《肿瘤的气体治疗简介》1500字

肿瘤的气体治疗简介综述1.1气体治疗目前，已有不少的癌症治疗手段历经研究者的探索并逐渐发展成熟且应用于临床治疗，它们具有各自的优势与不足。比如手术治疗主要针对早期尚未转移的肿瘤，化学疗法由于其局限性常常伴有严重的副作用。随着科技的发展与更新，研究人员发现哺乳动物细胞之间的信号分子存在不少气体分子，例如一氧化氮（NO），硫化氢（H2S），一氧化碳（CO）以及氧气（O2）。由于这些气体的内源性特征，气体疗法便以“绿色”癌症治疗方法的方式呈现出来，现已有这些气体独特的功能及其抗癌效果的报道：（1）O2能够通过缓解缺氧耐药性从而提高SDT、PDT和PTT等治疗方式的疗效ADDINEN.CITEADDINEN.CITE.DATA[\o"Zhou,2018#35"121-124]；（2）NO具有抗多药耐药性以加强药物对肿瘤细胞的效果ADDINEN.CITEADDINEN.CITE.DATA[\o"Kim,2017#39"125,\o"Chung,2015#70"126]；（3）高水平CO可用于治疗炎症ADDINEN.CITEADDINEN.CITE.DATA[\o"Otterbein,2000#40"127]，中风ADDINEN.CITEADDINEN.CITE.DATA[\o"Nayor,2016#67"128]以及癌症ADDINEN.CITEADDINEN.CITE.DATA[\o"Wegiel,2013#68"129,\o"Li,2019#69"130]。鉴于此，利用现有的癌症治疗手段结合“绿色”气体疗法，有着提高各式治疗效果的潜力。1.2NO治疗NO是自然界中发现的10个最小分子之一，亦是首次发现的气体信号分子。Furchgott与Zawadzki在1980年报道了一种可以从内皮细胞中扩散，并在邻近的平滑肌肉组织中引起舒张放松的物质，当时他们尚未明确这种物质的具体化学成分，于是便称其为血管内皮舒张因子（EDRF）ADDINEN.CITE<EndNote><Cite><Author>Furchgott</Author><Year>1980</Year><RecNum>6</RecNum><DisplayText><styleface="superscript">[131]</style></DisplayText><record><rec-number>6</rec-number><foreign-keys><keyapp="EN"db-id="fefzva2arafxvjeezt3vr2rhx22ervre0wt2"timestamp="1585138798">6</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Furchgott,R.F.</author><author>Zawadzki,J.V.</author></authors></contributors><titles><title>Theobligatoryroleofendothelialcellsintherelaxationofarterialsmoothmusclebyacetylcholine</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title></periodical><pages>373-6</pages><volume>288</volume><number>5789</number><edition>1980/11/27</edition><keywords><keyword>Acetylcholine/*pharmacology</keyword><keyword>Animals</keyword><keyword>Aorta,Thoracic/cytology/*physiology</keyword><keyword>Endothelium/*physiology</keyword><keyword>Hypoxia/physiopathology</keyword><keyword>Male</keyword><keyword>MicrobialCollagenase/metabolism</keyword><keyword>Rabbits</keyword><keyword>Receptors,Cholinergic/*drugeffects</keyword><keyword>Receptors,Muscarinic/*drugeffects</keyword><keyword>VasomotorSystem/*drugeffects</keyword></keywords><dates><year>1980</year><pub-dates><date>Nov27</date></pub-dates></dates><isbn>0028-0836(Print) 0028-0836(Linking)</isbn><accession-num>6253831</accession-num><urls><related-urls><url>/pubmed/6253831</url></related-urls></urls><electronic-resource-num>10.1038/288373a0</electronic-resource-num></record></Cite></EndNote>[\o"Furchgott,1980#6"131]。几年后，经过研究人员的不断努力，实验所得的强有力证据证明了EDRF就是NO分子ADDINEN.CITE<EndNote><Cite><Author>Ignarro</Author><Year>1987</Year><RecNum>5</RecNum><DisplayText><styleface="superscript">[132]</style></DisplayText><record><rec-number>5</rec-number><foreign-keys><keyapp="EN"db-id="fefzva2arafxvjeezt3vr2rhx22ervre0wt2"timestamp="1585138562">5</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Ignarro,L.J.</author><author>Buga,G.M.</author><author>Wood,K.S.</author><author>Byrns,R.E.</author><author>Chaudhuri,G.</author></authors></contributors><auth-address>DepartmentofPharmacology,UniversityofCalifornia,LosAngeles,SchoolofMedicine90024.