ATRA联合奈达铂对人肝癌细胞株Huh-7增殖与凋亡的影响
摘要
目的：通过本实验观察全反式维甲酸(Alltrans Retinoic Acid,ATRA)、奈达铂(Nedaplatin,NDP)及其两药联合应用对人肝癌细胞株Huh-7增殖与凋亡的影响,探讨本实验中化疗药物联合应用的相互作用。
方法：
通过选取不同的实验浓度如下,ATRA分设10-6、10-5、10-4mol/L三组、NDP设1、2、5mg/L三组,随后通过预实验筛选出ATRA10-5mol/L联合不同浓度NDP(1、2、5mg/L)分别作用于肝癌Huh-7细胞24、48、72h；另外,将ATRA(10-5 mol/L)+NDP(1mg/L)作为联合处理药物组作用于肝癌Huh-7细胞24h、48h、72h；应用医用倒置显微镜观察实验前后HUh-7细胞的形态学变化,四甲基偶氮唑蓝(MTT)法观察ATRA、NDP及其两药联合应用对肝癌Huh-7细胞增殖的影响；同时采用流式细胞仪分析其对肝癌Huh-7细胞凋亡率的影响。
结果：
实验中不同浓度的全反式维甲酸ATRA(10-6、10-5、10-4 mol/L)和奈达铂NDP(1、2、5mg/L)单独作用于肝癌Huh-7细胞均有明显的抑制作用,且该作用随时间的延长、浓度的增高也渐增强；ATRA与NDP两药联合应用于HUh-7细胞后表现为协同作用,联合用药组与单药组相比,P<0.01。用流式细胞仪进行凋亡率检测,结果显示：ATRA处理HUh-7细胞48h后的凋亡率为：对照组0.82±0.15%, ATRA(10-6mol/L)组31.9±1.91%,ATRA(10-5mol/L)组42.57±1.03%,实验组与对照组比较(P<0.05)；NDP单药处理48h后,对照组为0.34±0.07%,药物组即1、2、5mg/L凋亡率分别为28.49±0.6%、38.53±0.7%、46.6±1.1%；ATRA、NDP两药联合作用48 h后,对照组为0.82%±0.15%,NDP 1 mg/L组为28.49%±0.6%,ATRA 10-5 mol/L组为42.57%±1.03%, ATRA10-5mol/L+NDP 1mg/L联合作用组为55.35%±1.30%,与单药比较差异有显著统计学意义(P<0.01)。
结论：
全反式维甲酸ATRA与奈达铂NDP对人肝癌Huh-7细胞株均有抑制增殖和诱导凋亡的作用,且联合用药组与单药组比较,全反式维甲酸ATRA与奈达铂NDP两药联合应用于肝癌Huh-7细胞,具有明显协同作用。
Objective:By this experiment, to observed the effects of Alltrans Retinoic Acid (ATRA) and Nedaplatin (NDP) alone and their combined effects for cell proliferation and apoptosis on human hepatoma cell line Huh-7 in vitro, and to investigated the effect combination of chemotherapy medicine to cure hepatoma.
Methods:By choosing the medicines at different concentrations of ATRA(10-6、10-5 10-4mol/L) and NDP (1、2、5mg/L)alone and combine effects for hepatoma cell 24、48、72h, Others, the medicines effective final concentration determined by pre-screen test, ATRA(10-5mol/1) combined with NDP (1mg/1) was used to treat hepatoma cells for 24、48、72h. Cell morphology changes was detected using inverted micros-copy; MTT-test was used to estimate the inhibition of proliferation on hepatoma cell line Huh-7;flow cytometry was applied to analyze the effect of cell apoptosis.
Results:Experiment with different concentrations of ATRA(10-6,10-5,10-4 mol/1) and NDP (1、2、5mg/1)could markedly inhibit the cell proliferation,and the effect depended on exposure time and concentration, and the effect of combining was additive and synergistic, which had statistical significance comparing with ATRA and Nedaplatin alone(P<0.01).Apoptosis rate by flow cytometry, and the results showed, ATRA effected Huh-7 cells apoptosis rate(48h):control group 0.82±0.15%, ATRA(10-6mol/L) 31.9±1.91%, ATRA (10-5mol/L) 42.57±1.03%, comparing with the experiment group and control group (P<0.05); NDP effected Huh-7 cells apoptosis rate(48h):the control group 0.34±0.07%, the drug groups of NDP(1、2、5 mg/L) were:28.49±0.6%,38.53±0.7% and 46.6±1.1%; and the combined use resulted in synergic effect, NDP (1 mg/1), ATRA (10-5ol/1) and the two combined,they induce the apoptosis rate of Huh-7 at 48h were 28.49%±0.6%、42.57%±1.03%、55.35%±1.30%. So that the combined group comparing with the single groups, P<0.01.
Conclusion:Both ATRA and NDP can inhibit cell proliferation and promote cell apoptosis of human hepatoma cell line Huh-7,and comparing with the single groups,ATRA combined with NDP can significantly increase the chemosensitivity on hepatoma cells.
方法：
通过选取不同的实验浓度如下,ATRA分设10-6、10-5、10-4mol/L三组、NDP设1、2、5mg/L三组,随后通过预实验筛选出ATRA10-5mol/L联合不同浓度NDP(1、2、5mg/L)分别作用于肝癌Huh-7细胞24、48、72h；另外,将ATRA(10-5 mol/L)+NDP(1mg/L)作为联合处理药物组作用于肝癌Huh-7细胞24h、48h、72h；应用医用倒置显微镜观察实验前后HUh-7细胞的形态学变化,四甲基偶氮唑蓝(MTT)法观察ATRA、NDP及其两药联合应用对肝癌Huh-7细胞增殖的影响；同时采用流式细胞仪分析其对肝癌Huh-7细胞凋亡率的影响。
结果：
实验中不同浓度的全反式维甲酸ATRA(10-6、10-5、10-4 mol/L)和奈达铂NDP(1、2、5mg/L)单独作用于肝癌Huh-7细胞均有明显的抑制作用,且该作用随时间的延长、浓度的增高也渐增强；ATRA与NDP两药联合应用于HUh-7细胞后表现为协同作用,联合用药组与单药组相比,P<0.01。用流式细胞仪进行凋亡率检测,结果显示：ATRA处理HUh-7细胞48h后的凋亡率为：对照组0.82±0.15%, ATRA(10-6mol/L)组31.9±1.91%,ATRA(10-5mol/L)组42.57±1.03%,实验组与对照组比较(P<0.05)；NDP单药处理48h后,对照组为0.34±0.07%,药物组即1、2、5mg/L凋亡率分别为28.49±0.6%、38.53±0.7%、46.6±1.1%；ATRA、NDP两药联合作用48 h后,对照组为0.82%±0.15%,NDP 1 mg/L组为28.49%±0.6%,ATRA 10-5 mol/L组为42.57%±1.03%, ATRA10-5mol/L+NDP 1mg/L联合作用组为55.35%±1.30%,与单药比较差异有显著统计学意义(P<0.01)。
结论：
全反式维甲酸ATRA与奈达铂NDP对人肝癌Huh-7细胞株均有抑制增殖和诱导凋亡的作用,且联合用药组与单药组比较,全反式维甲酸ATRA与奈达铂NDP两药联合应用于肝癌Huh-7细胞,具有明显协同作用。
Objective:By this experiment, to observed the effects of Alltrans Retinoic Acid (ATRA) and Nedaplatin (NDP) alone and their combined effects for cell proliferation and apoptosis on human hepatoma cell line Huh-7 in vitro, and to investigated the effect combination of chemotherapy medicine to cure hepatoma.
