药学研究进展论文.docx
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药学研究进展论文.docx
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药学研究进展论文
Theprogressofresearchwithantitumordrug
[abstract]:
Nearly50yearsofresearchanddevelopmentofanticancerdrugshasmadeconsiderableprogressincancerchemotherapy,particularlyitenablespatientswithhematologicmalignanciessignificantlyprolongsurvivaltime,Butaseriousthreattohumanlifeandhealthaccountedforover90%ofmalignantsolidtumorshasnotyetreachedasatisfactoryeffect.Halfofcancerpatientsarestillnoresponseorresistancetotreatmentandeventuallyleadtotreatmentfailure,sothediscoveryanddevelopmentofnewanticancerdrugsbypharmaceuticalcompaniesisstillverydifficulttobefacedwiththechallengeoflong-termmission[1].Thischapterprovidessomebriefabouthotareasandthelatestdevelopments.
[keyword]:
Antineoplastic,Traditionalanticancerdrugs,Newanticancerdrugs
1.Traditionalanticancerdrugs
1.1Classification:
Accordingtothechemicalstructureandsourcesofdrugsitincludesalkylatingantineoplasticagents(Cyclophosphamide),Antimetabolite
(Fluorouracil),Antibiotics(doxorubicin.etc.),plantalkaloids(vincristine),hormones.
1.2Cytotoxicanticancermechanismofaction:
①Interferingnucleicacidbiosynthesis②thedrugthatdirectlyaffectstheDNAstructureandfunction③thedrugthatinterfereswiththeprocessoftranscriptionandRNAsynthesis④thedrugthatinterfereswithproteinsynthesisandfunction
1.3Feature:
Currentlyconsiderableperiodoftimeorintraditionalcytotoxiccancertherapydrugswillcontinuetobethesubjectofmajordrawbackofthesedrugsispoorsolidtumorefficacy,sideeffects,easytoproducedrugresistance.Inrecentyears,throughthecancerpatientsduringchemotherapyadversereactionsanalysisconcludedthatmostoftheexistingchemotherapydrugsisnotstrongselectivityininhibitingorkillingtumorcellswhilenormalcells,especiallyproliferativecells(suchasbonemarrow,hairfollicles)alsoinhibitcytotoxicity.Thus,inthenormaltherapeuticdosechemotherapydrugswhenyoucanmakethebodyproduceadversereactions
2.Newanticancerdrugs
2.1Moleculartargetedanticancerdrugs
Atthemolecularlevel,consideringthedifferencebetweennormalcellsandthetumorcells,directedtothetumorcells’sometargets,effectivelykilltumorcellswhileminimizetheimpactonnormalcells,Thishighselectiveeffectsignificantlyreducedtoxicity,increasedpatienttoleranceandcompliance,Theemergenceofmoleculartargeteddrugstoovercomethetraditionalpoorselectivityofcytotoxicdrugs,sideeffects,easytoproducedrugresistanceandothershortcomings[2],Alargenumberoftargeteddrugshavebeenputintoclinical,includingcellsignalingmoleculesGoinhibitors,angiogenesisinhibitors,tumordifferentiationinducedbydrugs.
2.1.1Cellularsignaltransductionmoleculeinhibitors
Manydifferentiationfactorsignaltransductionduringcelldifferentiationcontainsproteinkinasefamily.Overexpressionofthisproteinkinasecaninducetumor.Sincetheseproteinkinasegenemutationorrearrangementresultinginsignaltransductionprocessesobstaclesandanomalies,whichbyaffectingcellgrowth,differentiation,metabolismandbiologicalbehaviorandcausetumors.Currently,anumberofproteinkinaseinhibitorsandthedifferentproteinkinaseATPbindingsiteofasmallmoleculetherapeuticagenthasbeeninclinicalstudies.Thesenewdrugsaretargetedinhibitionofcellcyclekinases,suchastyrosinekinases,proteinkinaseC,proteinkinaseAandsoon.
Currently,thenewcellularsignaltransductioninhibitorwasdevelopedfortargetedcancertherapyresearchfocus,therearesomeproteinkinaseinhibitorsarebeingdeveloped,includingtheWesttoNeeb,axitinib,etc.[3],inrecentyears,thereareavarietyofcellularsignaltransductionmoleculeinhibitorslisted.
2.1.2Angiogenesisinhibitors
Angiogenesishasacrucialroleintumorgrowthandmetastasis.SinceFoikman[4]proposedtheconceptofangiogenesisinthe1970s,thentheinhibitionofangiogenesishasalsobeenaresearchfocus,tumorangiogenesisbybothpositiveandnegativeregulatoryfactorcontrol.Andvascularendothelialgrowthfactorreceptortyrosinekinaseintumorangiogenesisandtumorbloodvesselstomaintainexistinghasitsimportantroleinblockingtumorangiogenesisisanimportanttarget.Avastinthatiscurrentlyrepresentedinclinicaltumorangiogenesisinhibitorshasbeenwidelyrecognized,includingChinathereare28countrieshavingratifiedtheclassinhibitorsactontheclinicaltreatmentofcancer[5].Recentstudieshavefoundthat,AngiostatinandEndostatincanalsoplayahighlyeffectiveanti-tumoreffectthroughantagonizeangiogenicfactors.
