胃肠道肿瘤与一氧化氮关系研究进展

在肿瘤生物学中，一氧化氮(NO)具有复杂的浓度依赖效应。越来越多的证据表明，NO在胃肠道肿瘤的发生发展过程中起重要作用。NO与机体免疫反应、DNA损伤、凋亡发生有关。机体炎性反应可以诱导NO合成，参与肿瘤的发生。另外，NO可以引起肿瘤血管生成及血管扩张，从而利于肿瘤生长和转移。目前的研究结果NO在胃肠道肿瘤中的作用仍不一致，诱导型NOS在胃肠道肿瘤的表达研究尚不统一。本文对近年来NO在胃肠道肿瘤中的作用的研究进展作一综述。     

诱导型一氧化氮合酶与乳腺癌关系的研究进展

越来越多的证据表明,NO在乳腺癌的发生发展过程中起重要作用。诱导型一氧化氮合酶(iNOS)通常在炎症或肿瘤等病理条件下诱生,产生大量NO,参与肿瘤的发生。NO可以引起肿瘤血管生成及血管扩张,促进肿瘤生长和转移。NO具有细胞毒性,与机体免疫反应、DNA损伤、凋亡发生有关。文章对近年来iNOS/NO在乳腺癌中的作用的研究进展作一综述。     

一氧化氮介导的肿瘤治疗研究进展

一氧化氮(nitric oxide,NO)是一种半衰期短的多效分子,参与机体内的多种生理和病理反应。它作为重要的生物介质在肿瘤发生、发展和死亡中的作用已成为肿瘤研究及治疗的热点。研究发现NO具有促瘤或抗瘤的作用,这种双重作用取决于NO生成的浓度、时间和效应部位。持续低浓度的NO可以促进肿瘤的生长;高浓度NO则通过产生细胞毒性,诱导细胞凋亡而抗瘤。NO的这种浓度依赖性机制是目前NO介导的肿瘤治疗的理论基础,这些治疗方法可分为以下几类：包括化疗药物、中药、一氧化氮合酶的诱导剂和抑制剂在内的药物治疗;放疗和光动力学治疗;基因水平治疗等。本文从NO生成的浓度、时间和效应部位三个方面阐述NO和肿瘤的关系及其作用机制,并综述NO介导的各种肿瘤治疗方法的研究进展。     

一氧化氮与肿瘤的研究进展

一氧化氮(NO)是一种具有水溶性、携带自由基团的普遍存在的气体，在生理学和病理学上扮演着重要角色。然而，NO在肿瘤生物学中的作用存在较大争议和误解。研究显示NO具有抗癌和促癌双重作用，它破坏肿瘤组织和对肿瘤的促进效应与它存在的时间、位置及其浓度相关。已经证实NO可以调节与肿瘤相关的过程，包括血管生成、凋亡、细胞周期、侵袭和转移；另外，它还是一个潜在的抗癌剂。本文就NO与肿瘤的研究进展作一综述。     

一氧化氮与肿瘤的关系及其在鼻咽癌诊断中的研究

肿瘤的发生发展是一个与多基因、环境等多因素密切相关的复杂过程。近年发现的一氧化氮（nitrogen monoxidum，NO）是一种与其密切相关的化学物质。本文主要综述了NO的合成代谢及其生物学特性、在肿瘤生长转移中具有双重作用、在鼻咽癌（nasopharyngeal carcinoma，NPC）诊断中的研究及二者之间可能的关系，以为鼻咽癌的诊断和治疗提供新的思路和方法。     

iNOS/NO与胃癌关系的研究进展

胃癌是危害人类健康的主要恶性肿瘤之一,其发病原因尚未明了.近年来众多研究表明细胞凋亡异常、新生血管的形成与肿瘤的发生发展密切关系.一氧化氮（NO）是由NOS催化L-精氨酸生成的,NOS是体内产生NO的限速酶.NO与肿瘤发生、发展关系较为复杂,具体机制目前还不清楚.     

