoxynucleotides labeled with Auger-emitting radionuclides. Cancer Gene Ther. 1998;5:408-12.
[62] Wagner HN, Jr. 2003 SNM Highlights Lecture: From proof of principle to proof of value. J Nucl Med. 2003;44:11N-36N.
[63] Xu MH, Zhang GY. Effect of indomethacin on cell cycle proteins in colon cancer cell lines. World J Gastroenterol. 2005;11:1693-6.
[64] Mima S, Takehara M, Takada H, Nishimura T, Hoshino T, Mizushima T. NSAIDs suppress the expression of claudin-2 to promote invasion activity of cancer cells. Carcinogenesis. 2008;29:1994-2000.
[65] Gregoire V, Hunter NR, Brock WA, Hittelman WN, Plunkett W, Milas L. Improvement in the therapeutic ratio of radiotherapy for a murine sarcoma by indomethacin plus fludarabine. Radiat Res. 1996;146:548-53.
[66] Kishi K, Petersen S, Petersen C, et al. Preferential enhancement of tumor radioresponse by a cyclooxygenase-2 inhibitor. Cancer Res. 2000;60:1326-31.
[67] 周丽坤,张彩霞.氚标记吲哚美辛的亲肿瘤实验研究.中华核医学杂志. 2004;24:209-10.
[68]陈春梅,张彩霞,刁尧,董薇.吲哚美辛对荷瘤小鼠抗肿瘤作用机制的实验研究.同位素.2006;19:22-7.
[2] Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin.2008;58:71-96.
[3] Chan TA. Nonsteroidal anti-inflammatory drugs, apoptosis, and colon-cancerchemoprevention. Lancet Oncol. 2002 ;3:166-74.
[4] Caridad V, Arsenak M, Abad MJ, et al. Effective radiotherapy of primary tumorsand metastasis with 18F-2-deoxy-2-fluoro-D-glucose in C57BL/6 mice. CancerBiother Radiopharm. 2008;23:371-5.
[5] Rohren EM, Turkington TG, Coleman RE. Clinical applications of PET inoncology. Radiology. 2004;231:305-32.
[6] Gallagher BM, Fowler JS, Gutterson NI, MacGregor RR, Wan CN, Wolf AP.Metabolic trapping as a principle of oradiopharmaceutical design: some factorsresposible for the biodistribution of [18F] 2-deoxy-2-fluoro-D-glucose. J NuclMed. 1978;19:1154-61.
[7] Tian M, Zhang H, Oriuchi N, Higuchi T, Endo K. Comparison of HC-cholinePET and FDG PET for the differential diagnosis of malignant tumors. Eur J NuclMed Mol Imaging. 2004;31:1064-72.
[8] Haddad F, Ferrer L, Guertin A, et al. ARRONAX, a high-energy andhigh-intensity cyclotron for nuclear medicine. Eur J Nucl Med Mol Imaging.2008;35:1377-87.
[9] Moadel RM, Weldon RH, Katz EB, et al. Positherapy: targeted nuclear therapyof breast cancer with 18F-2-deoxy-2-fluoro-D-glucose. Cancer Res.2005;65:698-702.
[10] Seidlin SM, Marinelli LD, Oshry E. Radioactive iodine therapy. JAMA.1946;132:838-47.
[11] Alavi A, Dann R, Chawluk J, Alavi J, Kushner M, Reivich M. Positron emissiontomography imaging of regional cerebral glucose metabolism. Semin Nucl Med.1986;16:2-34.
[12] Moadel RM, Nguyen AV, Lin EY, et al. Positron emission tomography agent2-deoxy-2-[18F]fluoro-D-glucose has a therapeutic potential in breast cancer.Breast Cancer Res. 2003;5:R199-205.
[13] Knoess C, Siegel S, Smith A, et al. Performance evaluation of the microPET R4PET scanner for rodents. Eur J Nucl Med Mol Imaging. 2003;30:737-47.
[14] Weber S, Bauer A. Small animal PET: aspects of performance assessment. Eur JNucl Med Mol Imaging. 2004;31:1545-55.
