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。     

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。     

一氧化氮与肿瘤的发生、发展及转移相关的研究进展

一氧化氮（NO）作为一种自由基性质的气体分子,参与了肿瘤的发生、发展、转移等过程。NO一方面介导了巨噬细胞、内皮细胞的杀瘤作用,另一方面又通过促进血管生成、增加血流量肿瘤生成。对NO的深入研究,将为探索肿瘤的发生、发展和开辟新的治疗途径带来希望。     

胃肠道菌群与胃癌的关系及中医药的作用研究

随着现代分子生物学技术的发展、宏基因组学研究的深入和代谢组学的进步,肠道菌群及其代谢研究越来越受 到人们的重视。胃癌作为世界上第五大最常见的肿瘤,也是世界上肿瘤相关死亡中排名第三的肿瘤,其与胃肠道菌群的关 系也越来越引起大家的重视。胃肠道微生态系统内的微生物数量和种类最多,其平衡对人体健康起重要作用。早期,人类 认为胃内是无菌的,随着研究的深入,幽门螺杆菌感染与人类胃癌的发生关系也被逐渐揭示,人类胃肠道菌群与胃癌的 关系的报道也越来越多,研究证实胃肠道菌群可以参与机体的营养、代谢、免疫等作用,胃肠道菌群的改变也会导致炎 症的发生、发展。中医认为脾胃不合,必然会出现胃肠道菌群失调,而菌群失调又会引起机体不同程度的代谢异常。因此, 利用中医药辅助治疗胃癌不仅能改善胃癌患者脾胃不合症状,也能够调节胃癌患者的胃肠道菌群及机体的代谢,纠正胃肠 道菌群失调引起的不良症状。本文就胃肠道菌群代谢与胃癌的关系及中医药的作用进行概述。     

胃肠道恶性肿瘤患者一氧化氮与氧自由基的变化及其意义

目的　检测33例经病理检查证实胃肠道恶性肿瘤患者血清NO、LPO、SOD水平。结果与慢性浅表性胃炎组相比，恶性肿瘤患者NO水平显著低下（P＜0．05），LPO水平显著增高（P〈0．01）；其总SOD（T－SOD）水平降低（P＜0．05），主要系Mn－SOD水平明显降低所致（P＜0．01），而Cu，Zn－SOD则降低不明显。NO含量的降低与T－SOD活性的降低呈显著的正相关关系（r＝0．3471，P＜0．05）。结论恶性肿瘤患者抗氧化能力下降，氧化与抗氧化作用失衡，机体受过氧化损伤严重。特别是NO作为巨噬细胞免疫效应分子，其水平的低下，是肿瘤细胞逃避免疫监视而发生发展的重要机制之一。     

萘乙烯二胺盐显色法测定NO的初探

 一氧化氮（NO）是一种无机小分子,不仅是细胞 细胞间信息传递的重要调节因子,而且介导细胞免疫和细胞毒性。因此在机体许多生理和病理过程中,发挥不同的功能,近年来有关肿瘤与NO关系的研究也活跃起来［1］。因此准确地测定NO的含量也就显得格外重要。     

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.     

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.     

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.     

Role of nitric oxide in IL-2 therapy-induced capillary leak syndrome

Nitric oxide (NO) is a potent short-lived and short range bioactive molecule, which plays a key role in physiological and pathological processes including inflammation and cancer. Detrimental effects of excessive NO production during septic shock have been well recognized. We tested the hypothesis that capillary leak syndrome following systemic interleukin-2 (IL-2) therapy resulted from a cascade of events leading to the induction of NO which, directly or indirectly, injured capillaries and caused fluid leakage. Our results provided the first direct evidence that the induction of active NO synthase (NOS) leading to the overproduction of NO is instrumental in IL-2-induced capillary leakage in mice and that successful blocking of this overproduction with chronic oral administration of NOS inhibitors can mitigate this leakage without interfering with the beneficial antitumor effects of IL-2 therapy. NO blocking agents can, in fact, improve IL-2-induced antitumor effector cell activation, as well as tumor regression. In our studies, NO blocking agents alone reduced the growth and metastasis of a murine mammary carcinoma, at least in part, by mitigating the invasion and angiogenesis-stimulating role of tumor-derived NO. Thus, NOS inhibitors may be useful in treating certain tumors and serve as valuable adjuncts to systemic IL-2 based immunotherapy of cancer and infectious diseases.     

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.     

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.     

