二苯乙烯类考不他汀类似物抗肿瘤作用的体内外研究
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摘要
进展期晚期肿瘤常常最终会对传统的化疗药物耐药。实体瘤占全部恶性肿瘤的大约90%、包括200多种类型。实体瘤的生长、进展、转移都依赖于血管不断地供养。血管内皮细胞相比肿瘤细胞更稳定,突变率非常低,这就使得其可以作为很好的肿瘤治疗靶点。血管靶向药物VTAs分为两大类,抗血管生成剂AI和血管阻断剂VDAs。CA4是1989年从南非的Combretum caffrum的树皮中分离出来的,通过作用于微管蛋白的β亚基秋水仙碱作用位点,抑制微管蛋白的聚合,导致细胞骨破坏,导致增殖的未成熟的内皮细胞形态改变,进而导致肿瘤血流的阻断。CA4P是其水溶性前体,在体内经非特定磷酸酯酶作用可迅速去磷酸化而生成具有生物活性的CA4。恩度,一种新的重组人内皮抑素,在氮末端添加了9个氨基酸,这使得其更稳定。恩度已经被证实可以抑制内皮细胞的增殖、迁移和血管形成。恩度有广谱的抗实体瘤活性。本项研究的目的是评估抗血管生成剂恩度联合血管阻断剂CA4P的抗肿瘤作用,这项研究是首次评估恩度联合CA4P的抗肿瘤作用,也是首次评估血管生成剂联合血管阻断剂的抗骨肉瘤作用。
体外实验显示,恩度增强CA4P的抗肿瘤作用具有广泛性,其中在骨肉瘤MNNG/HOS中作用最强。流式细胞周期检测显示恩度单药对肿瘤细胞的周期并无明显的影响,CA4P单药可以导致肿瘤细胞G2/M期的阻滞,两者联合应用的阻滞作用更加显著。荧光定量PCR显示恩度和CA4P的联合应用引起促凋亡蛋白Bax的表达上调,激活Caspase3, Caspase8, Caspase9,下调抑制凋亡蛋白Bcl-2的表达。体内实验显示恩度增强CA4P的抗肿瘤作用,恩度联合CA4P组肿瘤生长缓慢,micro-PET的代表肿瘤代谢的SUV值最低,中央血流灌注最差、肿瘤的横切面坏死率最高、微血管密度最低,同时裸鼠体重跟对照组并没有明显差异。体内外实验显示恩度联合CA4P有很好的抗肿瘤作用,并且没有明显的毒性,并不劣于传统的抗骨肉瘤的主要药物阿霉素ADM。但是CA4P不稳定,作用时间短,需要重复给药,活性也不及CA4,因此,如何进一步提高CA4P的疗效是目前研究的热点。
本研究探索研发了CA4P的壳聚糖微囊制剂以及一系列的顺式或反式二苯乙烯类衍生物,对其活性进行了体内外的活性评估。抗血管生成剂联合血管阻断剂显著增强了抗肿瘤作用,提供了一种全新的肿瘤治疗模式,可以作为传统标准治疗的补充,坚信这种治疗模式有转化到临床肿瘤治疗中的潜能。
It is common for advanced or metastatic solid tumors to be resistant to conventional cytotoxic drugs. Nearly90%of all malignant tumors, of more than200types, are solid tumors, which are critically dependent on a continually developing vascular supply for their growth, progression, and metastasis. Vascular endothelial cells are more genetically stable, homogeneous, and have a lower mutational rate than tumor cells, which makes them a good anti-tumor therapeutic target. Vascular-targeting agents (VTAs) can be divided into two groups:anti-angiogenesis agents and vascular disrupting agents (VDAs).Combretastatin A4was discovered in1989and was originally isolated from a SouthAfrican tree Combretum caffrum. CA4P is a water-soluble prodrug of combretastatin A4.It inhibits tubulin polymerization at the colchicine binding site of β-tubulin leading to cytoskeletal and then morphological changes in immature or proliferating endothelial cells. These changes disrupt tumor blood flow. Endostar, a novel recombinant human endostatin, with an additional nine-amino acid sequence at the N terminus, is more stable than conventional endostatin, which has been demonstrated to inhibit the growth of avariety of human tumors by inhibiting neovascularization Endostar had been shown to inhibit endothelial cell proliferation,migration, and vessel formation. Endostar has a broad spectrum of activity against solid tumors. The purpose of this study was to evaluate the antineoplastic activity of a combination of the anti-angiogenesis agent, Endostar, and the VDA combretastatin, A4phosphate (CA4P). This study is the first to evaluate the activity of this combination against tumors and the first to investigate the activity of the combination against osteosarcoma.In vitro, Endostar could enhance the antineoplasm of CA4P on kinds of tumor cell lines, especially on the human osteosarcoma MNNG/HOS cell line. Endostar had no significant effect in tumor cell cycle, CA4P could lead to G2/M arrest, G2/M disturbance was more obvious when Endostar combinated with CA4P. Realtime PCR shows that Endostar combinated with CA4P could lead to the upregulation of Bax, downregulation of Bcl-2, activation of