近日美国研究人员发现一种仅存在大肠粘膜内的蛋白质,该蛋白质可有助于治疗结肠癌和其他肿瘤疫苗的问世。研究者在美国国立卫生研究院(National Institutes of Health, NIH)所属的美国《国立癌症研究所杂志》(Journal of the National Cancer Institute)上发表文章称,携带该蛋白质疫苗的老鼠,在实验感染结肠肿瘤时,有较少肿瘤细胞扩散到肺和肝,具有有效的抵抗癌细胞的作用。
据来自底特律 Barbara Ann Karmanos Cancer Institute 的研究员提交的调查结果显示,在常规化疗中加入姜黄素或白藜芦醇可有效防止抗化疗结肠癌细胞的生长。在加姜黄素或白藜芦醇一直以来被认定具有抗炎性能和其它健康益处。姜黄素系姜黄科,来源于印度咖喱粉中的姜黄,在印度和东南亚十分普遍。白藜芦醇取自天然植物,红葡萄皮和花生中也同样含有这种成分。
美国康奈尔大学的最新研究,苹果皮具有良好的抗癌防癌功效。,每天吃一个苹果的果皮可达到预防癌症的效果。研究的主要负责人华裔研究人员刘瑞海(Rui Hai Liu,音译)和同事发现苹果中几种化合物具有抗人类肝癌、结肠癌和乳腺癌细胞增殖的活性。这项研究的结果公布在本月的Journal of Agricultural and Food Chemistry的网络版上。
大家都知道有一句英语谚语:一天一个苹果,医生远离我(An apple a day keeps the doctor away)。不过,科学家的最新研究让这句话有了一个更精确的版本:一天一条苹果皮,癌症不会来找你(An apple peel a day might keep cancer at bay)。苹果皮中的三萜化合物对人类肝癌、乳腺癌和结肠癌细胞具有潜在的抗增殖活性。同时,这些化合物也能够部分解释“一天一个苹果,病痛远离我”的原因。
美国农业部及罗格斯大学(Rutgers University)的科学家发现蓝莓(blueberries)中的pterostilbene成份,在动物试验的模式能有效预防结肠癌(colon cancer),此研究发表于美国化学学会(American Chemical Society,简称ACS),而每年的三月也是美国的国家结肠直肠癌提醒月(National Colorectal Cancer Awareness Month)。
Reddy博士表示:「Pterostilbene其实很类似于白藜芦醇(resveratrol),两者都具有很强的抗氧化能力。在葡萄、蓝莓或红酒中都含有这些物质。另外还有许多研究也证实pterostilbene能降低记忆力的损失以及降低心脏病的风险,总而言之,饮食中多摄取蔬菜,水果或谷类食物都会有助于预防结肠癌。」此研究之经费来源为NCI (National Cancer Institute)。
1 Goodlad RA & Wright NA.Epithelial kinetics,control and consequences of alterations in disease.In:Whitehead r,ed.Gastrointestinal and oesophageal pathology.Edinbergh:Churchill livingstone,1995,97~116
2 杨工,郑林,余海,等.大肠癌发病的环境因素和遗传因素.中华流行病学杂志,1992,13∶30
3 Heaton KW.Dietary fiber in perspective.Hum Nutr:Clin Nutr,1983,37C∶151~156
4 Cheng BQ,Topping DL,Stone BA,et al.Comparative effect of dietary wheat bran and its morphological components (aleurone and pericarp-seed coat) on volatile fatty acid concentration in the rat.Brit J Nutr,1987,57∶69
来自霍德华休斯医学院,Ludwig癌症遗传与治疗中心(the Ludwig Center for Cancer Genetics and Therapeutics)以及约翰霍普金斯凯门综合癌症中心(Johns Hopkins Kimmel Comprehensive Cancer Center),GeneGo公司,礼来公司,瑞典乌普萨拉大学(Uppsala University)等处的研究人员分析了乳腺癌肿瘤和结肠癌肿瘤中的18000个基因,包括5000个之前未在图谱上出现的基因,发现在乳腺癌和结肠癌肿瘤中存在大量遗传差异,从而能帮助研究人员根据个体肿瘤差异靶向遗传靶标。
