《腫瘤的氣體治療簡介》1500字

腫瘤的氣體治療簡介綜述1.1氣體治療目前，已有不少的癌癥治療手段歷經(jīng)研究者的探索并逐漸發(fā)展成熟且應(yīng)用于臨床治療，它們具有各自的優(yōu)勢與不足。比如手術(shù)治療主要針對早期尚未轉(zhuǎn)移的腫瘤，化學療法由于其局限性常常伴有嚴重的副作用。隨著科技的發(fā)展與更新，研究人員發(fā)現(xiàn)哺乳動物細胞之間的信號分子存在不少氣體分子，例如一氧化氮（NO），硫化氫（H2S），一氧化碳（CO）以及氧氣（O2）。由于這些氣體的內(nèi)源性特征，氣體療法便以“綠色”癌癥治療方法的方式呈現(xiàn)出來，現(xiàn)已有這些氣體獨特的功能及其抗癌效果的報道：（1）O2能夠通過緩解缺氧耐藥性從而提高SDT、PDT和PTT等治療方式的療效ADDINEN.CITEADDINEN.CITE.DATA[\o"Zhou,2018#35"121-124]；（2）NO具有抗多藥耐藥性以加強藥物對腫瘤細胞的效果ADDINEN.CITEADDINEN.CITE.DATA[\o"Kim,2017#39"125,\o"Chung,2015#70"126]；（3）高水平CO可用于治療炎癥ADDINEN.CITEADDINEN.CITE.DATA[\o"Otterbein,2000#40"127]，中風ADDINEN.CITEADDINEN.CITE.DATA[\o"Nayor,2016#67"128]以及癌癥ADDINEN.CITEADDINEN.CITE.DATA[\o"Wegiel,2013#68"129,\o"Li,2019#69"130]。鑒于此，利用現(xiàn)有的癌癥治療手段結(jié)合“綠色”氣體療法，有著提高各式治療效果的潛力。1.2NO治療NO是自然界中發(fā)現(xiàn)的10個最小分子之一，亦是首次發(fā)現(xiàn)的氣體信號分子。Furchgott與Zawadzki在1980年報道了一種可以從內(nèi)皮細胞中擴散，并在鄰近的平滑肌肉組織中引起舒張放松的物質(zhì)，當時他們尚未明確這種物質(zhì)的具體化學成分，于是便稱其為血管內(nèi)皮舒張因子（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]。幾年后，經(jīng)過研究人員的不斷努力，實驗所得的強有力證據(jù)證明了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]。作為一種內(nèi)源性的氣體，NO的半衰期非常短，約3~5s，它在體內(nèi)由一氧化氮合成酶（NOS）合成?，F(xiàn)已在哺乳動物細胞中發(fā)現(xiàn)了三種NOS亞型，分別是由NOS1、NOS2與NOS3三個基因編碼，這三種NOS亞型在位置、調(diào)控和催化等方面約有50%的同源性ADDINEN.CITEADDINEN.CITE.DATA[\o"Bogdan,2015#90"133]。其中NOS1為神經(jīng)元NOS，也稱nNOS，它主要存在于神經(jīng)系統(tǒng)中，是神經(jīng)元信號傳導所必需的；NOS3為內(nèi)皮型NOS，也稱eNOS，它則位于內(nèi)皮中，對血管擴張和控制血壓至關(guān)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]，這兩種酶的活性依賴于Ca2+的濃度，處于Ca2+低濃度時才會在短時間內(nèi)產(chǎn)生納摩爾量的NOADDINEN.CITEADDINEN.CITE.DATA[\o"Abu-Soud,1997#87"135,\o"Kone,2003#88"136]。相反，NOS2亞型是可誘導性的，它并不一直存在于細胞之中，只有在細胞被誘導或刺激時才會表達出來，且它的的活性與Ca2+濃度無關(guān)，主要活性取決于表達水平和底物濃度，所以也被稱作iNOS（inducibleNOS），同時它也可以產(chǎn)生更高水平的NO，約可達到微摩爾量級ADDINEN.CITEADDINEN.CITE.DATA[\o"Anavi,2020#84"137,\o"Sharma,2007#89"138]。這三種同工酶在激活后都需要L-精氨酸（L-Arginine，L-Arg）作為底物以產(chǎn)生NO，L-Arg在NOS的存在下，脫去胍基生成L-瓜氨酸與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內(nèi)源性NO的產(chǎn)生。NO在體內(nèi)參與著許多的生理功能的調(diào)節(jié)，包括血流調(diào)節(jié)，抗病反應(yīng)，神經(jīng)傳遞和增強免疫反應(yīng)等，它最經(jīng)典的生理功能是介導血管平滑肌舒張ADDINEN.CITEADDINEN.CITE.DATA[\o"Hu,2020#91"140]。iNOS產(chǎn)生的NO在腫瘤的發(fā)生發(fā)展以及轉(zhuǎn)移中起著重要關(guān)系。根據(jù)現(xiàn)有的報道，NO對腫瘤有著雙重作用（圖1-6），部分對NO的作用的報道存在著矛盾之處，但較為明確統(tǒng)一的是，高水平的NO對腫瘤有殺傷的效果，低水平的NO則在某種程度上有利于腫瘤發(fā)生發(fā)展ADDINEN.CITEADDINEN.CITE.DATA[\o"Szabo,2016#92"141-143]。因此提高NO的濃度水平是一種潛在的腫瘤治療手段。腫瘤的發(fā)展依賴于血管生成，新形成的血管能夠為腫瘤生長提供所需要的氧氣和營養(yǎng)物質(zhì)。一些NO相關(guān)的代謝物，如單硝酸異山梨酯和二硝酸鹽，已被發(fā)現(xiàn)可以抑制體外培養(yǎng)的人結(jié)腸癌細胞中的VEGF蛋白水平，并抑制小鼠肺腫瘤異種移植體內(nèi)的血管生成ADDINEN.CITEADDINEN.CITE.DATA[\o"Pipili-Synetos,1995#95"144,\o"Pathi,2011#96"145]。NO不僅通過血管生成、新陳代謝和細胞凋亡幾個方面影響著腫瘤微環(huán)境，還在其免疫反應(yīng)中發(fā)揮著重要作用。有研究表明，NO代謝物抑制了T細胞的增值并導致T細胞凋亡ADDINEN.CITEADDINEN.CITE.DATA[\o"Brito,1999#158"146]，還有研究指出NO抑制了樹突狀細胞向CD4+輔助性T細胞呈遞抗原，這些結(jié)果表明NO在TME中存在免疫抑制的行為ADDINEN.CITEADDINEN.CITE.DATA[\o"Markowitz,2017#159"147]。圖1-6NO對腫瘤的雙重作用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內(nèi)源生成NO的底物，它是一種非必需氨基酸，人和動物體內(nèi)可以自身合成。在生理條件下，細胞內(nèi)的L-Arg濃度是遠遠超過NOS合成NO所需濃度的，然而外源性L-Arg卻能夠刺激細胞內(nèi)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