内皮型一氧化氮合酶来源的NO调节肿瘤血管的生成

背景与目的:内皮型一氧化氮合酶(endothelial nitric oxide synthase,eNOS)来源的一氧化氮(nitric oxicle,NO)广泛表达于肿瘤组织,调节着肿瘤血管的生长,但研究结果并不一致。本研究中探讨NO对肿瘤血管形成的作用及其机制。方法:将C57BL/6小鼠随机分为3组:NO组小鼠右胁下接种eNOS基因转染的Lewis肺癌细胞;eNOS拮抗组小鼠接种Lewis肺癌细胞后腹腔注射eNOS拮抗剂L-NAME;对照组接种Lewis肺癌细胞后注射同等体积的生理盐水。处理3周后,测定血浆内NO含量,计数外周血中内皮祖细胞(EPC)数;取肿瘤组织测定每高倍视野下(HPF)血管密度、EPC细胞数量和血管内皮细胞生长因子及其受体复合物(VEGF-VEGFR)的表达。结果:接种Lewis细胞4周后,对照组肿瘤体积为(3022±401)mm3,而L-NAME组和eNOS组分别为(1204±97)mm3和(1824±239)mm3,三组比较有显著性差异(P<0.01)。eNOS基因转染组肿瘤组织内eNOS蛋白表达和NO的生成显著高于对照组,但肿瘤组织中EPC数量[(48±19)/HPF]、血管密...     

Impairment of stimulation by estrogen of insulin-activated nitric oxide synthase in human breast cancer

Nitric oxide (NO) is reported to have several important effects in the control of neoplasm. We have reported before the presence of an insulin-activated constitutive form of membrane-bound nitric oxide synthase (IANOS) in various cells. Since the insulin-induced NO synthesis by IANOS could have important consequences on the pathophysiology of neoplastic cells, the role of estrogen on the activity of IANOS in malignant and nonmalignant breast tissue as well as in erythrocytes in breast cancer patients was determined. It was found that the IANOS activity of nonmalignant breast tissue was maximally stimulated by 4-fold over the basal activity in the presence of physiologic amounts of estrogen (8-32 nM). The enzymic activity was, however, inhibited by estrogen both below and above this range when compared to appropriate controls. In contrast, both the basal IANOS activity and the stimulatory effect of estrogen was markedly impaired in malignant breast tissue and in erythrocytes in these patients. It was also noted that tamoxifen, a widely used nonsteroidal compound in breast cancer, mimicked estrogen both in the stimulation and in the inhibition of IANOS activity in both of the tissues. These results indicated the probable existence of a novel pathway for estrogen effect independent of nuclear receptor for the stimulation of IANOS activity that might have important consequences in breast cancer and suggested that some of the beneficial effects of tamoxifen could be related to its estrogen-mimicking effect on IANOS independent of hormone-responsive elements sequence in the DNA.     

Poly‐S‐nitrosated human albumin enhances the antitumor and antimetastasis effect of bevacizumab,partly by inhibiting autophagy through the generation of nitric oxide

Autophagy is one of the major causes of drug resistance. For example, the angiogenesis inhibitor bevacizumab shows only transient and short‐term therapeutic effects, whereas long‐term therapeutic benefits are rarely observed, probably due to hypoxia‐induced autophagy. Nitric oxide (NO) is an important molecule with multiple functions, and it has recently been reported to function as a regulator of autophagy. Therefore, a reasonable therapeutic strategy for overcoming drug resistance by NO would involve it being directly delivered to the tumor. Here, we investigated the inhibitory effect of NO on autophagy by using a macromolecular NO donor S‐nitrosated human serum albumin (SNO‐HSA) with a high degree of NO loading and tumor targeting potential. In colon 26 (C26) cells, SNO‐HSA significantly suppressed hypoxia‐induced autophagy by inhibiting the phosphorylation of JNK1 and the expression of its downstream molecule Beclin1. The effect of SNO‐HSA was also confirmed in vivo by combining it with Bev. In C26‐bearing mice, significant suppression of tumor growth as well as lung metastasis was achieved in the combination group compared to the SNO‐HSA or bevacizumab alone group. Similar to the in vitro experiments, the immunostaining of tumor tissues clearly showed that SNO‐HSA inhibited the autophagy of tumor cells induced by bevacizumab treatment. In addition to other known antitumor effects of SNO‐HSA, that is, the induction of apoptosis and the inhibition of multidrug efflux pumps, these data may open alternate strategies for cancer chemotherapy by taking advantage of the ability of SNO‐HSA to suppress autophagy‐mediated drug resistance and enhance the efficacy of chemotherapy.