结直肠癌分子靶向治疗进展

近年来．结直肠癌内科治疗进展颇快．化疗新药奥沙利铂和依立替康相继获准治疗结直肠癌。5-Fu和甲酰四氢叶酸钙（5-Fu／LV）、卡培他滨、奥沙利铂和依立替康是四种治疗结直肠癌的有效药物．这些药物组成目前常用的一、二线治疗方案。在转移性结直肠癌的治疗不同阶段均能用这些药物治疗．生存期可提高至21个月。但随着肿瘤分子生物学深入研究．尤其阐明了分子信号通路对肿瘤细胞增殖和生长的作用机理．继而开发了特异性靶点的药物治疗．从而开创了临床肿瘤治疗的新领域。分子靶向药物已进入结直肠癌治疗的临床研究并取得了临床疗效。     

肿瘤干细胞学说与结直肠癌的形成和多药耐药

对化疗药物耐药是肿瘤化疗失败的主要原因,肿瘤干细胞理论为重新认识肿瘤化疗药物的耐药机制提供了新思路。近年,许多学者从结直肠肿瘤组织中分离出肿瘤干细胞,并提出肿瘤干细胞致瘤模型和耐药模型学说,很好地解释了药物治疗后肿瘤复发的最根本原因。本文就肿瘤干细胞与结直肠癌的形成和多药耐药作一综述,旨在为进一步研究肿瘤干细胞与结直肠癌的内在联系提供参考。     

结直肠癌靶向治疗中国专家共识

近年来，随着新型靶向药物的应用，靶向治疗已成为结直肠癌个体化治疗和综合治疗的一线方案，中国医师协会结直肠肿瘤专业委员会、中国抗癌协会大肠癌专业委员会以及国家癌症中心国家肿瘤质控中心结直肠癌质控专家委员会组织全国多位专家，讨论了结直肠肿瘤靶向药物的规范应用。     

晚期结直肠癌抗血管生成靶向治疗的若干热点

氟尿嘧啶类药物、伊立替康与奥沙利铂在晚期结直肠癌化学治疗(以下简称化疗)中呈三足鼎立之势,单药(除奥沙利铂)、两药乃至三药组合在临床均有尝试,核心在于高效低毒.随着表皮生长因子受体(epidermal growthfactor receptor,EGFR)单克隆抗体和血管内皮生长因子(vascularendothelial growth factor,VEGF)单克隆抗体等分子靶向治疗药物的出现,合理有效地布局总体治疗策略和选择合适的分子靶向药物,在目前可选药物不多的前提下使所用药物的效应最大化,分子靶向药物与化疗药物发挥协同增效作用以及在分子标志物指导下的个体化治疗等问题,已逐渐成为该领域的研究热点.现以抗血管生成靶向治疗为例,剖析晚期结直肠癌抗血管生成靶向治疗的若干进展.     

泰素帝治疗耐药结直肠癌的实验研究

化疗是目前结直肠癌主要的辅助治疗,但许多患者在化疗过程中肿瘤细胞形成多药耐药,从而导致化疗失败。有研究提示对耐药肿瘤应用具有抗血管生成的细胞毒药物能获得很好的抑瘤效应。Grant等认为泰素帝是一种强效血管生成抑制剂。为了探求耐药结、直肠癌应用泰素帝治疗的前景。我们设计了本研究。     