奥沙利铂和伊立替康在晚期结直肠癌的作用己经基本肯定。 De Gramont、Giachetta、Grothey等的研究均已证实,奥沙利铂或伊立替康联合5-Fu/LV方案与5-Fu/Lv的疗效相比较,能够增加有效率,延长患者的无病生存期,提高PFS,改善生活质量。但是,几项研究均显示,在改善病人的总生存率上无显著性差异。
2006年ASCO会议报告了N9741研究的新结果。在该研究中,研究者研究探讨奥沙利铂或伊立替康联合5-Fu/LV以及奥沙利铂和伊立替康联合治疗晚期结直肠癌的疗效。分3种方案进行,即IFL方案(伊立替康+5-Fu/LV)、FOLF0X4方案(奥沙利铂+5-Fu/Lv)和IROX方案(伊立替康+奥沙利铂)。结果显示:FOLFOX组患者的肿瘤进展时间为8.7个月、缓解率为45%,中位生存时间为19.5个月,优于IROX组(分别为6.5个月、35%和 17.4个月)。德国学者又比较了IROX方案(奥沙利铂+伊立替康)和FOLFIRI方案(5-FU/LV+伊立替康)一线治疗转移性结直肠癌的临床效果。结果显示,两组的缓解率、PFS、病情稳定率、OS、死亡率及毒性反应等方面无显著差异。目前的几项临床研究显示:IROX方案或者再与5-FU/LV联合的效果均未超过FOLFIRI和FOLFOX方案,在个别报告中,毒性反应增加。
2.2.2卡培他滨联合方案
在晚期结直肠癌治疗的联合方案中,卡培他滨是否可以取代5-FU/LV一直是这几年的研究重点。
在晚期结直肠癌治疗的联合方案中,卡培他滨是否可以取代5-FU/LV一直是这几年的研究重点。在2005ASCO大会上 Arkenau[76]报告了III期研究比较奥沙利铂联合5-FU/LV的FOLFOX方案和奥沙利铂联合卡培他滨的CAPOX方案一线治疗转移性结直肠癌的研究结果两组毒性相似,但CAPOX组手足综合征发生率比较高。从疗效上来说FOLFOX组的有效率比CAPOX组高2个百分点(49%:47%),而中位PFS和中位OS在联合5-Fu/Lv组均比联合卡培他滨多1个月(分别为8:7和172:163)。西班牙TTD组[77]也报道了采用同样的方案来比较联合5-FU/LV或联合卡培他滨的差异:一线治疗晚期或转移性结直肠癌,III期研究的初步结果该研究计划入组了348例患者,随机进入奥沙利铂联合5-FU持续静脉滴注组(L-OHP85mg/m2,2h,q2w;加每周5- Fu2250 mg/m2civ48h)或Capeox组(卡培他滨1000 mg/m2x2,d1~d15,L-OHP130 mg/m2,2h,d1,q3w)。中期分析可评价疗效两组分别为98例和97例患者,奥沙利铂联合5-Fu的RR分别为53.6%,而联合卡培他滨只有46.9%。本组实验亦表明:奥沙利铂联合5-Fu与联合卡培他滨治疗晚期大肠癌疗效相似,两组毒副作用均较轻,以后组方案毒副反应较小。且口服卡培他滨简单方便,相对安全并且无需滴注泵,可以在临床上广泛应用。
2.3靶向药物联合化疗
在转移性结直肠癌的一线治疗中,靶向治疗药物的发展越来越引起人们的重视,抗-VEGF单抗-贝伐单抗己被证明在一线治疗中与化疗联合能够带来实质性生存受益。一项在初治的转移性结直肠癌患者中进行的III期试验,考察了在IFL方案基础上加用贝伐单抗的疗效和安全性。该研究共纳入813例晚期结直肠癌病人,随机分配进入二个治疗组,分别为:IFL+安慰剂(411l例)和IFL+贝伐单抗(402例);试验组有效率为44.8%,对照组为34.8%,疾病无进展生存分别为:10.6个月和6.2个月,生存期为:20.3个月和15.6个月,贝伐单抗的应用使得总生存期延长了4.7个月,无进展生存增加了4.4个月:值得注意的是,各项差距都具有明显的统计学意义。这项研究的意义在于首次阐明了在传统细胞毒性药物治疗的基础上,加用分子靶向药物可以延长病人的生存时间,说明了针对血管生成治疗可使晚期结直肠癌病人从中获得生存受益,因此根据此关键性试验的结果,FDA批准贝伐单抗联合IFL作为转移性结直肠癌的一线治疗。Femando等进行的另一项研究则旨在评价贝伐单抗联合奥沙利铂以及卡培他滨一线治疗的作用,这项II期临床研究的初步结果表明贝伐单抗与奥沙利铂及卡培他滨联合治疗的有效率为57%,位TTP为11.9个月,毒性以手足综合征的发生较为明显,并导致卡培他滨减量应用,从TTP来看,贝伐单抗联合奥沙利铂及卡培他滨治疗似较以前的报道有所延长,但是因为研究的患者数量还较少,须等到最终结果证实。
