胰腺癌的基因治疗研究

胰腺癌的早期诊断不易，切除率不高，治疗的结果令人失望，近年来各种手术方式的改进以及化疗、放疗方案等综合措施的引进，手术并发症和死亡率有所降低，但5年生存率仍提高不多。随着免疫和分子生物学在肿瘤的发生、发展和转移机制研究的不断深入，为胰腺癌的治疗提供了新的治疗希望，不少免疫治疗已进入临床Ⅰ、Ⅱ期试验。     

基因治疗在胰腺癌中的应用

从1989年美国科学家Rosenberg等开始第一个人类基因治疗临床试验至今,基因治疗无论从基础研究到临床试验,都获得了长足进展。至2007年7月,全球27个国家和地区已完成、正在进行或已经批准的基因治疗临床试验项目共1309项,主要集中在肿瘤（66％）、遗传性疾病（9．8％）和心血管疾病（8．3％）等方面。对许多目前尚无有效治疗方法或疗效并不满意的疾病而言,基因治疗是其获得治愈的潜在希望。     

腺病毒介导的人血管抑素基因治疗胰腺癌

目的观察腺病毒介导的人血管抑素基因对胰腺癌的治疗作用。方法通过病毒重组技术将人血管抑素基因克隆入增殖缺陷型腺病毒基因组中,获得腺病毒滴度达5．5×10~(10) pfu/ ml,观察转染表达后的生物学活性,通过建立裸鼠动物模型(每组数n=15例),分析基因转导后胰腺癌组织中血管抑素的表达情况及对肿瘤血管的抑制作用。结果构建了血管抑素的重组腺病毒载体pCA13-hAG；检测到血管抑素在体外mRNA水平和蛋白质水平表达率分别为87%和81%,得到279 bp电泳条带和38 000大小的蛋白条带；荷瘤裸鼠体内肿瘤体积显著低于对照组(P＜0．05),治疗组MVD为9．85±1．20,两对照组肿瘤微血管密度(MVD)分别为20．35±2．15、17,66±2．34 (P＜0．05)。结论所构建的pCA13-hAG重组腺病毒载体可有效表达具有生物学活性的血管抑素,使肿瘤内微血管生成减少,肿瘤细胞增殖减慢,为抗血管生成治疗实体瘤的临床应用奠定基础。     

胰腺癌基因治疗靶点研究现状

胰腺癌具有高发病率和高死亡率的特点,并且是最难治疗的癌症之一。因此,迫切需要开展新的治疗方法。自1990年首次基因治疗临床试验以来,伴随分子生物学技术的进步,基因疗法得到了巨大的提高和空前的发展。在胰腺癌基因治疗过程中常采用外源基因的导入、表达,变异基因的修复,抑制转录,破坏癌变基因等方法来达到治疗目的,其中最关键的就是治疗靶点的选择。就近年胰腺癌基因治疗靶点研究成果与存在问题作一综述。     

胰腺癌的肿瘤标志物和免疫基因治疗研究进展

胰腺癌由于恶性程度高、手术切除率低、早期诊断困难 ,治疗的效果不尽人意。近年来 ,随着对肿瘤的发生、发展和转移机制认识的不断深入 ,尤其是肿瘤分子生物学与免疫学的进展 ,关于肿瘤相关的免疫调节与应答、癌变、转移以及癌基因和抑癌基因之间的作用机制的进一步了解 ,许多用于胰腺癌早期诊断的血清及基因标志物被发现 ,不少的免疫基因治疗手段已经进入临床试验[1,2 ] ,为胰腺癌的诊断和治疗提供了新的希望。胰腺癌的肿瘤标志物胰腺癌传统的肿瘤标志物通常指由肿瘤组织自身合成、分泌的某些抗原、激素及酶类等 ,但是 ,随着分子生物学技术…     

胰腺癌生物治疗现状与进展

近年来,对胰腺癌虽然在诊断技术和治疗手段上有了长足的进步,但胰腺癌患者的生存时间并没有延长.     