[15] 李建,吴志芳.最大后验概率重建算法在发射CT中的应用.CT理论与应用研究.2005:14:10-5.
[16] Sutherland BM, Bennett PV, Saparbaev M, Sutherland JC, Laval J. ClusteredDNA damages as dosemeters for ionising radiation exposure and biologicalresponses. Radiat Prot Dosimetry. 2001 ;97:33-8.
[17] Buchholz TA. Radiation therapy for early-stage breast cancer afterbreast-conserving surgery. N Engl J Med. 2009;360:63-70.
[18] Tuteja N, Tuteja R. Unraveling DNA repair in human: molecular mechanismsand consequences of repair defect. Crit Rev Biochem Mol Biol. 2001;36:261-90.
[19] Hays MT, Segall GM. A mathematical model for the distribution offluorodeoxyglucose in humans. J Nucl Med. 1999;40:1358-66.
[20] Barrington SF, Maisey MN. Skeletal muscle uptake of fluorine-18-FDG: effectof oral diazepam. J Nucl Med. 1996;37:1127-9.
[21] Moran JK, Lee HB, Blaufox MD. Optimization of urinary FDG excretion duringPET imaging. J Nucl Med. 1999;40:1352-7.
[22] Bruccoleri A, Pennypacker KR, Harry GJ. Effect of dexamethasone on elevatedcytokine mRNA levels in chemical-induced hippocampal injury. J Neurosci Res.1999;57:916-26.
[23] Macheda ML, Rogers S, Best JD. Molecular and cellular regulation of glucosetransporter (GLUT) proteins in cancer. J Cell Physiol. 2005;202:654-62.
[24] Mueckler M. Facilitative glucose transporters. Eur J Biochem. 1994;219:713-25.
[25] Bell GI, Kayano T, Buse JB, et al. Molecular biology of mammalian glucosetransporters. Diabetes Care. 1990;l3:198-208.
[26] Wincewicz A, Sulkowska M, Koda M, Sulkowski S. Clinicopathologicalsignificance and linkage of the distribution of HIF-1 alpha and GLUT-1 in humanprimary colorectal cancer. Pathol Oncol Res. 2007;13:15-20.
[27] Ito T, Noguchi Y, Udaka N, Kitamura H, Satoh S. Glucose transporter expressionin developing fetal lungs and lung neoplasms. Histol Histopathol.1999;14:895-904.
[28] Sakashita M, Aoyama N, Minami R, et al. Glutl expression in Tl and T2 stagecolorectal carcinomas: its relationship to clinicopathological features. Eur JCancer. 2001 ;37:204-9.
[29] Parente P, Coli A, Massi G, Mangoni A, Fabrizi MM, Bigotti G.Immunohistochemical expression of the glucose transporters Glut-1 and Glut-3in human malignant melanomas and benign melanocytic lesions. J Exp ClinCancer Res. 2008;27:34.
[30] Loges S, Roncal C, Carmeliet P. Development of targeted angiogenic medicine.J Thromb Haemost. 2009;7:21-33.
[31] Gorski DH, Beckett MA, Jaskowiak NT, et al. Blockage of the vascularendothelial growth factor stress response increases the antitumor effects ofionizing radiation. Cancer Res. 1999;59:3374-8.
[32] O'Reilly MS. The interaction of radiation therapy and antiangiogenic therapy.Cancer J. 2008;14:207-13.
[1] Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol. 2001;2:533-43.
[2] Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71-96.
[3] Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225-49.
[4] Zoller F, Eisenhut M, Haberkorn U, Mier W. Endoradiotherapy in cancer treatment-basic concepts and future trends. Eur J Pharmacol. 2009;625:55-62.
[5] Haberkorn U, Eisenhut M, Altmann A, Mier W. Endoradiotherapy with peptides - status and future development. Curr Med Chem. 2008;15:219-34.
[6] Wangler C, Buchmann I, Eisenhut M, Haberkorn U, Mier W. Radiolabeled peptides and proteins in cancer therapy. Protein Pept Lett. 2007;14:273-9.