一氧化氮与肿瘤的关系初步探讨

 一氧化氮这种物质，1987年才被证实是由血管内皮细胞释放的一种血管舒张因子。近年来的研究发现，NO作为传统介质和调节介质，与多种疾病，特别是与肿瘤的发生和发展密切相关。     

癌症患者血NOS、NO水平变化及临床意义

目的探讨恶性肿瘤患者血一氧化氮合成酶(NOS)和一氧化氮(NO)的水平变化及其临床意义.方法测定106例肿瘤患者和50例健康人血的NOS、NO水平,进行统计学分析,比较它们之间的差异.结果肿瘤患者的NOS、NO水平明显高于健康人(P＜0.01)、未手术切除者NO比手术切除者高(P＜0.05).结论 NO与肿瘤的发生、发展有密切的关系,检测NOS、NO的水平,可作为肿瘤诊断以及判断病情变化和预后的指标之一.     

一氧化氮与肿瘤转移

一氧化氮(NO)的生物学活性广泛，多种肿瘤组织存在一氧化氮合成酶(NOS)表达异常和(或)NO产生异常。宿主和肿瘤细胞的NOS表达及NO合成差异，对肿瘤细胞的生存和转移潜能有不同影响。研究NO及NOS在肿瘤细胞转移过程中的效应机制，有望发现防治肿瘤转移的潜在靶点。     

原发性肝癌血清一氧化氮的研究

目的　探讨原发性肝癌血清一氧化氮 (NO)含量变化及其临床意义。方法　检测 2 1例中晚期原发性肝癌患者及 36例健康对照者血清亚硝酸盐水平间接反应血清NO的含量 ,前者与所测量瘤体最大径进行相关分析。结果　原发性肝癌患者血清NO(12 .34± 3 .0 6 μmol/L)明显高于健康对照组 (9.6 6± 1.5 2 μmol/L) (P <0 .0 1)。原发性肝癌患者血清NO与肿瘤直径呈正相关关系 (r =0 .5 132 ,P =0 .0 174)。结论　NO在原发性肝癌的发生发展中起重要作用 ,肝癌患者血清NO水平测定对肝癌诊断、治疗及预后的评价具有一定的意义。     

Reactive oxygen species-mediated regulation of eNOS and iNOS expression in multicellular prostate tumor spheroids

Nitric oxide (NO) generated by either endothelial nitric oxide synthase (eNOS) or inducible nitric oxide synthase (iNOS) may be involved in prostate tumorigenesis through the inhibition of reactive oxygen species (ROS)-induced apoptosis. Multicellular DU-145 prostate tumor spheroids endogenously generated NO that paralleled the production of ROS. With increasing spheroid size, eNOS expression was downregulated, whereas an upregulation of iNOS expression was observed. In parallel, NO generation declined, as evaluated by the NO indicator diaminofluorescein-2 diacetate (DAF-2DA), suggesting that NO generation in DU-145 tumor spheroids is mainly mediated by eNOS. Elevation of ROS by treatment of tumor spheroids with either buthionine sulfoximine (BSO) or hydrogen peroxide resulted in upregulation of eNOS, whereas iNOS was downregulated. Furthermore, eNOS expression was increased by epidermal growth factor (EGF) in a redox-sensitive manner. Upregulation of eNOS after treatment with hydrogen peroxide was apparently transduced through receptor tyrosine kinase signaling pathways since it was abolished by the protein kinase C (PKC) inhibitor bisindolylmaleimide-1 (BIM-1), the p21(ras) inhibitor S-trans-trans-farnesylthiosalicylic acid (FTS), the c-Raf inhibitor ZM 336372 and PD98059, which inhibits ERK1/2 activation. Endogenous NO may serve to escape from oxidative stress-induced apoptosis since treatment of tumor spheroids with the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl imidazoline-1-oxyl 3-oxide (carboxy-PTIO) as well as the NO synthase inhibitor N-omega-amino-L-arginine (L-NAA) increased cleaved caspase-3. Consequently, lowering intracellular NO levels with either L-NAA or PTIO significantly raised ROS levels, indicating that endogenously generated NO may play a role as a ROS scavenger, thereby protecting exponentially growing tumor spheroids from ROS-induced apoptosis.     

