Farnesyltransferase inhibitors: antineoplastic properties, mechanisms of action, and clinical prospects

Farnesyltransferase (FTase) inhibitors are among the current wave of molecularly targeted anti-cancer agents being used to attack malignancy in a rational manner. A large body of preclinical data indicates that FTase inhibitors block cancer cell proliferation through both cytostatic and cytotoxic effects. Interestingly, FTase inhibitors have rather limited effects on normal cell function, suggesting that they may target unique aspects of cancer cell pathophysiology. The development of FTase inhibitors was predicated on the discovery that the Ras oncoproteins must be post-translationally modified to transform cells. However, recent work indicates that the anti-neoplastic effects of FTase inhibitors depend on altering the post-translational modifications of non-Ras proteins as well. In particular, a critical target protein that responds to FTase inhibition by blocking tumor cell growth is RhoB, an endosomal Rho protein that functions in receptor trafficking. In this review, we survey the biological foundations for the clinical development of FTase inhibitors, and consider some of the latest mechanistic studies that reveal how these agents affect cellular physiology.     

Targeting tumor vasculature with homing peptides from phage display

Tumor vasculature expresses a number of molecular markers at much lower levels than those seen in the blood vessels of normal tissues, and in some cases, such markers are undetectable. The presence of these markers relates to angiogenesis; the same markers are shared by all blood vessels undergoing angiogenesis. The endothelial cells, pericytes and smooth muscle cells, and the vascular extracellular matrix in angiogenic vessels can each express such markers. Molecularly, they represent vascular growth factor receptors, cell adhesion proteins and their receptors. Screening of phage display libraries for peptides that home to tumor vasculature when injected into mice has recently provided a new tool for analyzing the distinguishing features of tumor vasculature. Tumor-homing peptides isolated in this manner, as well as an antibody against a form of fibronectin expressed in tumor blood vessels, have been found to serve as targeting devices to concentrate drugs and other therapeutic materials to tumors in in vivo models. Such a targeting strategy can therefore potentially improve the efficacy of drugs and reduce their side effects.     

Identification of EBV transforming genes by recombinant EBV technology

Epstein-Barr virus (EBV) is able to infect primary B-lymphocytes but usually does not proceed to replicate more virions. Instead, EBV persists as an incomplete virus and expresses 12 gene products that transform the growth of these cells into continuously proliferating lymphoblastoid cell lines. Because EBV is associated with several human malignancies, there is intense interest in delineating the molecular functions of these EBV gene products in transformation. This review focuses on the recombinant EBV technologies that have been developed to introduce specific mutations into EBV and test the functions of these EBV genes in primary B-lymphocyte growth transformation.     

Matrix metalloproteinases in tumor invasion and metastasis

Extensive work on the mechanisms of tumor invasion and metastasis has identified matrix metalloproteinases (MMPs) as key players in the events that underlie tumor dissemination. Studies using natural and synthetic MMP inhibitors, as well as tumor cells transfected with cDNAs encoding the MMPs characterized thus far have provided compelling evidence that MMP activity can induce or enhance tumor survival, invasion and metastasis. Because of the ability of MMPs to degrade extracellular matrix (ECM) proteins, the principal mechanism whereby MMPs promote tumor development has been thought to be the proteolytic breakdown of tissue barriers to invasion and the associated facilitation of circulating tumor cell extravasation. However, recent evidence stemming from the use of novel experimental approaches indicates that MMPs do not play a major role in the process of extravasation itself. Rather, they appear to promote intravasation (the process of penetrating the circulation following invasion of blood vessels) and regulate the relationship between tumor cells and host tissue stroma subsequent to extravasation. In addition, the discoveries that a growing number of proteolytically active MMPs may localize to the cell surface in association with adhesion receptors, and that MMP substrates include latent cytokines and growth factors, provide a new conceptual framework for the mechanisms whereby MMPs influence tumor behavior.     

New aspects of integrin signaling in cancer

Members of the integrin family of cell adhesion receptors influence several important aspects of cancer cell behavior, including motility and invasiveness, cell growth, and cell survival. Engagement of integrins with extracellular matrix (ECM) proteins can activate members of the Rho-family of small GTPases; conversely, Rho- and Ras-family proteins can influence the ability of integrins to bind their ligands. These events impinge on the control of cell motility, and ultimately on invasive and metastatic behavior. Integrin engagement with ECM also has important effects on cell survival, particularly for cells of epithelial origin. In some cases, specific integrins have selective effects on the efficiency of signal transduction in cell survival pathways.     