TGF-β1磷酸化Smad4调控结直肠癌对奥沙利铂的反应性

[目的]探究转化生长因子β1(TGF-β1)通过靶向其下游基因SMAD家族成员4(Smad4),调节结直肠癌细胞对奥沙利铂敏感性的机制研究。[方法]根据结直肠患者对奥沙利铂的敏感性将其分为耐药组以及非耐药组,采用ELISA检测患者血清中TGF-β1的表达量,采用免疫组化检测患者体内Smad4磷酸化水平。采用Western blot检测结直肠癌细胞中Smad4磷酸化水平的变化,采用CCK8检测结直肠癌细胞增殖能力的变化。[结果]结直肠癌患者血清中TGF-β1表达量高于正常组(P<0.001),耐药组患者血清中TGF-β1的表达量高于非耐药组(P<0.001)。癌组织中Smad4磷酸化水平高于癌旁组织(P<0.001),且耐药组患者癌组织Smad4磷酸化水平高于非耐药组(P<0.001)。Pearson相关性分析显示耐药组血清中的TGF-β1表达水平与Smad4磷酸化程度呈正相关性。进一步证实TGF-β1刺激可增加结直肠癌细胞的耐药性;敲减Smad4后,结直肠癌细胞的耐药性下降。[结论]TGF-β1可通过靶向Smad4调控结直肠癌细胞对奥沙利铂的耐药性。     

NPRL2基因与奥沙利铂治疗结直肠癌的研究进展

结直肠癌(CRC)是全球三大恶性肿瘤之一,具有高发病率和高死亡率。研究发现,NPRL2基因与CRC发生、发展关系密切,CRC患者NPRL2基因表达显著降低。奥沙利铂是第三代铂类抗肿瘤药物,已广泛应用于胃肠道肿瘤化疗,可提高CRC患者生存率,但部分患者存在耐药。NPRL2基因可增加奥沙利铂治疗CRC的敏感性,是CRC潜在的治疗靶点。本文就NPRL2基因与奥沙利铂治疗CRC的研究进展作一综述。     

阿司匹林在结直肠癌防治中的意义

阿司匹林作为基础抗凝药物,在心血管疾病中已得到广泛应用。近20年来,随着结直肠癌发病率和死亡率的逐年升高,阿司匹林在结直肠癌患者中的应用和影响也逐渐受到关注。一些回顾性的临床研究发现规律服用阿司匹林的结直肠癌患者肿瘤特异生存率更高,且远隔转移率更低。在现有的抗结直肠癌药物(5－Fu、奥沙利铂、伊立替康和靶向药物)之外,阿司匹林是否也可能作为一种抗肿瘤药物应用于结直肠癌的预防和治疗一直成为学术界关注的热点问题。本文回顾了阿司匹林与结直肠癌相关的临床研究,尝试客观的分析阿司匹林在结直肠癌预防和辅助治疗中的作用及其局限性,以期为临床治疗和研究提供借鉴。     

含洛铂联合化疗方案治疗晚期消化道恶性肿瘤Meta分析

目的 探讨含洛铂联合化疗方案治疗常见晚期消化道恶性肿瘤的近期疗效及不良反应.方法 收集2005年来国内关于含洛铂化疗方案治疗晚期食管及胃肠恶性肿瘤的随机对照研究,并用Meta分析方法进行综合分析.结果 纳入文献6篇,其中食管癌3篇、胃癌1篇、结直肠癌2篇,含洛铂联合化疗方案与含顺铂/奥沙利铂联合化疗方案治疗食管癌、胃癌及结直肠癌相比,在有效率及临床受益率方面差异无统计学意义,在血液毒性、消化道反应、肝肾毒性、外周神经毒性等不良反应,尤其是血小板下降方面的差异无统计学意义.结论 含洛铂联合化疗方案可用于治疗晚期食管、胃及结直肠癌,尤其是对于不能耐受顺铂以及年老体弱患者,可以作为一个较好的替代选择.     