Caspase3, Caspase8, Caspase9, which then trigger major apoptotic cascades. In vivo, the tumor volumes of the Endostar combined with CA4P group was the smallest, and the standardized uptake value (SUV) of the Endostar combined with CA4P group was lower than that of the other groups by Positron emission tomography imaging (microPET). The Endostar combined with CA4P group had the most poorly perfused center by Dynamic contrast-enhanced ultrasound (DCE-US) or ultrasonic contrast, the highest incisal surface necrosis rate and the lowest microvascular density (MVD) In a word, Endostar combined with CA4P had a good anti-tumor effect with no significant toxicity, and was at least not inferior to adriamycin, which is the main drug for osteosarcoma. But CA4P is unstable, needed to administrate repeatly, less active than CA4, How to enhance the antineoplasm effect is the hot spot. The study synthetized a series of CA4P analogue and CA4P micro-capsule, also evaluated the effect of them.The use of VDAs combined with anti-angiogenic drugs can result in significantly enhanced anti-tumor effects, providing anovel approach to cancer treatment, which could effectively complement standard treatments. It is believed that this exciting new treatment has the potential to transform the management of cancer.
体外实验显示,恩度增强CA4P的抗肿瘤作用具有广泛性,其中在骨肉瘤MNNG/HOS中作用最强。流式细胞周期检测显示恩度单药对肿瘤细胞的周期并无明显的影响,CA4P单药可以导致肿瘤细胞G2/M期的阻滞,两者联合应用的阻滞作用更加显著。荧光定量PCR显示恩度和CA4P的联合应用引起促凋亡蛋白Bax的表达上调,激活Caspase3, Caspase8, Caspase9,下调抑制凋亡蛋白Bcl-2的表达。体内实验显示恩度增强CA4P的抗肿瘤作用,恩度联合CA4P组肿瘤生长缓慢,micro-PET的代表肿瘤代谢的SUV值最低,中央血流灌注最差、肿瘤的横切面坏死率最高、微血管密度最低,同时裸鼠体重跟对照组并没有明显差异。体内外实验显示恩度联合CA4P有很好的抗肿瘤作用,并且没有明显的毒性,并不劣于传统的抗骨肉瘤的主要药物阿霉素ADM。但是CA4P不稳定,作用时间短,需要重复给药,活性也不及CA4,因此,如何进一步提高CA4P的疗效是目前研究的热点。
本研究探索研发了CA4P的壳聚糖微囊制剂以及一系列的顺式或反式二苯乙烯类衍生物,对其活性进行了体内外的活性评估。抗血管生成剂联合血管阻断剂显著增强了抗肿瘤作用,提供了一种全新的肿瘤治疗模式,可以作为传统标准治疗的补充,坚信这种治疗模式有转化到临床肿瘤治疗中的潜能。
It is common for advanced or metastatic solid tumors to be resistant to conventional cytotoxic drugs. Nearly90%of all malignant tumors, of more than200types, are solid tumors, which are critically dependent on a continually developing vascular supply for their growth, progression, and metastasis. Vascular endothelial cells are more genetically stable, homogeneous, and have a lower mutational rate than tumor cells, which makes them a good anti-tumor therapeutic target. Vascular-targeting agents (VTAs) can be divided into two groups:anti-angiogenesis agents and vascular disrupting agents (VDAs).Combretastatin A4was discovered in1989and was originally isolated from a SouthAfrican tree Combretum caffrum. CA4P is a water-soluble prodrug of combretastatin A4.It inhibits tubulin polymerization at the colchicine binding site of β-tubulin leading to cytoskeletal and then morphological changes in immature or proliferating endothelial cells. These changes disrupt tumor blood flow. Endostar, a novel recombinant human endostatin, with an additional nine-amino acid sequence at the N terminus, is more stable than conventional endostatin, which has been demonstrated to inhibit the growth of avariety of human tumors by inhibiting neovascularization Endostar had been shown to inhibit endothelial cell proliferation,migration, and vessel formation. Endostar has a broad spectrum of activity against solid tumors. The purpose of this study was to evaluate the