Methods:By choosing the medicines at different concentrations of ATRA(10-6、10-5 10-4mol/L) and NDP (1、2、5mg/L)alone and combine effects for hepatoma cell 24、48、72h, Others, the medicines effective final concentration determined by pre-screen test, ATRA(10-5mol/1) combined with NDP (1mg/1) was used to treat hepatoma cells for 24、48、72h. Cell morphology changes was detected using inverted micros-copy; MTT-test was used to estimate the inhibition of proliferation on hepatoma cell line Huh-7;flow cytometry was applied to analyze the effect of cell apoptosis.
Results:Experiment with different concentrations of ATRA(10-6,10-5,10-4 mol/1) and NDP (1、2、5mg/1)could markedly inhibit the cell proliferation,and the effect depended on exposure time and concentration, and the effect of combining was additive and synergistic, which had statistical significance comparing with ATRA and Nedaplatin alone(P<0.01).Apoptosis rate by flow cytometry, and the results showed, ATRA effected Huh-7 cells apoptosis rate(48h):control group 0.82±0.15%, ATRA(10-6mol/L) 31.9±1.91%, ATRA (10-5mol/L) 42.57±1.03%, comparing with the experiment group and control group (P<0.05); NDP effected Huh-7 cells apoptosis rate(48h):the control group 0.34±0.07%, the drug groups of NDP(1、2、5 mg/L) were:28.49±0.6%,38.53±0.7% and 46.6±1.1%; and the combined use resulted in synergic effect, NDP (1 mg/1), ATRA (10-5ol/1) and the two combined,they induce the apoptosis rate of Huh-7 at 48h were 28.49%±0.6%、42.57%±1.03%、55.35%±1.30%. So that the combined group comparing with the single groups, P<0.01.
Conclusion:Both ATRA and NDP can inhibit cell proliferation and promote cell apoptosis of human hepatoma cell line Huh-7,and comparing with the single groups,ATRA combined with NDP can significantly increase the chemosensitivity on hepatoma cells.
引文
[1]Von D, Lersch C, Mayr M, et al. Capecitabine for treatment of advanced hepatocellular carcinoma. Hepatogastroenterology 2007; 54:2310.
[2]Zhou GB, Zhang J, Wang ZY, et al. Treatment of acute promyelocytic leukaemia with all-trans retinoic acid and arsenic trioxide:a para-digm of synergistic molecular targeting therapy. Philos Trans R Soc Lond B Biol Sci 2007; 362:959-971.
[3]Frankfurt O, Tallman MS. Strategies for the treat-ment of acute promyelocytic leukemia. J Natl Compr Cane Netw 2006; 4:37-50.
[4]Ozeki M, Shively JE. Differential cell fates induced by all-trans retinoic acid-treated HL-60 human leu-kemia cells. J Leukoc Biol 2008; 84:769-779.
[5]Jiang M, Zhu K, Grenet J,et al. Retinoic acid induces caspase-8 transcription via phospho-CREB and increases apoptotic responses to death stimuli in neuroblastoma cells. Biochim Biophys Acta 2008; 1783:1055-1067.
[6]Alique M, Herrero JF, Lucio-Cazana FJ. All-trans retinoic acid induces COX-2 and prostaglandin E2 synthesis in SH-SY5Y human neuroblastoma cells:involvement of retinoic acid receptors and extra-cellular-regulated kinase 1/2. J Neuroinflammation 2007; 4:1.
[7]Chlapek P, Redova M, Zitterbart K, et al. Enhancement of ATRA-induced differentiation of neuroblastoma cells with LOX/COX inhibitors:an expression profiling study. J Exp Clin Cancer Res 2010; 29:45.
[8]Cheepala SB, Yin W, Syed Z,et al. Identification of the B-Raf/Mek/Erk MAP kinase pathway as a target for all-trans retinoic acid during skin cancer promotion. Mol Cancer 2009; 8:27.
[9]Dutta A, Sen T, Banerji A, et al. Studies on Multifunctional Effect of All-Trans Reti-noic Acid (ATRA) on Matrix Metalloproteinase-2 (MMP-2) and Its Regulatory Molecules in Human Breast Cancer Cells (MCF-7). J Oncol 2009; 2009:627840
[10]Patel JB, Mehta J, Belosay A,et al. Novel reti-noic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cells and tumour growth. Br J Cancer 2007; 96:1204-1215.
[11]Phipps SM, Love WK, White T, et al. Retinoid-induced histone deacety-lation inhibits telomerase activity in estrogen recep-tor-negative breast cancer cells. Anticancer Res 2009; 29:4959-4964.
[12]Hong J, Samudio I, Chintharlapal liS, et al.1,1-bis(3'-indolyl)-1-(p-substituted phenyl) methanes decrease mitochondrial membrane potential and in-duce apoptosis in endometrial and other cancer cell lines. Mol Carcinog 2008; 47:492-507.
[13]Malik M, Webb J, Catherino WH. Retinoic acid treatment of human leiomyoma cells transformed the cell phenotype to one strongly resembling myo-metrial cells. Clin Endocrinol (Oxf) 2008; 69:462-470.
[14]Radu M, Soprano DR, Soprano KJ. S10 phosphory-lation of p27 mediates atRA induced growth arrest in ovarian carcinoma cell lines. J Cell Physiol 2008; 217:558-568.