</auth-address><titles><title>Endothelium-derivedrelaxingfactorproducedandreleasedfromarteryandveinisnitricoxide</title><secondary-title>ProcNatlAcadSciUSA</secondary-title></titles><periodical><full-title>ProcNatlAcadSciUSA</full-title></periodical><pages>9265-9</pages><volume>84</volume><number>24</number><edition>1987/12/01</edition><keywords><keyword>Animals</keyword><keyword>BiologicalAssay</keyword><keyword>Cattle</keyword><keyword>CyclicGMP/physiology</keyword><keyword>Endothelium,Vascular/*physiology</keyword><keyword>Hemoglobins</keyword><keyword>InVitroTechniques</keyword><keyword>MuscleRelaxation</keyword><keyword>Muscle,Smooth,Vascular/*physiology</keyword><keyword>NitricOxide/*physiology</keyword><keyword>SpectrumAnalysis</keyword><keyword>*Vasodilation</keyword></keywords><dates><year>1987</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0027-8424(Print) 0027-8424(Linking)</isbn><accession-num>2827174</accession-num><urls><related-urls><url>/pubmed/2827174</url></related-urls></urls><custom2>PMC299734</custom2><electronic-resource-num>10.1073/pnas.84.24.9265</electronic-resource-num></record></Cite></EndNote>[\o"Ignarro,1987#5"132]。作为一种内源性的气体，NO的半衰期非常短，约3~5s，它在体内由一氧化氮合成酶（NOS）合成。现已在哺乳动物细胞中发现了三种NOS亚型，分别是由NOS1、NOS2与NOS3三个基因编码，这三种NOS亚型在位置、调控和催化等方面约有50%的同源性ADDINEN.CITEADDINEN.CITE.DATA[\o"Bogdan,2015#90"133]。其中NOS1为神经元NOS，也称nNOS，它主要存在于神经系统中，是神经元信号传导所必需的；NOS3为内皮型NOS，也称eNOS，它则位于内皮中，对血管扩张和控制血压至关重要ADDINEN.CITE<EndNote><Cite><Author>Alderton</Author><Year>2001</Year><RecNum>86</RecNum><DisplayText><styleface="superscript">[134]</style></DisplayText><record><rec-number>86</rec-number><foreign-keys><keyapp="EN"db-id="fefzva2arafxvjeezt3vr2rhx22ervre0wt2"timestamp="1617114945">86</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Alderton,W.K.</author><author>Cooper,C.E.</author><author>Knowles,R.G.</author></authors></contributors><auth-address>InVitroPharmacologyDepartment,GlaxoSmithKlineResearchandDevelopment,MedicinesResearchCentre,GunnelsWoodRoad,StevenageSG12NY,UK.</auth-address><titles><title>Nitricoxidesynthases:structure,functionandinhibition</title><secondary-title>BiochemJ</secondary-title></titles><periodical><full-title>BiochemJ</full-title></periodical><pages>593-615</pages><volume>357</volume><number>Pt3</number><edition>2001/07/21</edition><keywords><keyword>AlternativeSplicing</keyword><keyword>Animals</keyword><keyword>Catalysis</keyword><keyword>Dimerization</keyword><keyword>GeneExpressionRegulation,Enzymologic</keyword><keyword>Humans</keyword><keyword>Isoenzymes/antagonists&inhibitors/*chemistry/genetics/metabolism</keyword><keyword>Models,Molecular</keyword><keyword>NitricOxide/*metabolism</keyword><keyword>NitricOxideSynthase/antagonists&inhibitors/*chemistry/genetics/metabolism</keyword><keyword>ProteinStructure,Tertiary</keyword></keywords><dates><year>2001</year><pub-dates><date>Aug1</date></pub-dates></dates><isbn>0264-6021(Print) 0264-6021(Linking)</isbn><accession-num>11463332</accession-num><urls><related-urls><url>/pubmed/11463332</url></related-urls></urls><custom2>PMC1221991</custom2><electronic-resource-num>10.1042/0264-6021:3570593</electronic-resource-num></record></Cite></EndNote>[\o"Alderton,2001#86"134]，这两种酶的活性依赖于Ca2+的浓度，处于Ca2+低浓度时才会在短时间内产生纳摩尔量的NOADDINEN.CITEADDINEN.CITE.DATA[\o"Abu-Soud,1997#87"135,\o"Kone,2003#88"136]。相反，NOS2亚型是可诱导性的，它并不一直存在于细胞之中，只有在细胞被诱导或刺激时才会表达出来，且它的的活性与Ca2+浓度无关，主要活性取决于表达水平和底物浓度，所以也被称作iNOS（inducibleNOS），同时它也可以产生更高水平的NO，约可达到微摩尔量级ADDINEN.CITEADDINEN.CITE.DATA[\o"Anavi,2020#84"137,\o"Sharma,2007#89"138]。这三种同工酶在激活后都需要L-精氨酸（L-Arginine，L-Arg）作为底物以产生NO，L-Arg在NOS的存在下，脱去胍基生成L-瓜氨酸与NOADDINEN.CITEADDINEN.CITE.DATA[\o"Vannini,2015#8"139]。