2.1.3Tumordifferentiationinducedbydrugs
Evilcancerisadisorderofcelldifferentiation,celldifferentiationdisordercausedbythisspecificgenesincertainconditionsisreversible.Inducingdrugsbyaffectingcelldifferentiationgenecertaindecisionstofurtherdifferentiation,itsvaluecanbereversed,invasion,andmetastasisofmalignantmanifestations,makingnormalornearnormalcells,thusbecominganewapproachtocancercontrol.Currently,themaindrugsincludetumornecrosisfactor,vitaminAacidcompounds,choleratoxinandsoon.Tumornecrosisfactorcaninduceapoptosisincertaintumorcells,inhibitcancercellproliferation,butalsoactontheendothelialcells,thetumorvascularinjuryorthrombosis,leadingtotumornecrosis.VictoriaAacidcompoundscanpromoteapoptosisoftumorcells,inductionofdifferentiationandinhibitionofthegrowth,currentlyitmainlyusedintheclinicaltreatmentofleukemia.CholeratoxincaninhibitcellPI3K/PKBpathwayactivatedkinaseCSK-3ß,CyclinD1inducedphosphorylation,andultimatelyreducetheamountofintracellularCyclinD1toinducedifferentiationintoevilgliomanormalglialcells.
2.2Metalcomplexesantineoplastic
Metalsandtheircompoundsinmedicinehasbeenusedfor5,000years[6],Since40yearsago,theanticancerdrugcisplatinhasbeensuccessfullyappliedinthefieldofanti-tumor,anti-cancerdrugresearchmetalhasneverbeeninterrupted,researchershavefoundthatmanymetalcompoundswithanticanceractivity,someofwhichhavehighactivityandlowtoxicityfeatures.Currentplatinumandrutheniumcompoundshavebeenusedandstudiedmostinclinical.
2.2.1Platinum
ThecompositionandstructureofPlatinumcomplexesmosthavesimilarcharacteristics:
squareplanarstructure,neutralnon-electrolytecomplexes,havingapairisintheortho(overall)moderateactivityradicalligandandapairoflowactivityLigands.Itsprincipleiscombinedwithintracellularnucleophilicgroups,inparticularthecombinationoftheDNAchain,byinterferingwiththeonsetoftumorcellproliferation[7],Currentlythemainplatinumanti-cancerdrugsusedinclinicalhavesixkinds,includingCisplatin,Carboplatin,Nedaplatin,
Oxaliplatin,Sunpla,Lobaplatinandcycloplatin,JM216,SK12053R,ZD0473,sulfurandplatinumareinpre-clinicalresearchstage.StatisticsshowthatChina'santi-tumorchemotherapyprogram,70%-80%basedoncisplatinorcisplatinparticipatecompatible[8],Thefuturedirectionofresearchfocusedonthedevelopmentofplatinumdrugscanbeadministeredorally,throughthetransformationofplatinumitself,spaceorcombinationassociatedwiththecarriertoincreaseitssolubility,reduceresistance,prolongeddurationofactionandreducedtoxicity.
2.2.2Ruthenium
Sincerutheniumandrutheniumcomplexeshavelowtoxicity,readilyabsorbedandexcretedquicklyinthebody,etc.,itisinternationallyrecognizedasapromisinganticancermetal.Nowbeensynthesizedhundredsofrutheniumcomplexes,themechanismofanticanceractivityliesinitsnucleusfirstandN7ofguanineresiduescovalentbond,theDNAinterstrandcross-linktoformimpedeDNAreplication.
NAMI-A(31)whichwassynthesisbyAlessioin1998isthefirsttoenterclinicalrutheniumcomplexes,theirlungcancer,breastcancershowedaspecialtransferactivity,butinthekillingofprimarytumorcellsaspectspoorabilitytohavenoactivityinvitro[9].KP1019(32)isthesecondtoenterclinicaltrialsrutheniumcomplexesofprimarycolorectalcancerandLewislungcancerandeffective.Althoughtherearealreadyalotofclassanditsrutheniumcomplexeswerefoundtohaveanti-tumoractivity,buttheiranti-tumormechanismisnotclear.Eventhecurrentlyusedinclinicalantineoplasticrutheniumisnoexception,requirefurtherstudyitsanti-tumormechanismforthedevelopmentofnewcompoundsandtofindnewtargetsofareference.Inrecentyears,alsofoundthatsomerutheniumcomplexesthroughnon-covalentbindingtoDNAexertantitumoractivity.
2.3Marinefungusantineoplasticactivesubstance
Theoceanistheoriginoflife,themarineenvironmentwithhighsalt,highpressure,lowtemperature,etc.Unliketheterrestrialenvironmentoligotrophiccharacteristics.Manymarineorganismsinsuchextremeenvironmentsproducedalargenumberofbiologicallyactivesubstances,includingantibacterial,antiviral,anti-tumoractivematerial.Amongthem,theanti-tumorsubstances,especiallyimpressive,marineanti-tumorsubstanceshasbeenafocusofthestudyofmarinedrugs[10],butalsotheworld'soneofthefocusofcommonconcern.
2.3.1Fromseawater,mud,marinesedimentsfungiantitumorsubstances
Marinefungusinwater,sediment,marinesedimentdistributionisuneven,mud,marinesedimentsofmarinefungiisobviousthatwater,whichmaybemud,marinesedimentshighcontentoforganicmatter,oradsorbedonmarinefungusmorelikemud,marinesedimentsrelated.
Trisorbicillinoneisthefirstonefromthed
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