[15]Xu Q, Zhang Z, Zhang P, et al. Antisense oli-gonucleotides and all-trans retinoic acid have a synergistic anti-tumor effect on oral squamous cell carcinoma. BMC Cancer 2008; 8:159.
[16]Choi EJ, Whang YM, Kim SJ, et al. Combinational treatment with retinoic acid deriva-tives in non-small cell lung carcinoma in vitro. J Korean Med Sci 2007; 22:52-60
[17]Singh B, Murphy RF, Ding XZ, et al. On the role of transforming growth factor-beta in the growth inhibitory effects of retinoic acid in human pancreatic cancer cells. Mol Cancer 2007; 6:82.
[18]Huynh CK, Brodie AM, Njar VC. Inhibitory effects of retinoic acid metabolism blocking agents (RAM-BAs) on the growth of human prostate cancer cells and LNCaP prostate tumour xenografts in SCID mice. Br J Cancer 2006; 94:513-523.
[19]Lee JH, Kishikawa M, Kumazoe M, et al. Vitamin A enhances antitumor effect of a green tea polyphenol on melanoma by upregu-lating the polyphenol sensing molecule 67-kDa laminin receptor. PLoS One 2010; 5:11051.
[20]Sekine I, Sumi M, Ito Y, et al. Phase Ⅰ study of cisplatin analogue nedaplatin, paclitaxel, and thoracic radiotherapy for unresectable stage Ⅲ non-small cell lung cancer. Jpn J Clin Oncol 2007;37:175-183.
[21]Fuwa N, Kodaira T, Tachibana H, et al. Dose escalatin study of nedaplatin with 5-fluorouracil in combination with alternating radiotherapy in patientswith head and neck cancer. Jpn J Clin Oncol 2007;37:161-167.
[22]Desoize B,Madoulet C.Particular aspects of platinum compounds used at present in cancer treatment[J].Crit Rev Oncol Hematol 2002;42:317-325.
[23]管忠震,徐瑞华.奈达铂临床研究进展.中国肿瘤临床2004；31：774-780.
[24]Takaoka E, Kawai K, Ando S, et al. Neutropenic colitis during standard dose combination chemotherapywith nedaplatin and irinotecan for testicular cancer Jpn J Clin Oncol 2006;36:60-67.
[25]Breitman TR,Selonick SE,Collins SJ.Induclion of differentiation of the human promyelocytic leukemia cell line(HL-60) by retinoic acid.proc Natl Acad Sci USA 1980;77:2936-2940.
[26]王振义,孙关林,叶裕春等.全反式维甲酸治疗急性早幼粒细胞白血病90例的临床研究.中华血液学杂志1990,11：480.
[27]Zhang XK. Vitamin A and apoptosis in prostate cancer. Endocr Relat Cancer 2002; 9: 87-102.
[28]Chen Y, Dokmanovic M, Stein WD, et al. Agonist and antagonist of retinoic acid receptors cause similar changes in gene expres-sion and induce senescence-like growth arrest in MCF-7 breast carcinoma cells. Cancer Res 2006; 66:8749-8761.
[29]Kerr JFR,Wyllie AH,Currie AR.Apoptosis:a basic biological phenomenon with wide ranging implications in tissue kinetics [J].Br J Cancer 1972,26:239-257.
[30]Billotet C, Banerjee L, Vanhaesebroeck B,et al.Inhibition of Class Phosphoinositide 3-Kinase Activity Impairs Proliferation and Triggers Apoptosis in Acute Promyelocytic Leukemia without Affecting Atra-Induced Differentiation[J].Cancer Res 2009;69:1027-1036.
[31]Prakash P,Rusell RM,Krinsky NI,et al.In vitro inhibition of proliferation of estrogen-dependent and estrogen-independent human breast cancer cells treated with carotenoids or retinoids[J].J Nutr 2001;131:1574-1580.
[32]Zhang JP, Chen XY, Li JS. Effects of all-trans-retinoic on human gastric cancer cells BGC-823.J Dig Dis 2007;8:29-34.
[33]Nakanishi M, Tomaru Y, Miura H, et al. Identification of transcriptional regula-tory cascades in retinoic acid-induced growth arrest of HepG2 cells. Nucleic Acids Res 2008; 36: 3443-3454.
[34]MOSMAN T. Rap id Colorimetric Assay for Cellular Gr owth and Survival:App lication t o Proliferati on and Cyt otoxicity Assays[J]. J I mmunolMethods 1983; 65:55263.
[35]Hsu SL, Chen MC, Chou YH, et al. Induction of p21(CIP1/Wafl) and activation of p34(cdc2) involved in retinoic acid-induced apoptosis in human hepatoma Hep3B cells. Exp Cell Res 1999; 248:87-96.
[36]Srivastava RK, Srivastave AR, Cho-Chung YS. Syn-ergistic effects of 8-C1-cAMP and retinoic acids in the inhibition of growth and induction of apoptosis in ovarian cancer cells: induction of retinoic acid receptor beta. Mol Cell Biochem 2000; 204:1-9.
[37]Das A, Banik NL, Ray SK. Retinoids induce differentiation and downregulate telomerase activity and N-Myc to increase sensitivity to flavonoids for apoptosis in human malignant neuroblastoma SH-SY5Y cells. Int J Oncol 2009; 34:757-765.
[38]Zhang H, Satyamoorthy K, Herlyn M,et al. All-trans retinoic acid (atRA) differentially induces apoptosis in matched primary and metastatic melanoma cells-a speculation on damage effect of atRA via mitochondrial dysfunction and cell cycle redistribution. Carcinogenesis 2003; 24:185-191.
[39]Jimenez-Lara AM, Aranda A, Gronemeyer H et al. Reti-noic acid protects human breast cancer cells against etoposide-induced apoptosis by NF-kappaB-de-pendent but cIAP2-independent mechanisms. Mol Cancer 2010; 9:15.
[40]耿慧霞,王来,王强。流式细胞仪在自物学中的应用[J].生物学杂志2005；22(4).
[41]赵利红,崔利法,李陈莉。细胞凋亡的检测的检测方法[J]河北医药2005；27(10).
[42]周庚寅。组织病理学技术[J].北京大学医学出版社.
[43]Kameyama Y, Okazaki N, Nakagawa M, et al. Nephrotoxicity of a new platinum compound,254-S, evaluated with rat kidney cortical slices. Toxicol Lett 1990;52:15-24.
[44]Furuse K, Fukuoka M, Kurita Y, et al.A phase Ⅱ clinical study of cis-diammine glycolato platinum,254-S, for primary lung cancer. Gan To Kagaku Ryoho 1992; 19:879-884.