因此，提高底物L-Arg的水平能在一定程度上增大内源性NO的产生。NO在体内参与着许多的生理功能的调节，包括血流调节，抗病反应，神经传递和增强免疫反应等，它最经典的生理功能是介导血管平滑肌舒张ADDINEN.CITEADDINEN.CITE.DATA[\o"Hu,2020#91"140]。iNOS产生的NO在肿瘤的发生发展以及转移中起着重要关系。根据现有的报道，NO对肿瘤有着双重作用（图1-6），部分对NO的作用的报道存在着矛盾之处，但较为明确统一的是，高水平的NO对肿瘤有杀伤的效果，低水平的NO则在某种程度上有利于肿瘤发生发展ADDINEN.CITEADDINEN.CITE.DATA[\o"Szabo,2016#92"141-143]。因此提高NO的浓度水平是一种潜在的肿瘤治疗手段。肿瘤的发展依赖于血管生成，新形成的血管能够为肿瘤生长提供所需要的氧气和营养物质。一些NO相关的代谢物，如单硝酸异山梨酯和二硝酸盐，已被发现可以抑制体外培养的人结肠癌细胞中的VEGF蛋白水平，并抑制小鼠肺肿瘤异种移植体内的血管生成ADDINEN.CITEADDINEN.CITE.DATA[\o"Pipili-Synetos,1995#95"144,\o"Pathi,2011#96"145]。NO不仅通过血管生成、新陈代谢和细胞凋亡几个方面影响着肿瘤微环境，还在其免疫反应中发挥着重要作用。有研究表明，NO代谢物抑制了T细胞的增值并导致T细胞凋亡ADDINEN.CITEADDINEN.CITE.DATA[\o"Brito,1999#158"146]，还有研究指出NO抑制了树突状细胞向CD4+辅助性T细胞呈递抗原，这些结果表明NO在TME中存在免疫抑制的行为ADDINEN.CITEADDINEN.CITE.DATA[\o"Markowitz,2017#159"147]。图1-6NO对肿瘤的双重作用ADDINEN.CITE<EndNote><Cite><Author>Keshet</Author><Year>2018</Year><RecNum>45</RecNum><DisplayText><styleface="superscript">[148]</style></DisplayText><record><rec-number>45</rec-number><foreign-keys><keyapp="EN"db-id="fefzva2arafxvjeezt3vr2rhx22ervre0wt2"timestamp="1597920076">45</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Keshet,R.</author><author>Erez,A.</author></authors></contributors><auth-address>DepartmentofBiologicalRegulation,WeizmannInstituteofScience,Rehovot7610001,Israel. DepartmentofBiologicalRegulation,WeizmannInstituteofScience,Rehovot7610001,Israelayelet.erez@weizmann.ac.il.</auth-address><titles><title>Arginineandthemetabolicregulationofnitricoxidesynthesisincancer</title><secondary-title>DisModelMech</secondary-title></titles><periodical><full-title>DisModelMech</full-title></periodical><volume>11</volume><number>8</number><edition>2018/08/08</edition><keywords><keyword>Animals</keyword><keyword>AntineoplasticAgents/therapeuticuse</keyword><keyword>Arginine/*metabolism</keyword><keyword>Humans</keyword><keyword>Models,Biological</keyword><keyword>Neoplasms/drugtherapy/*metabolism</keyword><keyword>NitricOxide/*biosynthesis</keyword><keyword>*Arginine</keyword><keyword>*Cancermetabolism</keyword><keyword>*Nitricoxidemetabolism</keyword></keywords><dates><year>2018</year><pub-dates><date>Aug6</date></pub-dates></dates><isbn>1754-8411(Electronic) 1754-8403(Linking)</isbn><accession-num>30082427</accession-num><urls><related-urls><url>/pubmed/30082427</url></related-urls></urls><custom2>PMC6124554</custom2><electronic-resource-num>10.1242/dmm.033332</electronic-resource-num></record></Cite></EndNote>[\o"Keshet,2018#45"148]。L-Arg是NOS内源生成NO的底物，它是一种非必需氨基酸，人和动物体内可以自身合成。在生理条件下，细胞内的L-Arg浓度是远远超过NOS合成NO所需浓度的，然而外源性L-Arg却能够刺激细胞内NO的生成ADDINEN.CITE<EndNote><Cite><Author>Vallance</Author><Year>2001</Year><RecNum>97</RecNum><DisplayText><styleface="superscript">[149]</style></DisplayText><record><rec-number>97</rec-number><foreign-keys><keyapp="EN"db-id="fefzva2arafxvjeezt3vr2rhx22ervre0wt2"timestamp="1617276890">97</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Vallance,P.</author><author>Chan,N.</author></authors></contributors><auth-address>CentreforClinicalPharmacology,UniversityCollegeLondon,London,UK.patrick.vallance@ucl.ac.uk</auth-address><titles><title>Endothelialfunctionandnitricoxide:clinicalrelevance</title><secondary-title>Heart</secondary-title></titles><periodical><full-title>Heart</full-title></periodical><pa