胰腺癌基因治疗新进展

胰腺癌高度恶性，是威胁人类健康与死亡的主要敌人。在美国已成为第二大消化道肿瘤的死因，在西方国家中列第四位；在上海发病率20年内增加了4倍。尽管胰腺癌诊断和围手术期处理有了提高，可是预后并没有显著改善。国际胰腺癌协会(IARC)2000年的一项报告表明：2000年新发胰腺癌病例217000人，其中当年死亡213000人。总体5年生存率仅为0．4％。当今，我们已进入“分子时代”，人们寄希望于依据胰腺癌的分子和基因异常发展的新治疗方法——基因治疗，能够带给胰腺癌病人光明的明天。     

胰腺癌基因治疗研究进展

胰腺癌传统治疗方法主要是手术切除、放射治疗和化学药物治疗。虽然近年来出现了如术中放射治疗和经门静脉化疗等治疗措施,但胰腺癌总体5年生存率仍不到4％,总的中位生存期不到20月,出现转移后中位生存期则低于6月。近年来随着分子生物学的进步,人们对肿瘤发生发展机制的认识有长足的进步,为胰腺癌开辟新的治疗途径提供了广阔的前景。本文将从以下几个方面综述胰腺癌基因治疗的进展。     

胰腺癌基因诊治的新进展

胰腺癌基因诊断和治疗的进展有助于改善胰腺癌的预后。人们在研究中不断发现新的癌基因参与胰腺癌的发生和发展 ,同时还寻求置换有正常功能的基因或增补缺陷基因的方法治疗胰腺癌。可以预见 ,基因诊断和治疗作为一种全新的胰腺癌诊治手段 ,将一定程度改变人类疾病治疗的进程。一、基因诊断随着分子生物学技术的进展 ,现在我们可以直接检测和鉴定缺陷基因 ,使胰腺癌的诊断从传统的表型诊断上升到基因诊断。现已证实胰腺癌的发生和发展与抑癌基因、原癌基因、ＤＮＡ错配修复基因及雌激素诱导基因等有关。1.抑癌基因 :已知至少 10种抑癌基因与…     

胰腺癌发病危险因素的研究现状

在北美洲和欧洲 ,胰腺癌分别占因癌症死亡原因的第4位和第 6位[1] ,在我国为前 10位[2 ] 。胰腺癌发病隐匿 ,病程进展快 ,诊断后平均生存时间为 3个月。适合手术治疗者低于 15 % ,术后 5年生存率低于 4 % [3 ] 。现就胰腺癌发病危险因素的国内外研究现状综述如下。一、生理因素流行病学研究提示 ,5 0岁以上人群发生胰腺癌的危险性大约是年轻人的 2 0倍。在西方国家 ,胰腺癌患者就诊时的年龄多为 6 5～ 70岁 ,而已经患有慢性胰腺炎的患者 ,发病年龄可提前 10～ 2 0年。在东亚 ,一组资料显示中国人胰腺癌发病年龄在 (5 5 7± 11 5 )岁 ,日本…     

Gene therapy for pancreatic cancer based on genetic characterization of the disease

In order to develop an effective therapeutic intervention for patients with pancreatic cancer, we analyzed the association of loss of heterozygosity (LOH) with the clinicopathological features of the disease. Based on these results, we are developing a new gene therapy that targets the genetic character of pancreatic cancer, using mutant adenoviruses that are selectively replication-competent in tumor cells. LOH of 30% or more was observed on chromosome arms 17p (47%), 9p (45%), 18q (43%), 12q (34%), and 6q (30%). LOH of 12q, 17p, and 18q showed significant association with poor prognosis. These data strongly suggest that mutations of the putative tumor suppressor genes, TP53 and SMAD4, play significant roles in the disease progression. Based on this rationale, we are developing a new gene therapy that targets tumors without normal TP53 function. The E1B-55kDa-deleted adenovirus can selectively replicate in TP53-deficient human tumor cells, but not in cells with functional TP53. We evaluated the therapeutic effect of this E1B-55kDa-deleted mutant adenovirus on pancreatic cancer without normal TP53 function. The growth of a human pancreatic tumor in a severe combined immunodeficiency (SCID) mouse model was markedly inhibited by consecutive injections of the E1B-55kDa-deleted adenovirus. Furthermore, the replication-competent adenovirus is not only a strong weapon itself but it is also a useful carrier of genes that possess antitumor activities, as a virus vector specific to tumors without normal TP53 function. Received: April 23, 2001 / Accepted: May 11, 2001     

胰腺癌综合治疗的现状

胰腺癌是一种难治性消化系统恶性肿瘤,具有病程短、进展快、病死率高等特点.由于胰腺解剖位置特殊,且缺乏特异性症状及检查手段,导致胰腺癌早期诊断困难.胰腺癌生物学行为特殊,早期易发生胰内、外的转移和侵犯.手术切除率<15%,病程不到1年.即使手术切除肿瘤,胰腺癌局部复发率和远处转移率仍相当高,患者5年生存率<5%,预后极差<'[1-2]>.同时,胰腺癌的发病率呈明显上升趋势,近20年增加了1～5倍.我国胰腺癌的发病率已由第22位(20世纪60年代)上升到第5位(20世纪90年代),相应的病死率由第15位上升至第6位<'[3-4]>.临床流行病学调查进一步显示,上海市胰腺癌发病率正以每年2%的速度增加,且病死率和发病率非常接近<'[5]>.如何进行合理的胰腺癌综合治疗已成为当务之急.纵观胰腺癌综合治疗的现状,主要包括以下7个方面.     