[45]Yamamoto N, Tamura T, Kurata T, et al. Phase I and pharmacokinetic (PK) study of (Glycolate-0,00)-diammine platinum (II) (Nedaplatin:254-S) in elderly patients with non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2000; 19:203.
[46]Nemoto K, Matsushita H, Ogawa Y, et al. Radiation therapy combined with cis-diammine-glycolatoplatinum (Nedaplatin) and 5-fluorouracil for untreated and recurrent esophageal cancer. Am J Clin Oncol 2003;26:46-49.
[47]Kurita H, Yamamoto E, Nozaki S, et al.Multicenter phase I trial of induction chemotherapy with docetaxel and nedaplatin for oral squamous cell carcinoma. Oral Oncol 2004; 40:1000-1006.
[48]Ita M, Okafuji M, Fukuda K, et al.Concurrent chemoradiotherapy with new platinum compound nedaplatin in oral cancer. Oral Oncol 2003;39:144-149.
[49]Takeda Y, Kasai H, Uchida N, et al.Enhanced antitumor efficacy of nedaplatin with 5-fluorouracil against human squamous carcinoma xenografts. Anticancer Res 1999;9: 4059-4064.
[50]Niu CS, Li MW, Ni Y F,et al. Effect of all-trans retinoic acid on the proliferation and differentiation of brain tumor stem cells Journal of Experimental & Clinical Cancer Research 2010;29:113.
[51]Chi HT, Ly BTK, Taguchi T, et al. All-trans retinoic acid inhibits KIT activity andinduces apoptosis in gastrointestinal stromal tumor GIST-T1 cell line by affecting on the expression of survivin and Bax protein. Journal of Experimental & Clinical Cancer Research 2010;29:165.
[52]Kucukzeybek Y, Gul MK, Cengiz E, et al. Enhancement of docetaxel-induced cytotoxicity and apoptosis by all-trans reti-noic acid (ATRA) through downregulation of sur-vivin (BIRC5), MCL-1 and LTbeta-R in hormone-and drug resistant prostate cancer cell line, DU-145. J Exp Clin Cancer Res 2008; 27:37.
[53]Koay DC,Zerillo C, Narayan M,et al. Anti-tumor effects of retinoids combined with trastuzumab or tamoxifen in breast cancer cells:induction of apoptosis by retinoid/ trastuzumabcombinations. Breast Cancer Research 2010;12:62.
[54]Chlapek P, Redoval M, Zitterbart K et al. Enhancement of ATRA-induced differentiation of neuroblastoma cells with LOX/COX inhibitors:an expression profiling study. Journal of Experimental & Clinical Cancer Research 2010;29:45.
[1]Mark M, Ghyselinck NB, Chambon P. Function of retinoid nuclear receptors:lessons from genetic and pharmacological dissections of the retinoic acid signaling pathway during mouse embryogenesis [J]. Annu Rev Pharmacol Toxicol 2006; 46:451-480.
[2]Hong WK Itri LM. Retinoids and human cancer.Chemistry and Medicine 1994; 597-658.
[3].Kelloff G.J. Perspectives on cancer chemoprevention research and drug development. Adv. Cancer Res 1999; 278:199-334.
[4]Raffo P, Emionite L, Colucci L.et al. Retinoid receptors:pathways of proliferation inhibitionand apoptosis induction in breast cancer cell lines. Anticancer Res 2000; 20:1535-1543.
[5]Dimberg A, Nilsson K, O " berg F,et al. Phosphorylation-deficientStatl inhibits retinoic acid-induced differentiation and cell cycle arrest inU-937 monoblasts. Blood 2000;96: 2870-2878.
[6]Seewaldt VL, Kim JH, Caldwell LE,et al. All-trans-retinoid acid mediates G1 arrest but not apoptosis of normal human mammary epithelial cells. Cell Growth Differ 1997;8:631-641.
[7]Atencia R, Garcia-Sanz M, Unda F,et al. Apoptosis during retinoic acid-induced differentiation of F9 embryonal carcinomacells. Exp. Cell Res 1994; 214:663-667.
[8]Hsu SL, Wu WS, Tyan YS,et al. Retinoic acid-induced apoptosis is prevented by serum albumin and enhanced by Lipiodolin human hepatoma Hep3B cells. Cancer Lett 1998; 129: 205-214.
[9]Islam TC, Skarin T, Sumitran S,et al. Retinoids induce apoptosis in cultured keratinocytes. Br J Dermatol 2000; 143:709-719.
[10]Seewaldt VL, Johnson BS, Parker MB, et al. Expression of retinoic acid receptor beta mediates retinoic acid-induced growth arrest and apoptosis in breast cancer cells. Cell Growth Differ 1995;6:1077-1088.
[11]Kim MJ, Ciletti N, Michel S, et al. The role of specific retinoid receptors in sebocyte growth and differentiation in culture. J Invest Dermatol 2000; 114:349-353.
[12]Mangelsdorf DJ, Thummel C, BeatoM, et al. The nuclear receptor superfamily:the second decade. Cell 1995;83:835-839.
[13]王振义.维甲酸的代谢及作用方式.肿瘤的诱导分化和凋亡疗[M].1998；65-66.
[14]Y. Chen, M. Dokmanovic, W. D. Stein, et al. Agonist and antagonist of retinoic acidreceptors cause similar changes in gene expression and inducesenescence-like growth arrest in MCF-7 breast carcinomacells. Cancer Research 2006;66:8749-8761.
[15]Jemal A, Murray T, Ward E, et al. Cancer statistics, [J]. CA Cancer J Clin 2005;55:10-30.
[16]Dutta A, Sen T, Banerji A,et al.Studies on Multifunctional Effect of All-Trans Retinoic Acid (ATRA) on Matrix Metalloproteinase-2 (MMP-2) and Its Regulatory Molecules in Human Breast Cancer Cells (MCF-7).J Oncol 2009; 2009:627840
[17]Hong J, Samudio I, Chintharlapalli S, et al.1,1-Bis(3'-Indolyl)-1-(p-Substituted Phenyl) Methanes Decrease Mitochondrial Membrane Potential and Induce Apoptosis in Endometrial and Other Cancer Cell Lines.Mol Carcinog 2008;47:492-507.
[18]Radu M, Soprano DR, Soprano KJ,et al.S10 phosphorylation of p27 mediates ATRA induced growth arrest in ovarian carcinoma cell lines.J Cell Physiol 2008;217:558-568.