EGFR是靶向药物的重要靶点之一。西妥昔单抗即是一种针对EGFR胞外配体结合域的人源化嵌合型单抗,目前的研究尚未最终肯定西妥昔单抗联合伊立替康或奥沙利铂在晚期结直肠癌一线治疗中的地位,但是几项研究已经显示出良好的治疗疗效以及耐受性,两项关键性研究对西妥昔单抗联合伊立替康和奥沙利铂分别进行了考察。一项研究对西妥昔单抗联合伊立替康及5-Fu/LV的三种用法进行了研究,周方案的5-FU/LV/伊立替康联合西妥昔单抗、FOLFIRI及IFL联合西妥昔单抗,在周方案中,RR达到了67%,而FOLFIR和IFL方案分别为:43%和48%,疾病控制率都在88%以上。在西妥昔单抗联合奥沙利铂的研究中,FOLFOX4联合西妥昔单抗有效率达到了惊人的81%。这两项研究最常见的III~IV度不良反应为白细胞下降、腹泻、呕吐、乏力等,但是易于控制,这些结果显示了西妥昔单抗联合化疗在一线治疗中良好的治疗效果以及耐受性,后续的研究正在确定西妥昔单抗联合伊立替康还是奥沙利铂能够真正带来生存期的延长,获得最佳疗效。
2.4淋巴靶向化疗
淋巴靶向化疗是利用淋巴系统能吞噬大分子物质和微粒的特性,将它们作为载体与化疗药物共价结合、物理包裹或吸附,共同构成淋巴靶向给药系统,进入人体后经淋巴途径吸收,有效杀伤淋巴系统肿瘤,降低淋巴转移,并减少体循环药量、降低毒性[78].目前,淋巴靶向化疗有关研究相对落后,对如何选用理想的药物、剂型、给药途径等有待进一步的探讨。
2.5“ stop and go”策略
一直以来,结直肠癌的化疗主张以连续化疗直至患者不能耐受,使患者常常承受生命不息、化疗不止的痛苦。OPTMOXI和OPTMOX2的临床研究打破了这一壁垒。OPTMOXI临床研究采用随机对照方法,在累积神经毒性出现前停止给予含奥沙利铂的FOLFOX7方案,然后用LV5-FU2维持治疗共12周期,在疾病进展前、神经感觉异常基木恢复后再次开始应用第二阶段FOLFOX7,与常规的连续应用FOLFOX4方案直至患者病情进展或不能耐受组进行对照,结果表明两组客观疗效相似,而且第二阶段应用FOLFOX7者仍有69.4%的患者获益,生存期有所改善。而III~IV度不良反应有所减少,特别是在LV5-FU2阶段,III度神经毒性明显减少,从而改善了奥沙利铂连续应用带来的神经感觉异常等不良反应,并且达到了延长生存期的目的。OPTMOX2则在维持期彻底停止化疗,与维持治疗组比较,二组均直至肿瘤进展方重新开始FOLFOX7的治疗。结果显示,二组的中位疾病控制时间分别为36周和41周,后者略有优势。这种打打停停(stop and go)策略改变了目前的单一治疗模式,使化疗更能按照肿瘤的生物学行为和患者的病理生理学特点进行,改善了生活质量,同时减少了患者的经济负担,而且为今后的靶向药物治疗提供了另一可能的维持治疗模式(OPTMOX3)。
3小结
结直肠癌是最常见的恶性肿瘤之一,确诊时有25%的患者已经存在转移病变,根治术后50%的患者会发生复发或转移,因此绝大多数结直肠癌患者需要化学治疗。多年来的临床研究表明,根治术后辅助化疗可明显改善结直肠癌的生活质量和存活。术后辅助化疗的常用方案仍为LV/5-Fu,比较不同给药方法(包括每月一次连续5天的Mayo方案、每周l次持续l年的5-Fu+左旋咪唑方案、 de Gramont的双周方案以及高剂量LV等),无复发存活和5年生存率无统计学差异。2003年美国ASCO年会上 de Gramont介绍的L-OHP联合LV5-F U2的FOLFOX方案用于结直肠癌根治术后的辅助化疗,无复发存活和总存活优于Lv/5-Fu方案,可作为高危因素较多的结直肠癌患者的辅助化疗方案。对于有化疗禁忌证或老年(>75岁)患者可考虑口服希罗达(2500mg/m2X2,d1~d14,休息7天,总共6周期即可)。希罗达的不良反应主要为消化道反应和手足综合征,补充维生素和对症处理即可解决,一般不需停药。CPT-11在结直肠癌根治术后辅助化疗中的作用还需进一步观察。辅助放射治疗可以降低直肠癌根治术后的局部复发,已经成为直肠癌根治术后的标准治疗,多数学者采用先放疗后化疗的辅助综合治疗模式。L-OHP作为晚期大肠癌1、2线化疗疗效可靠,安全性好,恶心呕吐易被控制,虽可增加LV/5-Fu的骨髓抑制,但较少为III/IV度,血小板减少多发生于复治患者的多程治疗后。