重视胰腺癌的综合治疗

Pancreatic cancer is a common malignancy of gastrointestinal system, with features of early metastasis, easy invasion to adjacent tissues and organs and neural metastasis. Therapies include surgery, chemotherapy, radiotherapy, physi-cal and biological therapy and so on. Surgical management, including radical resection and palliative operation, is a major approach. Radiotherapy and chemotherapy could improve the resectional rate and decrease the tumor dissemination. Physical and biological therapies are widely recommended, and there is a rapid progress in zoopery. However, the efficacy of all the thera-pies is far from satisfactory. Recently, the therapy consisting of surgical resection, radiotherapy, chemotherapy, physical and biological therapy in increasing the long-term survival rate and improving the life quality of patients, along with combined thera-py has attracted the attention of surgeons.     

Adjuvant treatments for resectable pancreatic cancer

Pancreatic cancer remains one of the most challenging malignancies to treat successfully. The majority of patients present with unresectable advanced-stage cancer, and only 20% of patients can undergo resection. Even if surgical resection is performed, the recurrence rate is high and the survival rate after surgery is poor. Therefore, effective adjuvant therapy is needed to improve the prognosis of patients with pancreatic cancer. Until now, no universally accepted standard adjuvant therapy for this disease has been available: chemoradiotherapy followed by chemotherapy is considered the optimal therapy in the United States, while chemotherapy alone is the current standard in Europe. However, recent randomized controlled trials (RTOG [Radiation Therapy Oncology Group] 9704; CONKO [Charité Onkologie]-001; and a Japanese study) have suggested a benefit of adjuvant chemotherapy with gemcitabine for patients with resectable pancreatic cancer. This article will review the clinical trials of adjuvant therapy for this disease, including the results of recent trials.     

光动力治疗裸小鼠胰腺移植癌的实验研究

目的 研究光动力治疗（ＰＤＴ）对胰腺癌的治疗效果,为胰腺癌寻找有效的治疗手段。方法 接种人胰腺癌细胞ＳＷ１９９０于裸小鼠皮下,建立移植癌模型,以血卟淋衍生物（ＨｐＤ）作为光敏剂,采用腹腔和瘤内局部注射两种不同方式给药,继以波长６３２．８ｎｍ的Ｈｅ－Ｎｅ激光照射肿瘤局部,观察光动力治疗后肿瘤的生长速度和组织形态学变化,并测定了肿瘤组织内脂质过氧化产物丙二醛（ＭＤＡ）的含量,对其治疗机制进行了初步探讨     

胰腺癌的放射治疗

胰腺癌的治疗主要是手术切除,但适应者仅20％,且治疗效果也不佳.虽然非手术治疗的效果很差,但化疗的地位已被确立,而放疗的地位尚未被完全肯定.现代的放疗作为局部治疗的手段参与胰腺癌的治疗,已经开始显现有可能改善肿瘤局控,提高生存率,有望成为胰腺癌局部治疗的一部分,但到目前还缺乏高级别的循证医学证据支持.就放疗技术本身而言,也存在诸多未解决的问题,包括照射靶区运动,靶区的定义,合适的分割剂量,总剂量和照射时间,放疗和手术、化疗的应用次序.然而下述观点是业界的共识:现代的放疗技术值得进一步研究,以明确其在胰腺癌综合治疗中的作用和地位.     