Liver endothelial cells: participation in host response to lymphoma metastasis

Interactions between metastasizing tumor cells and host cells in target organs determine the outcome of metastasis. This review discusses the dual role of activated host endothelial cells in the metastatic process. On one hand, the upregulation of the expression of particular adhesion molecules leads to increased tumor cell binding, and the stimulation of angiogenesis provides the vascular support for the growth of already established metastases. On the other hand, endothelial cells can contribute to host anti-metastatic responses, e.g. by production of the cytotoxic molecule nitric oxide (NO) from arginine with the help of the inducible nitric oxide synthase (iNOS). Using a well-characterized ESbL-lacZ mouse T lymphoma model with a typical three phasic growth profile, we showed during the period of growth retardation a stimulation of NO production by ex vivo isolated liver sinusoidal endothelial cells. The induction of NO synthesis in liver endothelial cells did not require the presence of Kupffer cells and appeared to be stimulated by and dependent on mature T lymphocytes. A breakdown of this NO synthesis coincided with the second tumor expansion phase.Abbreviations IL interleukin - TGF transforming growth factor - VEGF vascular endothelial growth factor - PG prostaglandin - bFGF basic fibroblast growth factor - TNF tumor necrosis factor - ICAM-1 intercellular adhesion molecule-1 - VCAM-1 vascular cell adhesion molecule - VLA-4 very late activated antigen - LFA-1 leucocyte function-associated antigen - NO nitric oxide - iNOS inducible NO synthase - NK-B nuclear factor kappa B - IFN- interferon - CL₂MBP dichloromethylenebisphosphonate     

Nitric Oxide and Angiogenesis

The steps required for new vessel growth are biologically complex and require coordinate regulation of contributing components, including modifications of cell–cell interactions, proliferation and migration of endothelial cells and matrix degradation. The observation that in vivo angiogenesis is accompanied by vasodilation, that many angiogenesis effectors possess vasodilating properties and that tumor vasculature is in a persistent state of vasodilation, support the existence of a molecular/biochemical link between vasodilation and angiogenesis. Several pieces of evidence converge in the indication of a role for nitric oxide (NO), the factor responsible for vasodilation, in physiological and pathological angiogenesis. Data originated in different labs indicate that NO can act both as an 'actor' of angiogenesis and as a 'director of angiogenesis', both functions being equally expressed during physiological and pathological processes. NO significantly contributes to the prosurvival/proangiogenic program of capillary endothelium by triggering and transducing cell growth and differentiation via endothelial-constitutive NO synthase (ec-NOS) activation, cyclic GMP (cGMP) elevation, mitogen activated kinase (MAPK) activation and fibroblast growth factor-2 (FGF-2) expression. Re-establishment of a balanced NO production in the central nervous system results in a reduction of cell damage during inflammatory and vascular diseases. Elevation of NOS activity in correlation with angiogenesis and tumor progression has been extensively reported in experimental and human tumors. In the brain, tumor expansion and edema formation are sensitive to NOS inhibition. On this basis, the nitric oxide pathway appears to be a promising target for consideration in pro- and anti-angiogenic therapeutic strategies. The use of NOS inhibitors seems appropriate to reduce edema, block angiogenesis and facilitate antitumor drug delivery.     