Role of LMP1 in immune control of EBV infection

The Epstein-Barr virus (EBV) encoded latent membrane protein (LMP1) plays a crucial role in the long-term persistence of this virus within the cells of the immune system. Not only is this protein critical for the transformation of resting B cells by EBV, it also displays pleiotropic effects on various cellular proteins expressed in the host cell. These include up-regulation of expression of B cell activation antigens, adhesion molecules and various components of the antigen processing pathway. Here we discuss how LMP1 acts like an expression 'switch' which, depending on the stage of EBV infection, manoeuvres various pathways that either modulate the immune system towards or against its survival.     

腹部压块对膈肌运动影响的研究

目的 :研究腹部压块对膈肌运动的影响。方法 :选择拟行立体适形放疗患有肺癌或肝脏肿瘤的患者 2 0例。按治疗体位仰卧于体部立体放疗定位负压袋内 ,待患者呼吸平稳后 ,将灯光野的中心点置于膈顶运动的最低点 ,在膈肌运动至最高位时拍摄照片 ,测量膈肌运动的最大幅度 ;然后 ,将心形腹部压块放置于患者剑突下 ,并用定位框架的腹带交叉固定 ,按压程度以不引起患者呼吸困难或其他不适为标准 ,5min后按上述方法再次测量膈肌运动的最大幅度。结果 :2 0例患者未加腹部压块的运动幅度为0 6 2～ 2 6 7cm ,平均 (1 4± 0 6 4)cm ,加腹部压块后的膈肌运动幅度为 0 2 8～ 2 0 8cm ,平均 (1 0±0 5 5 )cm ,加腹部压块后膈肌运动幅度平均减小 (0 4± 0 34)cm ,P =0 0 0 0。加腹部压块后 90 % (18/2 0 )的患者膈肌运动幅度受到不同程度的限制 ,但有 10 % (2 /2 0 )的患者膈肌运动幅度增加。结论 :腹部压块可使大部分患者膈肌运动的幅度减小 ,但少部分患者例外 ,即腹部压块并不能使所有膈肌周围肿瘤的照射容积减少。建议在制定放射治疗计划前应预先进行测量和评价     

ABCG2在肺癌中表达的定量研究

目的 观察ABCG2在肺癌和癌周肺组织的表达,从量化角度阐明其在肺癌组织中表达的病理学意义.方法 常规石蜡包埋、HE切片确诊,用免疫组化SP法检测ABCG2在肺癌和癌周肺组织的定位和表达,用LeicaQ500MC图像分析系统对其表达强度进行定量分析,并用表达的阳性单位(positive unit PU)反映其表达强度.结果 ABCG2蛋白在肺癌和癌周正常肺组织中的表达主要定位在细胞质和细胞膜.在癌周正常肺组织的支气管和细支气管上皮呈弥漫表达,腺上皮呈灶性表达;肺鳞癌和肺腺癌弥漫或大片表达,肺鳞癌表达的PU值高于肺腺癌(P＜0.001),肺大细胞癌和肺小细胞癌不表达,PU值接近于零.癌周肺组织表达的PU值高于各型肺癌(P＜0.05).ABCG2蛋白表达的PU值在肺癌原发灶和转移灶之间无差别(P＞0.05),且与肺癌患者的性别、年龄、转移和TNM分期未见明显相关性(P＞0.05),与肺癌分化程度有关(P＜0.001).分化程度越高,PU值越高,但高分化肺癌和癌周肺组织的表达PU值差异无显著性(P＞0.05).结论 ABCG2蛋白表达程度与肺癌类型及分化程度具有相关性,可能成为判断其指标之一.     