L-OHP不需水化,可作为晚期大肠癌的l线、2线化疗用药。对于不能手术切除的肝转移患者,L-OHP联合化疗可望降低分期,创造手术机会,可作为新辅助化疗用药。对于肝转移瘤较多,患者一般条件较好者,也可考虑试用肝动脉介入化疗。L-OHP的剂量限制性毒性为外周感觉神经病变,通过仔细监护病人,延长输注时间,必要时下调剂量强度,及时处理冷相关感觉异常或障碍,可使治疗获满意疗效。过去40年来,5-Fu始终是治疗晚期结直肠癌的主要化疗药物。但是,单用5-Fu的有效率很少能达到15%;对5-Fu的有效剂量、给药途径和输注时间也无一致意见。应用四氢叶酸作为5-Fu的生化调节剂,虽可提高客观疗效,但是是否能够显著延长病人的生存期还有争议;长期静脉持续滴注较静冲给药在延迟复发,提高生存率方面经统计学比较有显著意义,然而持续静脉滴注实际操作不够简便,花费也较多(包括中心静脉导管和静脉微量输液泵的应用),因此无论辅助化疗还是姑息化疗,至今5-Fu静冲(Bolus)和持续滴注(CIV)都在普遍使用。对于部分敏感患者,可考虑给与谷胧甘肤、钙镁等。CPT-11和希罗达也是晚期大肠癌的常用化疗药物,雷替曲塞、某些单克隆抗休在大肠癌中的应用仍在临床试用中。
简而言之,新药的开发,不同的给药途径、方法,不同的联合用药方案的实施,使结直肠癌的化疗取得了很大的进步。另一方面,新疗法的探询,单抗及及其与化疗的联合应用,无疑会使结直肠癌治疗水平上一个新台阶。随着近年来对结直肠癌多药耐药研究,给我们展示了结直肠癌治疗的新突破点,对于结直肠癌多药耐药逆转剂的开发应用,将使结直肠癌的治疗出现质的飞跃[79]。
参考文献
1、董志伟,谷铣之.临床肿瘤学.北京:人民卫生出版社, 2003:935-971.
2、万德森,王冬梅.直肠癌围手术期的辅助溜宇.国外医学(肿瘤分册),2003,30:44-47
3、Obrand DI,Gordon PH.Incidence and Pattems of recurreece following curative resection for colorectal careinoma.Dis Colon Rectum,1997,40:15-24.
4、徐从高,张茂宏,杨兴季,主译:癌-肿瘤学原理和实践,第5版.济南:山东科学技术出版社,2002,181-1276.
5、Buyse M,Zeleniuch JA,Chalmers TC.Adjuvant therapy of colorectal eancer:Why we still don’t know?JAMA,1988,259:3571.
6、Mihael Hamilton JM,Friedman MA.Adjuvant chemotheracy of colorectal eancer.In:Wanebo HJ.ed.Surgery for gastroiniestinal caneer:A multidisciplinary approach.Philadephiaippincott Raven Publishers.1997,709.
7、O’Connell MJ,Laurie JA,Kahn M,et al.Prospectively randomized trial of Postoperative adjuvant ehemotherapy in patients with high risk colon cancer. Jclin Oncol,1998,16:295.
8、Asehele C,Lonardi S,Monfardini S, et al.Thymidylate synthase expression as a predietor of clinical response to fluoropy rimdine-based chemotherapy in advanced coloreetal caneer.Cancer Treat Rev,2002,28:27.
9、Johnston PG,Benson A,Catalano P,et al.The clinical significance ofthy midylate synthase(TS)expression in Primary colorectal cancer:AN intergroup combined analysis.Proc Am Soc Clin Oncol, 2005(Abstr3510).