Role of nitric oxide in tumor progression: Lessons from experimental tumors

Nitric oxide (NO), a potent biological mediator, plays a key role in physiological as well as pathological processes, including inflammation and cancer. The role of NO in tumor biology remains incompletely understood. While a few reports indicate that the presence of NO in tumor cells or their microenvironment is detrimental to tumor cell survival and consequently their metastatic ability, a large body of clinical and experimental data suggest a promoting role of NO in tumor progression and metastasis. We suggest that tumor cells capable of very high levels of NO production die in vivo, and those producing or exposed to lower levels of NO, or capable of resisting NO-mediated injury undergo a clonal selection because of their survival advantage; they also utilize certain NO-mediated mechanisms for promotion of growth, invasion and metastasis. The possible mechanism(s) are: (a) a stimulatory effect on tumor cell invasiveness, (b) a promotion of tumor angiogenesis and blood flow in the tumor neovasculature, and (c) a suppression of host anti-tumor defense. In this review, we discuss these mechanisms on the basis of data derived from experimental models, in particular, a mouse mammary tumor model in which the expression of eNOS by tumor cells is positively correlated with invasive and metastatic abilities. Tumor-derived NO was shown to promote tumor cell invasiveness and angiogenesis. The invasion-stimulating effects of NO were due to an upregulation of matrix metalloproteases and a downregulation of their natural inhibitors. Treatment of tumor-bearing mice with NO-blocking agents reduced the growth and vascularity of primary tumors and their spontaneous metastases. We propose that selected NO-blocking drugs may be useful in treating certain human cancers either as single agents or as a part of combination therapies.     

Investigating the role of tumour cell derived iNOS on tumour growth and vasculature in vivo using a tetracycline regulated expression system

Nitric oxide (NO) is a free radical signalling molecule involved in various physiological and pathological processes, including cancer. Both tumouricidal and tumour promoting effects have been attributed to NO, making its role in cancer biology controversial and unclear. To investigate the specific role of tumour‐derived NO in vascular development, C6 glioma cells were genetically modified to include a doxycycline regulated gene expression system that controls the expression of an antisense RNA to inducible nitric oxide synthase (iNOS) to manipulate endogenous iNOS expression. Xenografts of these cells were propagated in the presence or absence of doxycycline. Susceptibility magnetic resonance imaging (MRI), initially with a carbogen (95% O₂/5% CO₂) breathing challenge and subsequently an intravascular blood pool contrast agent, was used to assess haemodynamic vasculature (ΔR₂*) and fractional blood volume (fBV), and correlated with histopathological assessment of tumour vascular density, maturation and function. Inhibition of NO production in C6 gliomas led to significant growth delay and inhibition of vessel maturation. Parametric fBV maps were used to identify vascularised regions from which the carbogen‐induced ΔR₂* was measured and found to be positively correlated with vessel maturation, quantified ex vivo using fluorescence microscopy for endothelial and perivascular cell staining. These data suggest that tumour‐derived iNOS is an important mediator of tumour growth and vessel maturation, hence a promising target for anti‐vascular cancer therapies. The combination of ΔR₂* response to carbogen and fBV MRI can provide a marker of tumour vessel maturation that could be applied to non‐invasively monitor treatment response to iNOS inhibitors.     

Tumoricidal activity of high-dose tumor necrosis factor-alpha is mediated by macrophage-derived nitric oxide burst and permanent blood flow shutdown