Telomerase and human tumorigenesis

Human cancer cells, unlike their normal counterparts, have shed the molecular restraints to limited cell growth and are immortal. Exactly how cancer cells manage this at the molecular level is beginning to be understood. Human cells must overcome two barriers to cellular proliferation. The first barrier, referred to as senescence, minimally involves the p53 and Rb tumor-suppressor pathways. Inactivation of these pathways results in some extension of lifespan. However, inactivation of these pathways is insufficient for immortalization. As normal cells undergo repeated rounds of DNA replication, their telomeres shorten due to the inability of traditional DNA polymerases to completely replicate the end of the chromosomal DNA. This shortening continues until the cells reach a second proliferative block referred to as crisis, which is characterized by chromosomal instability, end-to-end fusions, and cell death. Stabilization of the telomeric DNA through either telomerase activation or the activation of the alternative mechanism of telomere maintenance (ALT) is essential if the cells are to survive and proliferate indefinitely. Conversely, loss of telomere stabilization by an already-immortalized cell results in loss of immortality and cell death. Together this indicates that telomere maintenance is a critical component of immortality. In this review we attempt to describe our current understanding of the role of telomere maintenance in senescence, crisis, and tumorigenesis.     

Post-translational regulation of COX2 activity by FYN in prostate cancer cells

While increased COX2 expression and prostaglandin levels are elevated in human cancers, the mechanisms of COX2 regulation at the post-translational level are unknown. Initial observation that COX2 forms adduct with non-receptor tyrosine kinase FYN, prompted us to study FYN-mediated post-translational regulation of COX2. We found that FYN increased COX2 activity in prostate cancer cells DU145, independent of changes in COX2 or COX1 protein expression levels. We report that FYN phosphorylates human COX2 on Tyr 446, and while corresponding phospho-mimetic COX2 mutation promotes COX2 activity, the phosphorylation blocking mutation prevents FYN-mediated increase in COX2 activity.     

LMP1 structure and signal transduction

The oncogenic Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) has structural features and functions reminiscent of a constitutively active TNF family receptor. LMP1 aggregates at the plasma membrane and initiates the activation of signalling pathways, such as NF- kappa B, the mitogen-activated protein kinases JNK and p38, the small GTPase Cdc42 and the JAK/STAT cascade. The constitutive engagement of these signals and the characteristic molecular interactions that regulate them provide the basis for the molecular explanation of the transforming properties of this key EBV protein.     

Interferon regulatory factor 7: a key cellular mediator of LMP-1 in EBV latency and transformation

Interferon regulatory factor 7 (IRF-7) was cloned within the biological context of Epstein-Barr virus (EBV) latency, and has an intimate relation with EBV. EBV latent membrane protein 1 (LMP-1) regulates IRF-7 both by inducing the expression of IRF-7 and by activating IRF-7 protein through phosphorylation and nuclear translocation in a post-translational manner. The activated IRF-7 then functions to regulate both EBV and cellular target genes involved in latency, transformation and immune regulation. IRF-7 appears to be a key cellular latency protein involved in both the pathogenesis and persistence of EBV infection.     

早期鼻腔NK/T细胞淋巴瘤治疗方法和预后分析

Objective To investigate the prognosis of patients with nasal NK/T cell lymphoma receiving different treatment modalities. Methods From 1990 to 2004, 85 patients with stage ⅠE and ⅡE primary nasal NK/T cell lymphomas were retrospectively studied. Twenty patients received chemotherapy of CHOP regimen alone, 11 patients received radiotherapy only, 6 patients received radiotherapy followed by more than 2 cycles of chemotherapy, and 48 patients received more than 2 cycles of chemotherapy followed by radiotherapy. Survival analysis was performed by the Kaplan-Meier method, the difference between groups was evaluated by the Log-rank test, and the Cox regression model was used for multivariate analysis. Results The 5-year overall survival rate (OS) was 40%. The 5-year OS was 57% and 28% for limited stage ⅠE and extended stage ⅠE(X2 =8. 87, P =0. 003), and 23% for stage ⅡE, which was similar to extended stage ⅠE (X2 =0. 19, P-0. 664). The 5-year OS was 13%, 54% and 47% for chemotherapy alone, radiotherapy followed with or without chemotherapy, and chemotherapy followed by radiotherapy, respectively. The last two groups had better OS than chemotherapy alone (P = 0. 030 and 0.049). The 5-year OS was 58% and 12% for patients achieving complete response (CR) and uncomplete response (X2 = 30.68, P = 0. 000).The CR rate was 56% and 86% for radiotherapy of ≤50 Gy and >50 Gy (X2 =6.11, P=0. 013). The corresponding 5-year relapse-free survival rate was 89% and 84% (X2 =0.36, P=0.551). Of 68 patients receiving initial chemotherapy, the CR rate of those who received ≤2, 3-4 and ≥5 cycles was 0, 20%and 3 3 % , respectively (X2 = 7.65 , P = 0. 022) . For 5 0 patients who received ≥ 3 cycles of initial chemotherapy and 17 patients who received initial radiotherapy of ≥40 Gy, the CR rate was 28% and 88%(χ2= 18. 75, P= 0. 000). In patients with pathological nodular and ulcer type, the CR rates with radiotherapy were higher than with chemotherapy (100%: 38%, χ2 = 7.92, P = 0. 005; and 100%: 11%,χ2 = 14.40, P = 0. 000). Multivariate analysis showed that stage and recent effect were the independent prognostic factors. Conclusions The initial radiotherapy with 50 Gy is appropriate for early stage nasal NK/T cell lymphomas. Combined chemotherapy could be used for extended stage ⅠE and ⅡE, but the outcome of CHOP regimen is poor.     