antineoplastic activity of a combination of the anti-angiogenesis agent, Endostar, and the VDA combretastatin, A4phosphate (CA4P). This study is the first to evaluate the activity of this combination against tumors and the first to investigate the activity of the combination against osteosarcoma.In vitro, Endostar could enhance the antineoplasm of CA4P on kinds of tumor cell lines, especially on the human osteosarcoma MNNG/HOS cell line. Endostar had no significant effect in tumor cell cycle, CA4P could lead to G2/M arrest, G2/M disturbance was more obvious when Endostar combinated with CA4P. Realtime PCR shows that Endostar combinated with CA4P could lead to the upregulation of Bax, downregulation of Bcl-2, activation of Caspase3, Caspase8, Caspase9, which then trigger major apoptotic cascades. In vivo, the tumor volumes of the Endostar combined with CA4P group was the smallest, and the standardized uptake value (SUV) of the Endostar combined with CA4P group was lower than that of the other groups by Positron emission tomography imaging (microPET). The Endostar combined with CA4P group had the most poorly perfused center by Dynamic contrast-enhanced ultrasound (DCE-US) or ultrasonic contrast, the highest incisal surface necrosis rate and the lowest microvascular density (MVD) In a word, Endostar combined with CA4P had a good anti-tumor effect with no significant toxicity, and was at least not inferior to adriamycin, which is the main drug for osteosarcoma. But CA4P is unstable, needed to administrate repeatly, less active than CA4, How to enhance the antineoplasm effect is the hot spot. The study synthetized a series of CA4P analogue and CA4P micro-capsule, also evaluated the effect of them.The use of VDAs combined with anti-angiogenic drugs can result in significantly enhanced anti-tumor effects, providing anovel approach to cancer treatment, which could effectively complement standard treatments. It is believed that this exciting new treatment has the potential to transform the management of cancer.
引文
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[1]Folkman J. Angiogenesis[J]. Annu Rev Med.2006; 57:1-18.
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[1]Folkman J. Angiogenesis[J]. Annu Rev Med.2006; 57:1-18.
[2]Hinnen P, Eskens FA. Vascular disrupting agents in clinical development[J]. Br J Cancer.2007; 96(8):1159-1165.
[3]Folkman J. Tumor angiogenesis:therapeutic implications. N Engl J Med.1971. 285(21):1182-6.
[4]Panares RL, Garcia AA. Bevacizumab in the management of solid tumors [J]. Expert Rev Anticancer Ther.2007; 7(4):433-445.
[5]Khosravi Shahi P, Fernandez Pineda I. Tumoral angiogenesis:review of the literarure[J]. Cancer Invest.2008; 26(1):104-108.
[6]Delmonte A, Sessa C. AVE8062:a new combretastatin derivative vascular disrupting agent.[J]. Expert Opin Investig Drugs,2009,18(10):1541-1548.
[7]Denekamp J. Endothelial cell proliferation as a novel approach to targeting tumour therapy. Br J Cancer.1982.45(1):136-9.
[8]Daenen L G, Roodhart J M, Shaked Y, et al. Vascular disrupting agents (VDAs) in anticancer therapy.[J]. Curr Clin Pharmacol,2010,5(3):178-185.
[9]Tozer G M, Ameer-Beg S M, Baker J, et al. Intravital imaging of tumour vascular networks using multi-photon fluorescence microscopy.[J]. Adv Drug Deliv Rev,2005,57(1):135-152.