This study investigates the role of tumor nitric oxide (NO) and vascular regulation in tumor ulceration following high-dose tumor necrosis factor-alpha (TNF) treatment. Using TNF-responsive (MethA) and nonresponsive (LL2) mouse tumors, tumor NO concentration was measured with an electrochemical sensor and tumor blood flow by Doppler ultrasound. Mice were also pretreated with a selective inducible nitric oxide synthase (iNOS) inhibitor, 1400 W. Tumors harvested from TNF-treated mice were cryosectioned and immunostained for murine macrophages, or/and iNOS. MethA tumor-bearing mice were depleted of macrophages. Pre- and post-TNF tumor NO levels were measured continuously, and mice were followed for gross tumor response. In MethA tumors, TNF caused a 96% response rate, and tumor NO concentration doubled. Tumor blood flow decreased to 3% of baseline by 4 hr and was sustained at 24 hr and 10 days post-TNF. Selective NO inhibition with 1400 W blocked NO rise and decreased response rate to 38%. MethA tumors showed tumor infiltration by macrophages post-TNF and the pattern of macrophage immunostaining overlapped with iNOS immunostaining. Depletion of macrophages inhibited tumor NO increase and response to TNF. LL2 tumors had a 0% response rate to TNF and exhibited no change in NO concentration. Blood flow decreased to 2% of baseline by 4 hr, recovered to 56% by 24 hr and increased to 232% by 10 days. LL2 tumors showed no infiltration by macrophages post-TNF. We conclude that TNF causes tumor infiltrating, macrophage-derived iNOS-mediated tumor NO rise and sustained tumor blood flow shutdown, resulting in tumor ulceration in the responsive tumor.     

内源性一氧化氮在5-FU联合L-Arg治疗裸鼠人肝癌移植瘤中的作用

目的:观察内源性一氧化氮(NO)在5-氟尿嘧啶(5-FU)联合L-精氨酸(L-Arg)治疗裸鼠人肝癌移植瘤中的作用。方法:采用BEL-7402细胞株建立裸鼠人肝癌移植瘤模型,分别给裸鼠腹腔注射生理盐水、5-FU和(5-FU L-Arg),观察各组药物对肿瘤的抑制作用,病理学观察移植瘤的坏死程度和范围,TUNEL法检测细胞凋亡,免疫组化法检测诱导型一氧化氮合酶(inducible nitric oxidesyn-thesase,iNOS)、p16和Bax的表达,化学比色法检测iNOS的活性,硝酸还原酶法检测瘤组织内的NO浓度,对免疫组化结果采用BI2000免疫组化图像分析系统进行光密度测定,统计分析采用SPSS11.0软件进行One-Way ANOVA、Bonferroni、等级资料的秩和检验(Kruskal-Wallis H)及Pearson相关分析。结果:5-FU联合L-Arg能明显抑制移植瘤的生长,移植瘤组织的坏死范围明显增大,肿瘤细胞的凋亡指数增加,移植瘤组织内的iNOS表达与活性明显增加,NO含量增高,NO浓度与Bax和p16的表达有明显相关性。结论:5-FU联合L-Arg对裸鼠人肝癌移植瘤有明显的抑制作用,其机制可能与诱导iNOS表达和活性增强、内源性NO生成增加、NO诱导抑癌基因和凋亡相关基因表达有关。     

The Possible Role of Interleukin (IL)-18 and Nitrous Oxide and Their Relation to Oxidative Stress in the Development and Progression of Breast Cancer

Background: Cancer breast is the most common malignant tumor in females globally. Mechanisms linkinginflammatory cytokines and tumour growth and progression have not been established. Interleukin (IL)-18 has amodifying role in the immune defense against tumor cells. It induces production of IFN-γ. It also increases the immunecells cytotoxic activity and enhances the production of other proinflammatory cytokine. Nitric oxide (NO) has bothpromoting and inhibiting effects on tumorigenesis. Oxidative stress is a phenomenon that leads to oxidative damageof biomolecules, mutagenesis and carcinogenesis. Objective: The purpose of this research is to identify the potentialrole of IL18 and NO and their relation to oxidative stress in the development of cancer breast. Patients and Methods:This study included 120 women split into two groups ; control group and patient groups that divided into: group B (30patients with benign breast tumors), group N (30newly diagnosed cancer breast patients) ; and group M (30 metastaticcancer breast patients). Results: Serum total anti-oxidant capacity was significant high in both cancer breast groups.Total oxidative capacity was significantly higher level in metastatic group. NO levels were significantly higher valuesin the three cancer breast patients groups compared to control group.IL18 was significantly high in the metastaticgroup. Conclusions: Serum IL-18 and NO activity can be used as a marker for evaluating disease activity in patientswith cancer breast.