大肠癌术后吻合口漏的原因探讨及处理

 目的　探讨大肠癌术后吻合口漏的原因及治疗方法。方法　对我院近二年来收治的 15 5例大肠癌的临床资料进行回顾性分析。结果　 15 5例手术患者中共发生吻合口漏 9例 ,发生率为 5 .8%。吻合口在腹膜外的归为腹膜外吻合组 ;吻合口在腹腔内的归为腹腔内吻合组。前期 10 8例中行腹膜外吻合 35例 ,吻合口漏发生率为 17.1% (6 /35 ) ;行腹腔内吻合 73例 ,吻合口漏发生率为 4 .1% (3/70 )。二组比较有显著性差异 (P <0 .0 5 )。后期 4 7例手术中 ,术后行直肠内引流 ,均一期愈合。结论　行肠腔内引流以降低肠腔内压是减少吻合口漏的一种方法。吻合口漏的处理是通畅引流 ,促进漏口自行愈合 ,手术是最后的治疗措施     

EBNA2 and Notch signalling in Epstein–Barr virus mediated immortalization of B lymphocytes

Epstein-Barr virus (EBV) has the ability to immortalize B cells. A viral key protein for immortalization is the transactivator EBNA2 that controls expression of several viral and cellular genes. EBNA2 is tethered to promoters by interacting with the cellular repressor RBP-J. This resembles the physiological activation of RBP-J-repressed promoters by activated Notch receptors (Notch-IC). Since EBNA2 and Notch-IC have been shown to be partially interchangeable in regard to activation of target genes in B cell lines and modulation of differentiation processes it is conceivable that EBNA2 is a biological equivalent of an activated Notch receptor.     

早期鼻腔NK/T细胞淋巴瘤治疗方法和预后分析

Objective To investigate the prognosis of patients with nasal NK/T cell lymphoma receiving different treatment modalities. Methods From 1990 to 2004, 85 patients with stage ⅠE and ⅡE primary nasal NK/T cell lymphomas were retrospectively studied. Twenty patients received chemotherapy of CHOP regimen alone, 11 patients received radiotherapy only, 6 patients received radiotherapy followed by more than 2 cycles of chemotherapy, and 48 patients received more than 2 cycles of chemotherapy followed by radiotherapy. Survival analysis was performed by the Kaplan-Meier method, the difference between groups was evaluated by the Log-rank test, and the Cox regression model was used for multivariate analysis. Results The 5-year overall survival rate (OS) was 40%. The 5-year OS was 57% and 28% for limited stage ⅠE and extended stage ⅠE(X2 =8. 87, P =0. 003), and 23% for stage ⅡE, which was similar to extended stage ⅠE (X2 =0. 19, P-0. 664). The 5-year OS was 13%, 54% and 47% for chemotherapy alone, radiotherapy followed with or without chemotherapy, and chemotherapy followed by radiotherapy, respectively. The last two groups had better OS than chemotherapy alone (P = 0. 030 and 0.049). The 5-year OS was 58% and 12% for patients achieving complete response (CR) and uncomplete response (X2 = 30.68, P = 0. 000).The CR rate was 56% and 86% for radiotherapy of ≤50 Gy and >50 Gy (X2 =6.11, P=0. 013). The corresponding 5-year relapse-free survival rate was 89% and 84% (X2 =0.36, P=0.551). Of 68 patients receiving initial chemotherapy, the CR rate of those who received ≤2, 3-4 and ≥5 cycles was 0, 20%and 3 3 % , respectively (X2 = 7.65 , P = 0. 022) . For 5 0 patients who received ≥ 3 cycles of initial chemotherapy and 17 patients who received initial radiotherapy of ≥40 Gy, the CR rate was 28% and 88%(χ2= 18. 75, P= 0. 000). In patients with pathological nodular and ulcer type, the CR rates with radiotherapy were higher than with chemotherapy (100%: 38%, χ2 = 7.92, P = 0. 005; and 100%: 11%,χ2 = 14.40, P = 0. 000). Multivariate analysis showed that stage and recent effect were the independent prognostic factors. Conclusions The initial radiotherapy with 50 Gy is appropriate for early stage nasal NK/T cell lymphomas. Combined chemotherapy could be used for extended stage ⅠE and ⅡE, but the outcome of CHOP regimen is poor.     