[19]Xu Q, Zhang ZY, Zhang P, et al.Antisense oligonucleotides and all-trans retinoic acid have a synergistic anti-tumor effect on oral squamous cell carcinoma.BMC Cancer 2008; 8:159.
[20]Kim CJ,Chi J G,Thiele CJ.Insulin-like growth factor-2 expression isdown-regulated in TrkA-transfected.[J].Lab Invest 1999;79:1007-1013.
[21]Reynolds CP, Kane DJ, Einhorn PA,et al.Response of neuroblastoma to retinoic acid in vitro and in vivo. Prog Clin Biol Res 1991;366:203-211.
[22]Veal GJ, Errington J, Redfern CP, et al. Influence of isomerisation on the growth inhibitory effects and cellular activity of 13-cis and all-trans retinoic acid in neuroblastoma cells.Biochem Pharmacol 2002;63:207-215.
[23]Fong CJ, Sutkowski DM, BraunEJ, et al. Effect of retinoic acid on the proliferation and secretory activity of androgen-responsive prostatic carcinoma cells. J Urol 1993;149:1190-1194.
[24]刘波,王志新,陈正堂.丁酸、全反式维甲酸对肺腺癌细胞株A549体外增殖的影响.重庆医学2004；33：1006—1008
[25]Seewaldt VL, Johnson BS, Parker MB,et al.Expression of retinoic acid receptor beta mediates retinoic acid-induced growth arrest and apoptosis in breast cancer cells. Cell Growth Differ,1995;6:1077-1088.
[26]Hsu SL, Chen MC, Chou YH, et al. Induction of p21(CIP1/Wafl) and activation of p34(cdc2) involved in retinoic acid-induced apop-tosis in human hepatoma Hep3B cells. Exp Cell Res 1999; 248:87-96.
[27]陆祎,徐莺莺,范恺谊,等.全反式维甲酸通过内质网应激诱导N-乙酰氨基葡萄糖基转移酶V受阻的人肝癌SMMC-7721细胞凋亡[J].复旦学报(医学版)2006；33：285-290.
[28]陈舌,黄传新,殷祥雷,等.全反式维甲酸抑制反义N—乙酰氨基葡萄糖转移酶V转染的SMMC 7721肝癌细胞蛋白激酶B的表达[J].肿瘤2003；23：35-38.
[29]汪思应,江岩,郑红,等.全反式维甲酸抑制Ets-1介导的肝癌7402细胞离散和侵袭及其分子机制[J].中国药理学通报2003；19：689-693.
[30]谢斌,左莉,江志奎,等.全反式维甲酸诱导HepG2细胞分化和降低软琼脂克隆形成.安徽医科大学学报2007；42：143—146.
[31]Jiang W, Li CY, Wang SS, et al.All-Retinoic Acid Down-regulate the Expression of AFP Binding Protein in HepG2 Cell.Chinese Journal of Biochemistry and Molecular Biology 2010; 26:1009-1015.
[32]Tammela T, Enholm B, Alitalo K, et al. The biology of vascular endothelial growth factors. Cardiovascular Research 2005; 65:550-563.
[33]Lamoreaux WJ, Fitzgerald MEC, Reiner A,et al. Vascular endothelial growth factor increases release of gelatinase A and decreases release of tissue inhibitor of metalloproteinases by microvascular endothelial cells in vitro. Microvascular Research 1998; 55:29-42.
[34]Liaudet-Coopman ED,Berchem GJ,Wellstein A.In vivo inhibition of angiogenesis and induction of apoptosis by retinoic acid in squamous cell carcinoma.[J].Clin Cancer Res 1997;3:179-184.
[35]Jiang GS, Yang WH.Hif-1 Independent Down-Regulation of VEGF Expression in HL60-Cells after In Vitro Exposure to ATRA.[J].Blood(ASH Annual Meeting Abstracts) 2007; 110:4290.
[36]Akiko S,Akira S, Akira U,et al.All-transRetinoicAcid Induces in Vitro Angiogenesis via RetinoicAcid Receptor:Possible Involvement of Paracrine Effects of Endogenous Vascular Endothelial Growth Factor Signaling.[J].Endocrinology 2007;148:1412-1423.
[37]朱兆华,夏忠胜,何守搞.全反式维甲酸和5-Fu对胃癌细胞端粒酶活性和细胞生长的影响.世界华人消化杂志2000；8：669-673.
[38]Zhang P,Xu Q,Chen WT,et al.Synergistic down-regulation of telomerase by all-trans retinoic acid and antisense oligonucleotide in oral squamous cell carcinoma cell line.[J].Oral Oncol 2005;41:909-915.
[39]何冬梅,张洹.全反式维甲酸对HL-60细胞hTERT基因表达和端粒酶活性的影响.[J].中德临床肿瘤学杂志(英文版)2003；2.
[40]Pendino F,Hillion J,Dudognon C,et al.Telomerase targeting by retinoids in cells from patients with myeloid leukemias of various subtypes.not only APL.[J].Leukemia 2006;20:599-603.
[2]Zhou GB, Zhang J, Wang ZY, et al. Treatment of acute promyelocytic leukaemia with all-trans retinoic acid and arsenic trioxide:a para-digm of synergistic molecular targeting therapy. Philos Trans R Soc Lond B Biol Sci 2007; 362:959-971.
[3]Frankfurt O, Tallman MS. Strategies for the treat-ment of acute promyelocytic leukemia. J Natl Compr Cane Netw 2006; 4:37-50.
[4]Ozeki M, Shively JE. Differential cell fates induced by all-trans retinoic acid-treated HL-60 human leu-kemia cells. J Leukoc Biol 2008; 84:769-779.
[5]Jiang M, Zhu K, Grenet J,et al. Retinoic acid induces caspase-8 transcription via phospho-CREB and increases apoptotic responses to death stimuli in neuroblastoma cells. Biochim Biophys Acta 2008; 1783:1055-1067.
[6]Alique M, Herrero JF, Lucio-Cazana FJ. All-trans retinoic acid induces COX-2 and prostaglandin E2 synthesis in SH-SY5Y human neuroblastoma cells:involvement of retinoic acid receptors and extra-cellular-regulated kinase 1/2. J Neuroinflammation 2007; 4:1.
[7]Chlapek P, Redova M, Zitterbart K, et al. Enhancement of ATRA-induced differentiation of neuroblastoma cells with LOX/COX inhibitors:an expression profiling study. J Exp Clin Cancer Res 2010; 29:45.
[8]Cheepala SB, Yin W, Syed Z,et al. Identification of the B-Raf/Mek/Erk MAP kinase pathway as a target for all-trans retinoic acid during skin cancer promotion. Mol Cancer 2009; 8:27.