[7] Ting G, Chang CH, Wang HE. Cancer nanotargeted radiopharmaceuticals for tumor imaging and therapy. Anticancer Res. 2009;29:4107-18.
[8] Ishihara S, Watanabe T. [Significance of chemo-radiotherapy of rectal neoplasms]. Gan To Kagaku Ryoho. 2009;36:1822-5.
[9] Yeung AH, Sughrue ME, Kane AJ, Tihan T, Cheung SW, Parsa AT. Radiobiology of vestibular schwannomas: mechanisms of radioresistance and potential targets for therapeutic sensitization. Neurosurg Focus. 2009;27:E2.
[10] Colangelo JE, Johnston J, Killion JB, Wright DL. Radiation biology and protection. Radiol Technol. 2009;80:421-41.
[11] Powers WE. Radiation biological contributions to radiation therapy. Proc Can Cancer Conf. 1967;7:405-32.
[12] 王荣福.核医学. 林景辉,王荣福.放射性核素治疗.北京:北京大学医学出版社；2004:190-1.
[13] Malone JF. The radiation biology of the thyroid. Curr Top Radiat Res Q. 1975;10:263-368.
[14] 黄建敏,曲雁,王荣福.恶性肿瘤骨转移骨痛的核素诊治现状与进展.中国医学影像技术杂志.2004;20:480-3.
[15] Clark JC, Dass CR, Choong PF. Current and future treatments of bone metastases. Expert Opin Emerg Drugs. 2008;13:609-27.
[16] 欧阳巧洪,田嘉禾,滕小梅,刘加昌,张瑾,文志道.153Sm-EDTMP治疗癌性骨痛的影响因素研究.感染、炎症、修复.2001;2:120-3.
[17] 冯真贵.153Sm-EDTMP治疗骨转移瘤前后骨摄取比变化及与镇痛效果比较.实用肿瘤杂志2002;17:98-101.
[18] Lessig MK. The role of 131I-MIBG in high-risk neuroblastoma treatment. J Pediatr Oncol Nurs. 2009;26:208-16.
[19] Vlcek P, Michalova K, Taborska K, Sykorova P. [Radionuclide screening in endocrinology]. Vnitr Lek. 2006;52:969-72.
[20] Loh KC, Fitzgerald PA, Matthay KK, Yeo PP, Price DC. The treatment of malignant pheochromocytoma with iodine-131 metaiodobenzylguanidine (131I-MEBG): a comprehensive review of 116 reported patients. J Endocrinol Invest. 1997;20:648-58.
[21] Rose B, Matthay KK, Price D, et al. High-dose 131I-metaiodobenzylguanidine therapy for 12 patients with malignant pheochromocytoma. Cancer. 2003;98:239-48.
[22] Lam MG, Lips CJ, Jager PL, et al. Repeated [131I]metaiodobenzylguanidine therapy in two patients with malignant pheochromocytoma. J Clin Endocrinol Metab. 2005;90:5888-95.
[23] Ciezki JP, Klein EA. Brachytherapy or surgery? A composite view. Oncology (Williston Park). 2009;23:960-4.
[24] Sandier HM, Mirhadi AJ. Radical radiotherapy for prostate cancer is the 'only way to go'. Oncology (Williston Park). 2009;23:840-3.
[25] Winterhalder RC. [Prostate cancer: a review of therapeutic strategies]. Praxis (Bern 1994). 2009;98:1149-53.
[26] Bagshaw MA, Kaplan ED, Cox RC. Prostate cancer. Radiation therapy for localized disease. Cancer. 1993;71:939-52.
[27] Ray GR, Bagshaw MA. The role of radiation therapy in the definitive treatment of adenocarcinoma of the prostate. Annu Rev Med. 1975;26:567-88.
[28] Del Regato JA. Radiotherapy in the conservative treatment of operable and locally inoperable carcinoma of the prostate. Radiology. 1967;88:761-6.
[29] del Regato JA, Trailins AH, Pittman DD. Twenty years follow-up of patients with inoperable cancer of the prostate (stage C) treated by radiotherapy: report of a national cooperative study.Int J Radiat Oncol Biol Phys. 1993;26:197-201.