10、Tskebe N, Zhao SC,Ural AU, et al.Retroviral transduction of human dihydro- primidine dehydrogenase cDNA confers resistance to 5-fluorouracil in murine hemmatopoieyic progenitor cells and humanCD34+/- enriched peripheral blood progenitor cells.Cancer GeneTher,2001,8:966.
11、SalongaD,Danenberg KD,Johnson M, et al.Colorestal tumoes responding to 5- fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase,and thymidine phosPhorylase.Clin Cancer Res,2000,6:1322.
12 、Meleod HL,Sluden J, Murray Gl,et al.Charaeterization of dihydropyrimi-Dine dehydrogenase in human colorectal tumors.Br J Cancer,1998,77:461.
13、Tsuji T,Sawai T,Takeshita H, et al.Tumor dihydropyrimidine dehydmgenase in stage II and III colorectal cancer: Low level expression is a benefieial marker in oral- adjuvant chemotherapy,but is also a predietor for poor prognosis in patients treated with curative surgery alone.Cancer LTT.2004,204:97.
14、Othsu A,Baba H,SakataY,et al.Phase II study of s-l,a novel oral fluoropyfin idine derivative in patients with metastatic colorectal cancer.Br J Cancer,2000,83:141-145.
15、Miwa M,Ura M, Nish idaM,et al.Design of a norel oral fluoropyrinidine carbamate,capecitabine, which generatess 5- fluorouracil selectively in tumours by enzymes concentra ted in human liver and cancer tissue. Eur J Cancer,1998,34:1274一1281.
16、M iyadera K,Sum izawa T,Haraguchi M,et al.Role of thymidine phosphory lase aetivity in the angiogenic effeet of platelet derived endothelial cell growth faetor/thym idine phosphorylase.Cancer Res,1995,55:1687-1690.
17、Mettem J,Koommagi R,Volm M.Bionlogical charaeterization of subgroups of squamous cell lung carcinomas.Clin Caneer Res,1999,5:1459.
18、Koizumi W,Salgenji K,Nakamaru N,et al.Prediction of response to 5-deoxy-5-fiuorouridine(5- DFUR)in patiens with inoperable advance.gastric cancer by immunostaining of thylnidine phosphorylase/plateletderived endothelial cell growth factor.Oncology, 1999,56:215.
19、 Cutsem EV,Findlay M,Osterwalder B,et al.Capecitabine, an oral fluoropyrimidine
Carbamate with substantial activity in advanced colorectal cancer:Results of a randomized phase II study.J Clin Oncol,2000,18:1337~1345.
20、 Hoff PM,Ansari R,Batist G,et al.Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first- line treatment in 605 patients with metastatic coloreetal cancer:Reusults of a randomized Phase III study.J Clin Oncol,2001,19:2282-2292.
21、张军,王严庆,吴凯南.甲酰四氢叶酸钙对5-Fu的增效作用及在结直肠癌化疗中的应用,国外医学外科学分册,1996,23:340-344.
22、刘新春,程玉峰,李得爱.实用抗肿瘤药物治疗学.北京:人民卫生出版社,2001.636.
23、林万隆.奥沙利铂的药理作用及临床应用,中国肿瘤临床,2000,27:872-874.
24、Bleierg H.Oxaliplatin(L-OHP):a new reality in colorectal cancer. Br J Cancer,1998,77:l-3.
25、BecouarnY, Rougier P.Clinical efficacy of oxaliplatin monotherapy:phase trials
in advanced colorectal cancer, Semin oncol,1998,25:23-31.
26、 Jin ML,Chen Q, Cheng FQ,et al.Oxaliplatin(OXA) in combination with LV/5- FU2 inChinese patients with advanced gastric cancer(AGC).Proc ASCO,2002,21:558-560.
27、Raymond E,Faivre S, Woynarow ski JM,et al.Oxaliplatin in echanism of action and antineoplastic activity.Semin oncol,1998,25:4-12.
28、刘基巍,班丽英,高亚杰,等.国产奥沙利铂治疗结直肠癌II期临床研究.临床肿瘤杂志,2000,5:178-180.
29、金憋林,陈强,程凤歧,等.奥沙利铂联合亚叶酸钙和5-氟尿嘧啶治疗晚期胃癌的研究.中华肿瘤杂志,2003, 25:172- 174.
30、Louvet C,De gramant A.Role and value of oxaliplatin in metastatic colorectal cancers.Rev Med Inteme,1997,18:368一371.