[9]Dutta A, Sen T, Banerji A, et al. Studies on Multifunctional Effect of All-Trans Reti-noic Acid (ATRA) on Matrix Metalloproteinase-2 (MMP-2) and Its Regulatory Molecules in Human Breast Cancer Cells (MCF-7). J Oncol 2009; 2009:627840
[10]Patel JB, Mehta J, Belosay A,et al. Novel reti-noic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cells and tumour growth. Br J Cancer 2007; 96:1204-1215.
[11]Phipps SM, Love WK, White T, et al. Retinoid-induced histone deacety-lation inhibits telomerase activity in estrogen recep-tor-negative breast cancer cells. Anticancer Res 2009; 29:4959-4964.
[12]Hong J, Samudio I, Chintharlapal liS, et al.1,1-bis(3'-indolyl)-1-(p-substituted phenyl) methanes decrease mitochondrial membrane potential and in-duce apoptosis in endometrial and other cancer cell lines. Mol Carcinog 2008; 47:492-507.
[13]Malik M, Webb J, Catherino WH. Retinoic acid treatment of human leiomyoma cells transformed the cell phenotype to one strongly resembling myo-metrial cells. Clin Endocrinol (Oxf) 2008; 69:462-470.
[14]Radu M, Soprano DR, Soprano KJ. S10 phosphory-lation of p27 mediates atRA induced growth arrest in ovarian carcinoma cell lines. J Cell Physiol 2008; 217:558-568.
[15]Xu Q, Zhang Z, Zhang P, et al. Antisense oli-gonucleotides and all-trans retinoic acid have a synergistic anti-tumor effect on oral squamous cell carcinoma. BMC Cancer 2008; 8:159.
[16]Choi EJ, Whang YM, Kim SJ, et al. Combinational treatment with retinoic acid deriva-tives in non-small cell lung carcinoma in vitro. J Korean Med Sci 2007; 22:52-60
[17]Singh B, Murphy RF, Ding XZ, et al. On the role of transforming growth factor-beta in the growth inhibitory effects of retinoic acid in human pancreatic cancer cells. Mol Cancer 2007; 6:82.
[18]Huynh CK, Brodie AM, Njar VC. Inhibitory effects of retinoic acid metabolism blocking agents (RAM-BAs) on the growth of human prostate cancer cells and LNCaP prostate tumour xenografts in SCID mice. Br J Cancer 2006; 94:513-523.
[19]Lee JH, Kishikawa M, Kumazoe M, et al. Vitamin A enhances antitumor effect of a green tea polyphenol on melanoma by upregu-lating the polyphenol sensing molecule 67-kDa laminin receptor. PLoS One 2010; 5:11051.
[20]Sekine I, Sumi M, Ito Y, et al. Phase Ⅰ study of cisplatin analogue nedaplatin, paclitaxel, and thoracic radiotherapy for unresectable stage Ⅲ non-small cell lung cancer. Jpn J Clin Oncol 2007;37:175-183.
[21]Fuwa N, Kodaira T, Tachibana H, et al. Dose escalatin study of nedaplatin with 5-fluorouracil in combination with alternating radiotherapy in patientswith head and neck cancer. Jpn J Clin Oncol 2007;37:161-167.
[22]Desoize B,Madoulet C.Particular aspects of platinum compounds used at present in cancer treatment[J].Crit Rev Oncol Hematol 2002;42:317-325.
[23]管忠震,徐瑞华.奈达铂临床研究进展.中国肿瘤临床2004；31：774-780.
[24]Takaoka E, Kawai K, Ando S, et al. Neutropenic colitis during standard dose combination chemotherapywith nedaplatin and irinotecan for testicular cancer Jpn J Clin Oncol 2006;36:60-67.
[25]Breitman TR,Selonick SE,Collins SJ.Induclion of differentiation of the human promyelocytic leukemia cell line(HL-60) by retinoic acid.proc Natl Acad Sci USA 1980;77:2936-2940.
[26]王振义,孙关林,叶裕春等.全反式维甲酸治疗急性早幼粒细胞白血病90例的临床研究.中华血液学杂志1990,11：480.
[27]Zhang XK. Vitamin A and apoptosis in prostate cancer. Endocr Relat Cancer 2002; 9: 87-102.
[28]Chen Y, Dokmanovic M, Stein WD, et al. Agonist and antagonist of retinoic acid receptors cause similar changes in gene expres-sion and induce senescence-like growth arrest in MCF-7 breast carcinoma cells. Cancer Res 2006; 66:8749-8761.
[29]Kerr JFR,Wyllie AH,Currie AR.Apoptosis:a basic biological phenomenon with wide ranging implications in tissue kinetics [J].Br J Cancer 1972,26:239-257.
[30]Billotet C, Banerjee L, Vanhaesebroeck B,et al.Inhibition of Class Phosphoinositide 3-Kinase Activity Impairs Proliferation and Triggers Apoptosis in Acute Promyelocytic Leukemia without Affecting Atra-Induced Differentiation[J].Cancer Res 2009;69:1027-1036.
[31]Prakash P,Rusell RM,Krinsky NI,et al.In vitro inhibition of proliferation of estrogen-dependent and estrogen-independent human breast cancer cells treated with carotenoids or retinoids[J].J Nutr 2001;131:1574-1580.
[32]Zhang JP, Chen XY, Li JS. Effects of all-trans-retinoic on human gastric cancer cells BGC-823.J Dig Dis 2007;8:29-34.
[33]Nakanishi M, Tomaru Y, Miura H, et al. Identification of transcriptional regula-tory cascades in retinoic acid-induced growth arrest of HepG2 cells. Nucleic Acids Res 2008; 36: 3443-3454.
[34]MOSMAN T. Rap id Colorimetric Assay for Cellular Gr owth and Survival:App lication t o Proliferati on and Cyt otoxicity Assays[J]. J I mmunolMethods 1983; 65:55263.
[35]Hsu SL, Chen MC, Chou YH, et al. Induction of p21(CIP1/Wafl) and activation of p34(cdc2) involved in retinoic acid-induced apoptosis in human hepatoma Hep3B cells. Exp Cell Res 1999; 248:87-96.
[36]Srivastava RK, Srivastave AR, Cho-Chung YS. Syn-ergistic effects of 8-C1-cAMP and retinoic acids in the inhibition of growth and induction of apoptosis in ovarian cancer cells: induction of retinoic acid receptor beta. Mol Cell Biochem 2000; 204:1-9.