[30] Bennett JE. Treatment of carcinoma of the prostate by cobalt-beam therapy. Radiology. 1968;90:532-5.
[31] Estrada PC, Scardino PL. Total perineal prostatectomy after cobalt 60 therapy: report of a case. J Urol. 1971;106:100-1.
[32] Davis WH, Scardino PL, Carlton FE. Radical perineal prostatectomy: a 20-year overview. J Urol. 1972;108:604-8.
[33] Scardino PT, Frankel JM, Wheeler TM, et al. The prognostic significance of post-irradiation biopsy results in patients with prostatic cancer. J Urol. 1986;135:510-6.
[34] Parker WR, Montgomery JS, Wood DP, Jr. Quality of life outcomes following treatment for localized prostate cancer: is there a clear winner? Curr Opin Urol. 2009;19:303-8.
[35] Parmentier C, Gardet P. The use of 32 phosphorus (32P) in the treatment of polycythemia vera. Nouv Rev Fr Hematol. 1994;36:189-92.
[36] Najean Y, Rain JD, Dresch C, et al. Risk of leukaemia, carcinoma, and myelofibrosis in 32P- or chemotherapy-treated patients with polycythaemia vera: a prospective analysis of 682 cases. The "French Cooperative Group for the Study of Polycythaemias". Leuk Lymphoma. 1996;22 Suppl 1:111-9.
[37] Berlin NI. Treatment of the myeloproliferative disorders with 32P. Eur J Haematol. 2000;65:1-7.
[38] Tefferi A, Silverstein MN. Treatment of polycythaemia vera and essential thrombocythaemia. Baillieres Clin Haematol. 1998;11:769-85.
[39] 梁培炎,李群,张伟光,杨小春,钱剑杨,张林.放射性核素磷近距离治疗小儿皮肤血管瘤的近期疗效.新医学.2002;33:67-71.
[40] Keezer MR, Del Maestro R. Radiation-induced cavernous hemangiomas: case report and literature review. Can J Neurol Sci. 2009;36:303-10.
[41] 邓敬兰.131I-MG7在胃癌患者体内的动态分布观察.中华核医学杂志.1997;17:114-6.
[42] Li Y, Tan T, Mo T, et al. [Pharmacokinetics of injection of iodine-131 labelling MEI-TUO-XI monoclonal antibody in human body]. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2007;24:857-61.
[43] Gold DV, Cardillo T, Goldenberg DM, Sharkey RM. Localization of pancreatic cancer with radiolabeled monoclonal antibody PAM4. Crit Rev Oncol Hematol. 2001;39:147-54.
[44] Alduaij W, Illidge TM. Radioimmunotherapy: strategies for the future in indolent and aggressive lymphoma. Curr Oncol Rep. 2009;11:363-70.
[45] Sharkey RM, Goldenberg DM. Novel radioimmunopharmaceuticals for cancer imaging and therapy. Curr Opin Investig Drugs. 2008;9:1302-16.
[46] Ansquer C, Kraeber-Bodere F, Chatal JF. Current status and perspectives in peptide receptor radiation therapy. Curr Pharm Des. 2009;15:2453-62.
[47] Zaccaro L, Del Gatto A, Pedone C, Saviano M. Peptides for tumour therapy and diagnosis: current status and future directions. Curr Med Chem. 2009;16:780-95.
[48] Hubalewska-Dydejczyk A, Trofimiuk M, Sowa-Staszczak A, et al. [Somatostatin receptors expression (SSTR1-SSTR5) in pheochromocytomas]. Przegl Lek. 2008;65:405-7.
[49] Volante M, Rosas R, Allia E, et al. Somatostatin, cortistatin and their receptors in tumours. Mol Cell Endocrinol. 2008;286:219-29.
[50] Waldherr C, Pless M, Maecke HR, Haldemann A, Mueller-Brand J. The clinical value of [90Y-DOTA]-D-Phel-Tyr3-octreotide (90Y-DOTATOC) in the treatment of neuroendocrine tumours: a clinical phase II study. Ann Oncol. 2001;12:941-5.