奥沙利铂在氟脲嘧啶／亚叶酸钙治疗无效的晚期大肠癌病人中的应用价值

联合化疗是晚期结直肠癌病人的主要治疗手段之一。奥沙利铂是近年来颇受关注的对大肠癌疗效肯定的铂类药物。2002-03／2004-05我们对32例曾用氟脲嘧啶／亚叶酸钙联合化疗失败的晚期大肠癌病人，加用奥沙利铂联用方案治疗，取得了较满意的临床效果，现报告如下。     

Micelles as potential drug delivery systems for colorectal cancer treatment

Despite the significant progress in cancer therapy, colorectal cancer (CRC) remains one of the most fatal malignancies worldwide. Chemotherapy is currently the mainstay therapeutic modality adopted for CRC treatment. However, the long-term effectiveness of chemotherapeutic drugs has been hampered by their low bioavailability, non-selective tumor targeting mechanisms, non-specific biodistribution associated with low drug concentrations at the tumor site and undesirable side effects. Over the last decade, there has been increasing interest in using nanotechnology-based drug delivery systems to circumvent these limitations. Various nanoparticles have been developed for delivering chemotherapeutic drugs among which polymeric micelles are attractive candidates. Polymeric micelles are biocompatible nanocarriers that can bypass the biological barriers and preferentially accumulate in tumors via the enhanced permeability and retention effect. They can be easily engineered with stimuli-responsive and tumor targeting moieties to further ensure their selective uptake by cancer cells and controlled drug release at the desirable tumor site. They have been shown to effectively improve the pharmacokinetic properties of chemotherapeutic drugs and enhance their safety profile and anticancer efficacy in different types of cancer. Given that combination therapy is the new strategy implemented in cancer therapy, polymeric micelles are suitable for multidrug delivery and allow drugs to act concurrently at the action site to achieve synergistic therapeutic outcomes. They also allow the delivery of anticancer genetic material along with chemotherapy drugs offering a novel approach for CRC therapy. Here, we highlight the properties of polymeric micelles that make them promising drug delivery systems for CRC treatment. We also review their application in CRC chemotherapy and gene therapy as well as in combination cancer chemotherapy.     

P-glycoprotein expression and chemosensitivity in highly purified fresh human gastrointestinal cancer cells

BACKGROUND/AIMS: Colorectal cancer is one of the tumors most refractory to treatment by chemotherapy. One of the major problems associated with cancer chemotherapy is drug-resistance of tumor cells, and resistance to doxorubicin (DOX) is mainly due to the effect of P-glycoprotein. We have tried to prove the correlation between P-glycoprotein expression and DOX-sensitivity in highly purified fresh human colorectal cancer and, moreover, to prove the differentiation of P-glycoprotein expression between the different kinds of cancers, including gastric cancer. METHODOLOGY: The present study was designed to quantify P-glycoprotein expression by flow cytometry, and DOX-sensitivity by MTT assay in highly purified fresh human tumor cells obtained from 29 cancer patients including 13 colorectal cancers and 16 gastric cancers. RESULTS: DOX-sensitivity decreased in proportion to P-glycoprotein expression in colorectal cancer. P-glycoprotein expression in colorectal cancer was higher than that in gastric cancer. Particularly, P-glycoprotein expression in colorectal cancer in the DOX low-sensitivity group was higher than in the DOX high-sensitivity group. CONCLUSIONS: The chemotherapeutic management of patients with colorectal cancer might be more effective if we can circumvent the effect of P-glycoprotein.     

Roscovitine synergizes with conventional chemo-therapeutic drugs to induce efficient apoptosis of human colorectal cancer cells