[10]Nagaiah G, Remick S C. Combretastatin A4 phosphate:a novel vascular disrupting agent.[J]. Future Oncol,2010,6(8):1219-1228.
[11]Hori K. Antineoplastic strategy:irreversible tumor blood flow stasis induced by the combretastatin A-4 derivative AVE8062 (AC7700) [J]. Chemotherapy.2005; 51(6):357-360.
[12]Tolcher AW, Forero L, Celio P, et al. Phase I, pharmacokinetic, and DCE-MRI correlative study of AVE8062A, an antivascular combretastatin analogue, administered weekly for 3 weeks every 28 days[J]. J Clin Oncol.2003; 22(Suppl):208.
[13]Demers, P. Vrignaud, M. Bissery. In vivo synergy combining oxaliplatin with AVE8062, a vascular-disrupting agent[J]. J Clin Oncol.2006; 24(18S):13074.
[14]Beerepoot LV, Radema SA, Witteveen EO, et al. Phase I clinical evaluation of weekly administration of the novel vascular-targeting agent, ZD6126, in patients with solid tumors[J]. J Clin Oncol.2006; 24(10):1491-1498.
[15]LoRusso PM, Gadgeel SM, Wozniak A, et al. Phase I clinical evaluation of ZD6126, a novel vascular-targeting agent, in patients with solid tumors[J]. Invest New Drugs.2008; 26(2):159-167.
[16]Gabra H. Phase Ⅱ study of DMXAA combined with carboplatin and paclitaxel in recurrent ovarian cancer[J]. J Clin Oncol.2006; 24(Suppl):263.
[17]McKeage M. Phase Ⅰb/Ⅱ study of DMXAA combined with carboplatin and paclitaxel in non-small cell lung cancer (NSCLC) [J]. J Clin Oncol.2006; 24(Suppl):389.
[18]Mckeage M J, Von Pawel J, Reck M, et al. Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer.[J]. Br J Cancer,2008,99(12):2006-2012.
[19]McKeage MJ. The potential of DMXAA (ASA404) in combination with docetaxel in advanced prostate cancer[J]. Expert Opin Investig Drugs.2008; 17(l):23-29.
[20]Rehman F, Rustin G. ASA404:update on drug development.[J]. Expert Opin Investig Drugs,2008,17(10):1547-1551.
[21]Mckeage M J, Baguley B C. Disrupting established tumor blood vessels:an emerging therapeutic strategy for cancer.[J]. Cancer,2010,116(8):1859-1871.
[22]Head M, Jameson M B. The development of the tumor vascular-disrupting agent ASA404 (vadimezan, DMXAA):current status and future opportunities.[J]. Expert Opin Investig Drugs,2010,19(2):295-304.
[23]ann DW. Characterizing the tumor response to treatment with combretastatin A4 phosphate[J]. Int J Radiat Oncol Biol Phys.2007; 68(1):211-217.
[24]Horsman MR, Siemann DW. Pathophysiologic effects of vascular-targeting agents and the implications for combination with conventional therapies[J]. Cancer Res.2006; 66(24):11520-11539.
[25]Ahmed B, Landuyt W, Griffioen AW, et al. In vivo antitumour effect of combretastatin A-4 phosphate added to fractionated irradiation[J]. Anticancer Res. 2006; 26(1A):307-310.
[26]Ng Q S, Goh V, Carnell D, et al. Tumor antivascular effects of radiotherapy combined with combretastatin a4 phosphate in human non-small-cell lung cancer.[J]. Int J Radiat Oncol Biol Phys,2007,67(5):1375-1380.
[27]Martinelli M, Bonezzi K, Riccardi E, et al. Sequence dependent antitumour efficacy of the vascular disrupting agent ZD6126 in combination with paclitaxel[J]. Br J Cancer.2007; 97(7):888-894.
[28]O'Connor JP, Jackson A, Parker GJ, et al. DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents[J]. Br J Cancer.2007; 96(2):189-195.
[29]Siemann D W, Shi W. Dual targeting of tumor vasculature:combining Avastin and vascular disrupting agents (CA4P or OXi4503).[J]. Anticancer Res,2008,28(4B):2027-2031.
[30]Shaked Y, Ciarrocchi A, Franco M, et al. Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors[J]. Science.2006; 313(5794):1785-1787.