[51] Forrer F, Waldherr C, Maecke HR, Mueller-Brand J. Targeted radionuclide therapy with 90Y-DOTATOC in patients with neuroendocrine tumors. Anticancer Res. 2006;26:703-7.
[52] Schumacher T, Hofer S, Eichhorn K, et al. Local injection of the 90Y-labelled peptidic vector DOTATOC to control gliomas of WHO grades Ⅱ and Ⅲ: an extended pilot study. Eur J Nucl Med Mol Imaging. 2002;29:486-93.
[53] Raty JK, Pikkarainen JT, Wirth T, Yla-Herttuala S. Gene therapy: the first approved gene-based medicines, molecular mechanisms and clinical indications. Curr Mol Pharmacol. 2008;1:13-23.
[54] Boland A, Ricard M, Opolon P, et al. Adenovirus-mediated transfer of the thyroid sodium/iodide symporter gene into tumors for a targeted radiotherapy. Cancer Res. 2000;60:3484-92.
[55] Rogers BE, Rosenfeld ME, Khazaeli MB, et al. Localization of iodine-125-mIP-Des-Metl4-bombesin (7-13)NH2 in ovarian carcinoma induced to express the gastrin releasing peptide receptor by adenoviral vector-mediated gene transfer. J Nucl Med. 1997;38:1221-9.
[56] Germann C, Shields AF, Grierson JR, Morr I, Haberkorn U. 5-Fluoro-1-(2'-deoxy-2'-fluoro-beta-D-ribofuranosyl) uracil trapping in Morris hepatoma cells expressing the herpes simplex virus thymidine kinase gene. J Nucl Med. 1998;39:1418-23.
[57] Lammering G, Hewit TH, Hawkins WT, et al. Epidermal growth factor receptor as a genetic therapy target for carcinoma cell radiosensitization. J Natl Cancer Inst. 2001;93:921-9.
[58] Ou XH, Tan TZ, Li YC. [Preparation and biodistribution of VIP-125I-ASON]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2005;36:713-6.
[59] Sedelnikova OA, Panyutin IG, Luu AN, et al. Targeting the human mdr1 gene by 125I-labeled triplex-forming oligonucleotides. Antisense Nucleic Acid Drug Dev. 2000;10:443-52.
[60] Gaidamakova EK, Neumann RD, Panyutin IG. Antisense radiotherapy: targeting full-size mdrl mRNA with 125I-labelled oligonucleotides. Int J Radiat Biol. 2004;80:889-93.
[61] Kairemo KJ, Tenhunen M, Jekunen AP. Gene therapy using antisense oligodeoxynucleotides labeled with Auger-emitting radionuclides. Cancer Gene Ther. 1998;5:408-12.
[62] Wagner HN, Jr. 2003 SNM Highlights Lecture: From proof of principle to proof of value. J Nucl Med. 2003;44:11N-36N.
[63] Xu MH, Zhang GY. Effect of indomethacin on cell cycle proteins in colon cancer cell lines. World J Gastroenterol. 2005;11:1693-6.
[64] Mima S, Takehara M, Takada H, Nishimura T, Hoshino T, Mizushima T. NSAIDs suppress the expression of claudin-2 to promote invasion activity of cancer cells. Carcinogenesis. 2008;29:1994-2000.
[65] Gregoire V, Hunter NR, Brock WA, Hittelman WN, Plunkett W, Milas L. Improvement in the therapeutic ratio of radiotherapy for a murine sarcoma by indomethacin plus fludarabine. Radiat Res. 1996;146:548-53.
[66] Kishi K, Petersen S, Petersen C, et al. Preferential enhancement of tumor radioresponse by a cyclooxygenase-2 inhibitor. Cancer Res. 2000;60:1326-31.
[67] 周丽坤,张彩霞.氚标记吲哚美辛的亲肿瘤实验研究.中华核医学杂志. 2004;24:209-10.
[68]陈春梅,张彩霞,刁尧,董薇.吲哚美辛对荷瘤小鼠抗肿瘤作用机制的实验研究.同位素.2006;19:22-7.