[37]Das A, Banik NL, Ray SK. Retinoids induce differentiation and downregulate telomerase activity and N-Myc to increase sensitivity to flavonoids for apoptosis in human malignant neuroblastoma SH-SY5Y cells. Int J Oncol 2009; 34:757-765.
[38]Zhang H, Satyamoorthy K, Herlyn M,et al. All-trans retinoic acid (atRA) differentially induces apoptosis in matched primary and metastatic melanoma cells-a speculation on damage effect of atRA via mitochondrial dysfunction and cell cycle redistribution. Carcinogenesis 2003; 24:185-191.
[39]Jimenez-Lara AM, Aranda A, Gronemeyer H et al. Reti-noic acid protects human breast cancer cells against etoposide-induced apoptosis by NF-kappaB-de-pendent but cIAP2-independent mechanisms. Mol Cancer 2010; 9:15.
[40]耿慧霞,王来,王强。流式细胞仪在自物学中的应用[J].生物学杂志2005；22(4).
[41]赵利红,崔利法,李陈莉。细胞凋亡的检测的检测方法[J]河北医药2005；27(10).
[42]周庚寅。组织病理学技术[J].北京大学医学出版社.
[43]Kameyama Y, Okazaki N, Nakagawa M, et al. Nephrotoxicity of a new platinum compound,254-S, evaluated with rat kidney cortical slices. Toxicol Lett 1990;52:15-24.
[44]Furuse K, Fukuoka M, Kurita Y, et al.A phase Ⅱ clinical study of cis-diammine glycolato platinum,254-S, for primary lung cancer. Gan To Kagaku Ryoho 1992; 19:879-884.
[45]Yamamoto N, Tamura T, Kurata T, et al. Phase I and pharmacokinetic (PK) study of (Glycolate-0,00)-diammine platinum (II) (Nedaplatin:254-S) in elderly patients with non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2000; 19:203.
[46]Nemoto K, Matsushita H, Ogawa Y, et al. Radiation therapy combined with cis-diammine-glycolatoplatinum (Nedaplatin) and 5-fluorouracil for untreated and recurrent esophageal cancer. Am J Clin Oncol 2003;26:46-49.
[47]Kurita H, Yamamoto E, Nozaki S, et al.Multicenter phase I trial of induction chemotherapy with docetaxel and nedaplatin for oral squamous cell carcinoma. Oral Oncol 2004; 40:1000-1006.
[48]Ita M, Okafuji M, Fukuda K, et al.Concurrent chemoradiotherapy with new platinum compound nedaplatin in oral cancer. Oral Oncol 2003;39:144-149.
[49]Takeda Y, Kasai H, Uchida N, et al.Enhanced antitumor efficacy of nedaplatin with 5-fluorouracil against human squamous carcinoma xenografts. Anticancer Res 1999;9: 4059-4064.
[50]Niu CS, Li MW, Ni Y F,et al. Effect of all-trans retinoic acid on the proliferation and differentiation of brain tumor stem cells Journal of Experimental & Clinical Cancer Research 2010;29:113.
[51]Chi HT, Ly BTK, Taguchi T, et al. All-trans retinoic acid inhibits KIT activity andinduces apoptosis in gastrointestinal stromal tumor GIST-T1 cell line by affecting on the expression of survivin and Bax protein. Journal of Experimental & Clinical Cancer Research 2010;29:165.
[52]Kucukzeybek Y, Gul MK, Cengiz E, et al. Enhancement of docetaxel-induced cytotoxicity and apoptosis by all-trans reti-noic acid (ATRA) through downregulation of sur-vivin (BIRC5), MCL-1 and LTbeta-R in hormone-and drug resistant prostate cancer cell line, DU-145. J Exp Clin Cancer Res 2008; 27:37.
[53]Koay DC,Zerillo C, Narayan M,et al. Anti-tumor effects of retinoids combined with trastuzumab or tamoxifen in breast cancer cells:induction of apoptosis by retinoid/ trastuzumabcombinations. Breast Cancer Research 2010;12:62.
[54]Chlapek P, Redoval M, Zitterbart K et al. Enhancement of ATRA-induced differentiation of neuroblastoma cells with LOX/COX inhibitors:an expression profiling study. Journal of Experimental & Clinical Cancer Research 2010;29:45.
[1]Mark M, Ghyselinck NB, Chambon P. Function of retinoid nuclear receptors:lessons from genetic and pharmacological dissections of the retinoic acid signaling pathway during mouse embryogenesis [J]. Annu Rev Pharmacol Toxicol 2006; 46:451-480.
[2]Hong WK Itri LM. Retinoids and human cancer.Chemistry and Medicine 1994; 597-658.
[3].Kelloff G.J. Perspectives on cancer chemoprevention research and drug development. Adv. Cancer Res 1999; 278:199-334.
[4]Raffo P, Emionite L, Colucci L.et al. Retinoid receptors:pathways of proliferation inhibitionand apoptosis induction in breast cancer cell lines. Anticancer Res 2000; 20:1535-1543.
[5]Dimberg A, Nilsson K, O " berg F,et al. Phosphorylation-deficientStatl inhibits retinoic acid-induced differentiation and cell cycle arrest inU-937 monoblasts. Blood 2000;96: 2870-2878.
[6]Seewaldt VL, Kim JH, Caldwell LE,et al. All-trans-retinoid acid mediates G1 arrest but not apoptosis of normal human mammary epithelial cells. Cell Growth Differ 1997;8:631-641.
[7]Atencia R, Garcia-Sanz M, Unda F,et al. Apoptosis during retinoic acid-induced differentiation of F9 embryonal carcinomacells. Exp. Cell Res 1994; 214:663-667.
[8]Hsu SL, Wu WS, Tyan YS,et al. Retinoic acid-induced apoptosis is prevented by serum albumin and enhanced by Lipiodolin human hepatoma Hep3B cells. Cancer Lett 1998; 129: 205-214.
[9]Islam TC, Skarin T, Sumitran S,et al. Retinoids induce apoptosis in cultured keratinocytes. Br J Dermatol 2000; 143:709-719.
[10]Seewaldt VL, Johnson BS, Parker MB, et al. Expression of retinoic acid receptor beta mediates retinoic acid-induced growth arrest and apoptosis in breast cancer cells. Cell Growth Differ 1995;6:1077-1088.
[11]Kim MJ, Ciletti N, Michel S, et al. The role of specific retinoid receptors in sebocyte growth and differentiation in culture. J Invest Dermatol 2000; 114:349-353.