31、孙燕,管忠震,金懋林,等.奥沙利铂单药或与氟尿嘧啶-甲酰四氢叶酸联合应用治疗晚期结直肠癌II期临床试用报告.癌症,1999,18:237-240.
32、Weh HJ, Wilke HJ,Dierlamm J,et al.Weekly therapy with folinic acid(FA) and high-dose 5-fluorouracil(5- Fu)24- hour infusion in pretreated patients with metastatic colorectal carcinoma.A multicenter study by the Association of Medical Oncology of the German Cancer Soeiety(AIO). Ann Oncol,1994,5:233-237.
33、Andre T,ColinP,Louvet C,et al.Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer:results of a randomized trial.J Clin Oncol,2003,21:2896-2903.
34、Lokich JJ, Ahlgren JD,Gullo JJ,etal. A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma:a Mid- Atlantic Oncology program study.J Clin Oncol, 19897:425-432.
35、Kohne CH,Wils J,Lorenz M,et al.Randomized phase IIIstudy of high-dose fluorouracil given as a weekly 24- hour infusion with or without leucovorin versus bolus fluorouracil plus leucovorin in advanced colorectal cancer:European organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952.. J Clin Oncol,2003,21:3721-2728.
36、 Meropol NJ.Oral fluoropyrimidines in the treatment of colorectal cancer.Eur J Cancer,1998,34:1509-1513.
37、Twelve C,Wong A, Nowacki MP,et al.Capecitabine as adjuvant treatment for
Starge III colon cancer.N Engl J Med,2005,352:2696-2704.
38、 De Gramont A, Bosset J-F, Milan CH, et al.Randomized trial compar-ing monthly
Low-dose leucoverin and fluorouracil bulos with bimonthly high-dose leucoverin and fluorouracil bolus plus continuous infusion for advanved colorectal cancer:A French Intergroup Study.J Clin Oncol,1997,15:808-815.
39、Entremont TS and Hallter DG.Recent advances in chemotherapy for colorectal cancer.Oncology,2003,6:151-161.
40、 De Gramont A,Boni C,Navarro M, et al.Oxaliplatin/5-Fu/ LV in the adjuvant treatment of stage IIand III colon cancer, Efficancy result with a median follow-up of 4 years.4lth ASCO Annal Meeting Proceeding.2005,2465:3501.
41、 Schuster L.针对结直肠癌肝转移的最新化疗方案.肿瘤时讯.2005.12:13.
42、 Braun MS,A dab F,Bradley C, et al.Modified de Gramont with oxalipatin in the first- line treatment of advanced colorectal cancer.Br J Cancer,2003, 89:1155- 1158.
43、Maindraul t-Goebel F, de Gramont A,Louvet C, et al.High- dose intensity Oxalipatin added to the simplified bimonthly leueovorin and 5-fluorouracil regimen as second- line therapy for metastatic colorectal cancer(FOLFOX7). Eur J Cancer.2001,37:1000一1005.
44、 William HI, ROW E PM.Camptothecin new enthusiasm for old drug.Lancet,1995,347:892.
45、徐工学,李志霞,陈佛来.结直肠癌术前区域化疗.国外医学外科学分册,2000,27:347-349.
45、朱培谦,谢敏,曹家庆.术前选择性区域动脉插管灌注化疗在直肠癌治疗中的应用.实用癌症杂志,2001,16:639
46、黄鸿遮,周小牛,黄金华.术前动脉灌注化疗治疗疗效的分析.中国实用外科杂志,1998,18:287.
47、刘勇敢,藏军现,许震,等.直肠癌根治术后行多动脉联合化疗对预防复发和转移的价值.中国肿瘤临床与康复, 2001,8:49.
48、Liver In fusion Meta-analysis Group.Portal vein chemotherapy for colorectal cancer meta- analysis of 4000 patients in studies.J Natl Cancer Inst,1997,89:497-505.
49、FunamiY,TokumoH M,YuchiH, et al.Prognostic value of peritoneal lavage eytology and chemotherapy daring surgery for advanced gastric cancer.Int Surg, 1999,84:220-224.
50、陆耀良.腹腔化疗在结直肠癌中的应用.国外医学肿瘤学分册,1998,25:112-114.
51、张守亮,王茂龙.结直肠癌淋巴靶向化疗的研究进展.国外医学肿瘤学分册,2003,30:381-384.
52、Chan L,Cunningham D:Adjuvant chemotherapy in colon cancer:State of the art .ASCO Educational book,2002,228-239.