CD基因联合GM-CSF基因对胰腺癌治疗作用的实验研究

目的：观察自杀基因CD联合GM—CSF基因的抗胰腺癌作用。方法：应用逆转录病毒方法转导CD和GM—CSF基因。皮下接种胰腺癌细胞TD2，肿瘤局部注射重组表达的pVITR02-CD-GM—CSF，然后连续10d给予5-氟胞嘧啶（5-Fc）300mg／kg治疗，观察肿瘤的生长情况。结果：CD／5-Fc联合GM—CSF治疗后，小鼠肿瘤体积显著缩小，存活期明显延长，与对照组以及GM—CSF组和CD／5-Fc组比较差异有统计学意义（P〈0．05，P〈0．01），且肿瘤瘤体内CD8^＋细胞浸润增加，MHC—Ⅰ和B7—1表达明显增加。结论：CD基因联合细胞因子基因GM—CSF可增强CD的抗肿瘤作用，其疗效要好于GM—CSF或CD基因单独治疗。     

结直肠癌基因治疗研究进展

【摘要】〓结直肠癌是常见的消化道恶性肿瘤,传统治疗以外科手术为主,辅以放、化疗,术后5年生存率仅为50%左右。近年来结直肠癌基因治疗备受人们青睐,且有许多研究成果成功运用于临床。目前对结直肠癌基因治的方法主要有原癌基因治疗、抑癌基因治疗、免疫基因治疗以及多基因联合治疗等。     

Preoperative chemoradiation in resectable pancreatic cancer

Despite advancements in the field of surgical oncology, the diagnosis of pancreatic cancer still carries a grave and dismal prognosis. Surgery alone for adenocarcinoma of the pancreatic head or uncinate process has a median survival time of 12 months. These grim statistics have led many to study the effects of combined multimodality therapy in the fight against pancreatic cancer. The long recovery time associated with pancreaticoduodenectomy has resulted in as many as 25% of patients unable to proceed with planned adjuvant therapy. For these reasons preoperative or neoadjuvant chemoradiation therapy (CRT) has been evaluated. Preoperative CRT ensures that all eligible patients receive the benefits of multimodality therapy, and patients who manifest metastatic disease on restaging evaluations are spared the morbidity of an unnecessary laparotomy. Multimodality therapy appears to lengthen the survival duration in patients with pancreatic cancer. It also affords a selection advantage, in that patients with aggressive disease biology with advanced metastatic disease following CRT are spared the morbidity of surgery. Conversely, a limited subset of patients may even be downstaged, allowing for a potentially curative resection. In this article we review the current status of neoadjuvant chemoradiation in adenocarcinoma of the pancreas. We discuss its rationale in light of the reported strengths and weaknesses of postoperative adjuvant CRT. Received: March 20, 2002 / Accepted: April 15, 2002 RID="*" ID="*" Offprint requests to: M.P. Callery     

Adenovirus-mediated wild-typep53 tumor suppressor gene therapy induces apoptosis and suppresses growth of human pancreatic cancer

Background: Thep53 tumor suppressor gene is mutated in up to 70% of pancreatic adenocarcinomas. We determined the effect of reintroduction of the wild-typep53 gene on proliferation and apoptosis in human pancreatic cancer cells using an adenoviral vector containing the wild-typep53 tumor suppressor gene. Methods: Transduction efficiencies of six p53-mutant pancreatic cancer cell lines (AsPC-1, BxPC-3, Capan-1, CFPAC-1, MIA PaCa-2, and PANC-1) were determined using the reporter gene construct Ad5/CMV/-gal. Cell proliferation was monitored using a³H-thymidine incorporation assay, Western blot analysis forp53 expression was performed, and DNA laddering and fluorescence-activated cell sorter analysis were used to assess apoptosis.p53 gene therapy was tested in vivo in a subcutaneous tumor model. Results: The cell lines varied in transduction efficiency. The MIA PaCa-2 cells had the highest transduction efficiency, with 65% of pancreatic tumor cells staining positive for beta-galactosidase (-gal) at a multiplicity of infection (MOI) of 50. At the same MOI, only 15% of the CFPAC-1 cells expressed the -gal gene. Adenovirus-mediatedp53 gene transfer suppressed growth of all human pancreatic cancer cell lines in a dose-dependent manner. Western blot analysis confirmed the presence of the p53 protein product at 48 hours after infection. DNA ladders demonstrated increased chromatin degradation, and fluorescence-activated cell sorter analysis demonstrated a four-fold increase in apoptotic cells at 48 and 72 hours following infection with Ad5/CMV/p53 in the MIA PaCa-2 and PANC-1 cells. Suppression of tumor growth mediated by induction of apoptosis was observed in vivo in an established nude mouse subcutaneous tumor model following intratumoral injections of Ad5/CMV/p53. Conclusions: Introduction of the wild-typep53 gene using an adenoviral vector in pancreatic cancer withp53 mutations induces apoptosis and inhibits cell growth. These data provide preliminary support for adenoviral mediatedp53 tumor suppressor gene therapy of human pancreatic cancer.Presented at the 51st Annual Cancer Symposium of The Society of Surgical Oncology, San Diego, California, March 26–29, 1998.