AIM： To examine the ability of cyclin-dependent kinase inhibitor （CDKI） roscovitine （Rosco） to enhance the antitumor effects of conventional chemotherapeutic agents acting by different mechanisms against human colorectal cancer. METHODS： Human colorectal cancer cells were treated, individually and in combination, with Rosco, taxol, 5-Fluorouracil （5-FU）, doxorubicine or vinblastine. The antiproliferative effects and the type of interaction of Rosco with tested chemotherapeutic drugs were determined. Cell cycle alterations were investigated by fluorescence-activated cell sorter FACS analysis. Apoptosis was determined by DNA fragmentation assay. RESULTS： Rosco inhibited the proliferation of tumor cells in a time-and dose-dependent manner. The efficacies of all tested chemotherapeutic drugs were markedly enhanced 3.0-8.42 × 10^3 and 130-5.28 × 10^3 fold in combination with 5 and 10 μg/mL Rosco, respectively. The combination of Rosco and chemotherapeutic drugs inhibited the growth of human colorectal cancer cells in an additive or synergistic fashion, and in a time and dose dependent manner. Rosco induced apoptosis and synergized with tested chemotherapeutic drugs to induce efficient apoptosis in human colorectal cancer cells. Sequential, inverted sequential and simultaneous treatment of cancer cells with combinations of chemotherapeutic drugs and Rosco arrested the growth of human colorectal cancer cells at various phases of the cell cycle as follows： Taxol/Rosco （G2/M-and S-phases）, 5-FU/Rosco （S-phase）, Dox/Rosco （S-phase） and Vinb/Rosco （G2/M-and S-phases）. CONCLUSION： Since the eff icacy of many anticancer drugs depends on their ability to induce apoptotic cell death, modulation of this parameter by cell cycle inhibi-tors may provide a novel chemo-preventive and chemo-therapeutic strategy for human colorectal cancer.     

Molecular predictors of treatment and outcome in colorectal cancer

Understanding of the metabolism and mechanisms of resistance of tumors to chemotherapeutic agents is essential so that we can administer therapy to maximize response and minimize toxicity. In this review we describe molecular markers associated with fluoropyrimidine and platinumbased chemotherapy that may predict the outcome of therapy when patients are treated with these agents. We discuss the ways in which determination of gene expression levels can enhance the treatment of colorectal cancer through prediction of patient response and tailoring of chemotherapy to the characteristics of an individual tumor.     

Increased expression of CEA and MHC class I in colorectal cancer cell lines exposed to chemotherapy drugs

PURPOSE: Cancer-specific immunotherapy holds great promise as an emerging treatment for advanced colorectal cancer and may be combined with standard chemotherapy to provide a synergistic inhibitory action against tumor cells. To examine the interrelationship between the immune system and chemotherapy, we studied the induction of both CEA, a tumor-associated antigen, and MHC class I, a major component of the antigen presenting system, in response to a number of chemotherapeutic agents. METHODS: The effect of a selection of standard chemotherapeutics on MHC class I and CEA expression in human colorectal cancer cell lines was determined by flow cytometry and semi-quantitative RT-PCR. In addition, studies using mice bearing tumors derived from an injected murine colon cancer cell line were performed to determine if alteration in MHC class I expression occurs in vivo following continuous infusion of chemotherapeutic agents into the peritoneal cavity, as well as to facilitate correlations between expression of this factor and therapeutic effectiveness. RESULTS: All anti-cancer drugs examined, when given at IC50 values, induced expression of MHC class I protein in the human colon cancer cell line, COLO201. However, expression of CEA mRNA was only induced upon exposure to 5-FU, in contrast to obscure induction following CDDP and SN-38 treatment. Combined treatment with 5-FU and CDDP gave additional effect on CEA expression in COLO201 cells. Regarding the in vivo studies in mice, the size of the murine colon cancer cell-derived tumors was reduced only in response to treatment with CDDP, which also mediated the highest induction of MHC class I expression. CONCLUSION: These results suggest that chemotherapeutic agents trigger the immune system and cancer-specific immunotherapy may be effective when used in combination with systemic chemotherapy.     

Modulation of drug resistance transporters as a strategy for treating myelodysplastic syndrome