53、Sargent DJ,Goldberg RM, Ja Cobson SD, et al.A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients.N Engl J Med,200l,345:1091一1097.
54、Rangier Palliative and adjuvant chemotherapy in colorectal cancer.ECCO Educational Book,200l, 185-202.
55、 Rubin P:Clinicol Oneology.W.B.Saunders Companyhiladelphia 8th edition,2001,729-730.
56、 De Gomont A,Banzi M, Navarro M et al:Oxaliplatin/5- FU/LV in adjuvant colon cancer:Safety result of the international randomized MOSAIO trial.Proceeding of ASCO,2002,12(Abstr525).
57、 De Gramont A,Banzi M,Navarro M et al:OxaliPlatin/5- FU/LV in adjuvant colon cancer:Results of the international randomized MOSAIO trial.Proeeeding of ASCO,2003,Abstrl015.
58、Pazdur R,Coia LR, Hoskins WJ,et al:Cancer Management:A multidisciplinary approach.Oncology New Intemational:New York.Seventh edition,2003,323:352.
59、 ROW E PM.Camptothecin new enthusiasm for old drug.Lancet,1995,347:892.
60、 ROTH ENBERH ML,LCKARDT JR,KUHN JG,et al.Phase II trail of irinotecan in patients with progressive of rapidly recurrent colorectal cancer.J Clin O ncol, 1996,14:1128- 1135.
61、BODLEY A,LIU LF,ISRAELM,et al.DNA topoisonerase II mediated,and daunoru- bicin of doxorubicin corgeners with DNA.Cancer Res,1989,29:5969-5978.
62、潘启超.抗癌新药-拓朴异构酶I抑制剂.中国新药杂志,1998,7:6-8.
63、傅枝莲,王日太,宗可诚.羟基喜树碱与喃氟啶治疗老年人结直肠癌临床观察.滨州医学院学报,2003,23:12-122.
64、张闯.羟基喜树碱联合化疗治疗晚期消化系统恶性肿瘤临床观察.四川治疗防治,2002,15:11- 12.
65、Cunningham D,Pyrh.Onen S, James RD,et al.Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer.Lancet,1998,352:1413-1418.
66、RougierP,Cutsem EV,Bajettae, et al.Randomized trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer Lancet,1998,352:1407-1412.
67、SaltZ LB,Cox JV,Blanke C,et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer.Nengl J Med,2000,343:905-914.
68、王肇炎,王尔兵.结直肠癌的靶向治疗.肿瘤研究与临床杂志2006,18:73-75.
69、Tabemero J,Rojo F,Jimenez E,et al.A phase I PK and sereial tumor and skin pharmacodynamic(PD)study of weekly(qlw),every2- week(q2w) or every 3-week(q3w) l- hour(h) infusion EMD 72000, a humanized monoclonal antiepidermal growth factor receptor(EGFR)antibody, in patients(pt) with [advanced tumors abstract] 770.Proc Am Soc Clin Oncol,2003,22:192.
70、Hurwitz H, Holden SN,Sarkar S, et al.Clinical benefit from bevacizumab(BV) in responding(R) and non- responding(NR) patients(pts) with metastatic colorectal cancer(mCRC).Proc Am Soc Clin Oncol, 2005(Abstr3514).
71、 Saltz LB,Cox JV,Blanke C,et al.Irinotecan plus fluorouracil and leucovorin for metastatic colorevctal cancer.Irinotecan study group.N Engl J Med,2000,343:905- 914.
72、Douillard JY,Cunningham D,Routh AD, et al.Irinotecan combined with fluorouracil compared with fluorouracil alone as first -line treatment for metastatic colorectal cancer.a multicentre randomized trial.Lancet,2000,355:1041-1047
73、 Kohne CH, Van Cutsem E, Wils JA, et al. Irinotecan improve the activity of the AIO regimen in metastatic colorectal cancer. Results of EORTC GI group study 40986.Proc Am Soc Clin Oncol,2003,22:abstr 1018.
74、 de Gramont A,Boni C,Navarro 1M et al.Oxaliplatin/ 5.Fu/LV in the adjuvant treatment of stage II and III colon cancer.Efficancy result with a median follow·up of 4years.4lth ASCO Annal Meeting Proceeding.2005,2465:3501.
75、Tournigand C,Andre T,Aehille E, et al.FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer. A randomized GERCOR study.J Clin Oncol,2004,22:229-237.