肝癌细胞,癌旁肝细胞转铁蛋白合成及分泌速率的研究

目的　研究肝癌细胞转铁蛋白 ( Tf)合成量及合成后分泌速率的变化 ,探讨肝癌组织中膜结合性 Tf含量降低的原因。方法　采用同位素掺入及免疫共沉淀的方法测定了肝癌细胞及癌旁肝细胞 Tf的合成及分泌速率。结果　与癌旁肝细胞相比 ,尽管肝癌细胞 Tf的合成量没有明显变化 ,但其合成 Tf后的分泌速率加快 ,从而使 Tf的贮存量减少。结论　以上结果可能有利于肝癌细胞的生长与增殖 ,并解释了肝癌组织中膜结合性 Tf含量降低的原因。     

端粒酶基因在脑胶质瘤中的原位表达

目的 :研究端粒酶基因 (hTR)在脑胶质瘤中的原位表达状况及其与分型、分级的关系 ,评估其对胶质瘤诊断的价值。方法 :用原位杂交技术检测了 79例甲醛固定、石蜡包埋的胶质瘤蜡块标本中端粒酶基因 (hTR)的表达状况并分析与组织学分级、WHO分型之间的关系。用ABC法检测PCNA的表达。 6例正常脑组织作对照。结果 :端粒酶基因 (hTR)在脑胶质瘤中的检出率为 5 9 2 % (4 7/ 79)。端粒酶基因 (hTR)在胶质瘤组织学分级中的分布为Ⅱ级 11/ 32 ,Ⅲ级 12 / 2 0 ,Ⅳ级 2 4 / 2 7,各级胶质瘤组间比较 ,差异有显著意义 ,P <0 0 5。端粒酶基因 (hTR)的表达强度与胶质瘤的组织学分级、WHO分型之间有相关性 ,P <0 0 5 ,Ⅲ级、Ⅳ级的检出率明显高于Ⅱ级。正常脑组织中未检出端粒酶基因。端粒酶阳性组与阴性组PCNA阳性细胞密度差异有显著意义 ,P <0 0 5。结论 :胶质瘤中端粒酶基因 (hTR)表达状况可能与胶质瘤的分化程度、组织学分级相关 ,提示端粒酶基因的过表达可能对胶质瘤的演化和进展具有一定重要作用 ,并可能作为胶质瘤的一个新的诊断标志物 ,结合PCNA评价胶质瘤的生物学行为更为可靠。     

奥沙利铂联合氟尿嘧啶和甲酰四氢叶酸治疗局部进展期胃癌临床研究

目的:评价奥沙利铂、5氟尿嘧啶(5FU)和甲酰四氢叶酸(CF)联合新辅助化疗治疗局部进展期胃癌的近期疗效和毒副反应。方法:选择2000年3月～2004年4月我科住院的胃癌患者42例入组,术前接受化疗,方案为:奥沙利铂130mg/m2,d1;5FU500mg/m2,d1～d3;CF300mg/d,d1～3。每3个周为1个周期,共2个周期。观察新辅助化疗后肿瘤原发病灶的缓解情况,并观察毒副反应。结果:42例患者中有38例获得手术切除,其中26例获得根治性切除,19例肿瘤原发病灶明显缩小,14例肿瘤TNM分期降低。毒副反应主要为白细胞减少、腹泻、恶心、呕吐、脱发、肝功能异常,经对症及营养支持治疗后均能缓解。结论:奥沙利铂联合5FU与CF新辅助化疗在局部进展期胃癌的治疗中近期疗效显著,耐受性良好。