Resistance to chemotherapy is an obstacle to the successful treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The failure of therapeutic treatment may be due to the development of multidrug resistance (MDR), mechanisms of which include upregulation of membrane-resident transporters which efflux chemotherapeutic drugs from tumor cells, and failure of the cancer cell to undergo apoptosis in response to chemotherapy. Membrane transporter-based drug efflux transporters have been extensively studied, and agents that block drug efflux have been found and investigated. Presence of P-glycoprotein (Pgp, MDR1, ABCB1), a member of the ATP-binding cassette (ABC) transporter family, has been reported to correlate with poor prognosis in AML and MDS. In MDS, Pgp expression increases as the disease progresses. Overexpression of other transporters, such as the multidrug resistance protein (MRP1, ABCC1), and the vault-associated transporter lung resistance protein have been shown as well in both MDS and AML, but their prognostic relevance is not clear. Recently, a novel ABC half-transporter, the breast cancer resistance protein (ABCG2) has been found in approximately 30% of AML cases, and may play a role in resistance to chemotherapy. In clinical trials in MDS, first-generation Pgp blockers, such as cyclosporin-A and verapamil, were minimally effective, non-specific, and toxic. However, another first-generation blocker, quinine, was used in MDS and may specifically benefit MDS patients overexpressing Pgp. A second-generation drug, the non-immunosuppressive cyclosporine analog valspodar (PSC833), was studied in AML and MDS, and was highly toxic, resulting in the need to reduce the dosage of the chemotherapeutic drugs as a result of valspodar reducing the clearance of the chemotherapeutic agents. Third-generation drugs, which are highly specific for Pgp and which seem to have only modest effects on drug clearance, include tariquidar, zosuquidar, laniquidar, and ONT-093. These are all in phase I/II trials and show promise for future treatment.     

Quantitative analysis of MDR1 (multidrug resistance) gene expression in human tumors by polymerase chain reaction.

The resistance of tumor cells to chemotherapeutic drugs is a major obstacle to successful cancer chemotherapy. In human cells, expression of the MDR1 gene, encoding a transmembrane efflux pump (P-glycoprotein), leads to decreased intracellular accumulation and resistance to a variety of lipophilic drugs (multidrug resistance; MDR). The levels of MDR in cell lines selected in vitro have been shown to correlate with the steady-state levels of MDR1 mRNA and P-glycoprotein. In cells with a severalfold increase in cellular drug resistance, MDR1 expression levels are close to the limits of detection by conventional assays. MDR1 expression has been frequently observed in human tumors after chemotherapy and in some but not all types of clinically refractory tumors untreated with chemotherapeutic drugs. We have devised a highly sensitive, specific, and quantitative protocol for measuring the levels of MDR1 mRNA in clinical samples, based on the polymerase chain reaction. We have used this assay to measure MDR1 gene expression in MDR cell lines and greater than 300 normal tissues, tumor-derived cell lines, and clinical specimens of untreated tumors of the types in which MDR1 expression was rarely observed by standard assays. Low levels of MDR1 expression were found by polymerase chain reaction in most solid tumors and leukemias tested. The frequency of samples without detectable MDR1 expression varied among different types of tumors; MDR1-negative samples were most common among tumor types known to be relatively responsive to chemotherapy.     

Predictive biomarkers with potential of converting conventional chemotherapy to targeted therapy in patients with metastatic colorectal cancer

The availability of systemic chemotherapy regimens for the treatment of patients with metastatic colorectal cancer (mCRC) is based on the results from large prospective, randomized studies. The main chemotherapeutic drugs used in treatment of mCRC are the fluoropyrimidines (5-fluorouracil (5-FU); capecitabine) in combination with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI). The objective response rate to either combination is approximately 50%, where no significant differences with regard to progression free survival or overall survival have been observed. Interestingly, a number of preclinical and clinical studies have indicated lack of full cross resistance between oxaliplatin based and irinotecan based treatment. Therefore, it is possible that certain mCRC patient subpopulations would benefit more from one drug combination rather than the other. To address this clinical problem there has been much focus on development and validation of predictive biomarkers for these three drugs. Here, we present a thorough review on the current status of predictive biomarkers for 5-FU, oxaliplatin and irinotecan treatment of mCRC patients. The overall conclusions were as follows: Several promising biomarker candidates were identified, notably thymidylate synthase for 5-FU, topoisomerase I for irinotecan and ERCC1 for oxaliplatin. However, these candidates warrant further analysis, where assay performance and clinical trial design should be in focus.