76、Arkenau H,Sehmoll H,Kubicka S,et al.Infusional 5-fluorouracil/folinic acid plus oxaliplatin(FUFOX) versus capecitabine plus oxaliplatin(CAPOX) as first line treatment of metastatic colorectal caneer(MCRC):Results of the safety and efficacy analysis.Proc Am Soc Clin Oncol, 2005:abstr3507.
77、 E.C.Popa,W.Luo,H.Hochster,B,et al.A phase II study of ORZEL(UFT+LV) in eldly (75 years old)patients with colorectal cancer:results of ECOG 1299.Proe Am Soc Clin Oncol, 2005:abstr3608.
78、张守亮,上茂龙.结直肠癌淋巴靶向化疗的研究进展.国外医学肿瘤学分册,2003,30:381-384.
79、李啸峰,迟宝荣,马琳.结直肠癌多药耐药研究进展.吉林大学学报(医学)饭),2003,29:700一702(转贴)
由复旦大学附属肿瘤医院主办,中国抗癌协会大肠癌专业委员会、美国Memorial Sloan-Kettering Cancer Center、复旦大学大肠癌诊治中心和《中国癌症杂志》共同协办的2009年中美大肠癌多学科综合治疗研讨会将历时两天,一批世界知名的大肠癌外科、化疗、放疗专家先后在会上作精彩演讲。
【参考文献】
[1]Ambrosini G,Adida C,Altieri DC.A novel antiapoptosis gene,survivin, expressed in cancer and lymphoma[J].Nat Med,1997,3(8):917
[2]Ikeguchi M,Kaibara N.survivin messenger RNA expression is a good prognostic biomarker for oesophageal carcinoma[J].Br J Cancer,2002,87(8):883
[3]Wheatley SP,McNeish IA.Survivin:A protein with dual roles in mitosis and apoptosis[J].Imernational Review of Cytology,2005,247:35
[4]Stauber RH, Rabenhorst U, Rekik A, et al. Nucleocytoplasmic shuttling and the biological activity of mouse survivin are regulated by an active nuclear export signal[J].Traffic,2006,7(11):1461
[5]Borbely AA,Murvai M,Konya J,et al.Effects of human papillomavirus type 16 oncoproteins on survlvln gene expression[J].The Journal of General Virology,2006,89(2):287
[6]Ikeguchi M,Yamaguchi K, Kaibara N. Survivin gene expression positively correlates with proliferative activity of cancer cells in esophageal cancer[J].Tumour Biol,2003,24(1):40
[7]Li YH, Hu CF, Shao Q,et al. Elevated expressions of survivin and VEGF protein are strong independent predictors of survival in advanced nasopharyngeal carcinoma[J].J Transl Med,2008,6:1
[8]Teh SH, Hill AK, Foley DA,et al. COX inhibitors modulate bFGFinduced cell survival in MCF7 breast cancer cells[J].J Cell Biochem,2004,91(4):796
[9]Bafford R,Sui XX,Wang G,et al.Angiotensin II and tumor necrosis factoralpha upregulate survivin and Kruppellike factor 5 in smooth muscle cells: Potential relevance to vein graft hyperplasia [J].Surgery, 2006,140(2):289
[10]Ikeguchi M,Ueda T,Sakatani T,et al.Expression of Survivin messenger RNA correlates with poor prognosis in patients with hepatocellular carcinoma[J].Diagn Mol Pathol,2002,11(1):33
[11]Shankar SI,Mani S,O’Guin KN,et al. Survivin inhibition induces human tumor cell death through caspase independent and dependent pathways[J].Nearoche,2001,92(2):426
[12]Yamamot T,Manome Y,Nakamura M,et al.Downregulation of Survivin expression by induction of the effector cell protease receptor 1 reduces tumor growth potential and results in an increased sensitivity to anticancer agents human colon cancer[J].Eur J Cancer,2002,38(17):2316
[13]Rodel F,Hoffman J,Hoas J,et al.Expression of Survivin in rectal cancer inversely correlated to apoptosis invivo and may predict tumor response to neoadjuvant radiochemotherapy[J].Radiation Oncology,2002,54(2):99
[14]Pennati M,Folini M,Zaffaroni N.Targeting survivin in cancer therapy: fulfilled promises and open questions[J].Carcinogenesis,2007,28(6):1133
[15]Capalbo G, Rodel C, Stauber RH,et al. The role of survivin for radiation therapy. Prognostic and predictive factor and therapeutic target[J].Strahlenther Onkol,2007,183(11):593
[16]Pennati M, Folini M, Zaffaroni N. Targeting survivin in cancer therapy[J]. Expert Opin Ther Targets,2008,12(4):463