[12]Mangelsdorf DJ, Thummel C, BeatoM, et al. The nuclear receptor superfamily:the second decade. Cell 1995;83:835-839.
[13]王振义.维甲酸的代谢及作用方式.肿瘤的诱导分化和凋亡疗[M].1998；65-66.
[14]Y. Chen, M. Dokmanovic, W. D. Stein, et al. Agonist and antagonist of retinoic acidreceptors cause similar changes in gene expression and inducesenescence-like growth arrest in MCF-7 breast carcinomacells. Cancer Research 2006;66:8749-8761.
[15]Jemal A, Murray T, Ward E, et al. Cancer statistics, [J]. CA Cancer J Clin 2005;55:10-30.
[16]Dutta A, Sen T, Banerji A,et al.Studies on Multifunctional Effect of All-Trans Retinoic Acid (ATRA) on Matrix Metalloproteinase-2 (MMP-2) and Its Regulatory Molecules in Human Breast Cancer Cells (MCF-7).J Oncol 2009; 2009:627840
[17]Hong J, Samudio I, Chintharlapalli S, et al.1,1-Bis(3'-Indolyl)-1-(p-Substituted Phenyl) Methanes Decrease Mitochondrial Membrane Potential and Induce Apoptosis in Endometrial and Other Cancer Cell Lines.Mol Carcinog 2008;47:492-507.
[18]Radu M, Soprano DR, Soprano KJ,et al.S10 phosphorylation of p27 mediates ATRA induced growth arrest in ovarian carcinoma cell lines.J Cell Physiol 2008;217:558-568.
[19]Xu Q, Zhang ZY, Zhang P, et al.Antisense oligonucleotides and all-trans retinoic acid have a synergistic anti-tumor effect on oral squamous cell carcinoma.BMC Cancer 2008; 8:159.
[20]Kim CJ,Chi J G,Thiele CJ.Insulin-like growth factor-2 expression isdown-regulated in TrkA-transfected.[J].Lab Invest 1999;79:1007-1013.
[21]Reynolds CP, Kane DJ, Einhorn PA,et al.Response of neuroblastoma to retinoic acid in vitro and in vivo. Prog Clin Biol Res 1991;366:203-211.
[22]Veal GJ, Errington J, Redfern CP, et al. Influence of isomerisation on the growth inhibitory effects and cellular activity of 13-cis and all-trans retinoic acid in neuroblastoma cells.Biochem Pharmacol 2002;63:207-215.
[23]Fong CJ, Sutkowski DM, BraunEJ, et al. Effect of retinoic acid on the proliferation and secretory activity of androgen-responsive prostatic carcinoma cells. J Urol 1993;149:1190-1194.
[24]刘波,王志新,陈正堂.丁酸、全反式维甲酸对肺腺癌细胞株A549体外增殖的影响.重庆医学2004；33：1006—1008
[25]Seewaldt VL, Johnson BS, Parker MB,et al.Expression of retinoic acid receptor beta mediates retinoic acid-induced growth arrest and apoptosis in breast cancer cells. Cell Growth Differ,1995;6:1077-1088.
[26]Hsu SL, Chen MC, Chou YH, et al. Induction of p21(CIP1/Wafl) and activation of p34(cdc2) involved in retinoic acid-induced apop-tosis in human hepatoma Hep3B cells. Exp Cell Res 1999; 248:87-96.
[27]陆祎,徐莺莺,范恺谊,等.全反式维甲酸通过内质网应激诱导N-乙酰氨基葡萄糖基转移酶V受阻的人肝癌SMMC-7721细胞凋亡[J].复旦学报(医学版)2006；33：285-290.
[28]陈舌,黄传新,殷祥雷,等.全反式维甲酸抑制反义N—乙酰氨基葡萄糖转移酶V转染的SMMC 7721肝癌细胞蛋白激酶B的表达[J].肿瘤2003；23：35-38.
[29]汪思应,江岩,郑红,等.全反式维甲酸抑制Ets-1介导的肝癌7402细胞离散和侵袭及其分子机制[J].中国药理学通报2003；19：689-693.
[30]谢斌,左莉,江志奎,等.全反式维甲酸诱导HepG2细胞分化和降低软琼脂克隆形成.安徽医科大学学报2007；42：143—146.
[31]Jiang W, Li CY, Wang SS, et al.All-Retinoic Acid Down-regulate the Expression of AFP Binding Protein in HepG2 Cell.Chinese Journal of Biochemistry and Molecular Biology 2010; 26:1009-1015.
[32]Tammela T, Enholm B, Alitalo K, et al. The biology of vascular endothelial growth factors. Cardiovascular Research 2005; 65:550-563.
[33]Lamoreaux WJ, Fitzgerald MEC, Reiner A,et al. Vascular endothelial growth factor increases release of gelatinase A and decreases release of tissue inhibitor of metalloproteinases by microvascular endothelial cells in vitro. Microvascular Research 1998; 55:29-42.
[34]Liaudet-Coopman ED,Berchem GJ,Wellstein A.In vivo inhibition of angiogenesis and induction of apoptosis by retinoic acid in squamous cell carcinoma.[J].Clin Cancer Res 1997;3:179-184.
[35]Jiang GS, Yang WH.Hif-1 Independent Down-Regulation of VEGF Expression in HL60-Cells after In Vitro Exposure to ATRA.[J].Blood(ASH Annual Meeting Abstracts) 2007; 110:4290.
[36]Akiko S,Akira S, Akira U,et al.All-transRetinoicAcid Induces in Vitro Angiogenesis via RetinoicAcid Receptor:Possible Involvement of Paracrine Effects of Endogenous Vascular Endothelial Growth Factor Signaling.[J].Endocrinology 2007;148:1412-1423.
[37]朱兆华,夏忠胜,何守搞.全反式维甲酸和5-Fu对胃癌细胞端粒酶活性和细胞生长的影响.世界华人消化杂志2000；8：669-673.
[38]Zhang P,Xu Q,Chen WT,et al.Synergistic down-regulation of telomerase by all-trans retinoic acid and antisense oligonucleotide in oral squamous cell carcinoma cell line.[J].Oral Oncol 2005;41:909-915.
[39]何冬梅,张洹.全反式维甲酸对HL-60细胞hTERT基因表达和端粒酶活性的影响.[J].中德临床肿瘤学杂志(英文版)2003；2.
[40]Pendino F,Hillion J,Dudognon C,et al.Telomerase targeting by retinoids in cells from patients with myeloid leukemias of various subtypes.not only APL.[J].Leukemia 2006;20:599-603.