Genasense(Bcl-2antisense)奥利默森钠--反义药物靶向抗癌药
FullName:Genasense?(oblimersensodium)
OtherNames:Bcl-2antisenseoligonucleotide,G-3139
Description:Antisensedrug(intravenous)
Phase:III
Company:GentaIncorporated
www.genta.com
WhatItIs
Genasenseisanantisensedrugbeinginvestigatedforuseasatreatment
formyelomaandothercancers,suchasmelanoma,leukemia,lymphoma,an
dcancersofthelung,prostate,andcolon.Theagentisbeingusedtoi
ncreasethecancer-killingactivityofstandardanticancertherapy
HowItWorks
Overview
Inmyelomacellsandothertumorcells,resistancetoanticancertherapy
isassociatedwiththepresenceofaproteincalledBcl-2.Genasenseisa
drugthatturnsofftheproductionoftheBcl-2protein,whichmayincre
aseatumorcell’ssensitivitytotherapyandultimately,cause
celldeath.
DetailsAboutAntisenseDrugs
Genasenseisanoveltypeofdrugknownasanantisensedrug.Whatisdi
fferentaboutantisensedrugsisthattheyaredesignedtoblockthepro
ductionofspecificproteins.Thisallowsfortargetedtherapytotheca
ncercellwithpotentiallyminimalsideeffectstonormalcells.
Proteinsareimportantinmostofacell’sfunctionsandintheirsurvi
valandgrowth.Genes,whicharecomposedofDNA,providethe"blueprin
t"forthecelltomakeproteins.InorderforaDNAcodetobetransla
tedintoaprotein,anintermediatestepisrequiredwherebytheDNAis
transcribedintoamessagethatthecellcanunderstand.Thismessageis
knownasmessengerRNA,ormRNAforshort.ThemRNAthenallowsthepro
teintobemade.
Antisensedrugsaresmall,chemicallymodifiedstrandsofDNAthatarec
omplementarytothespecificmRNA(hencetheterm"anti")thatcodesf
ortheprotein(the"sense").Antisensedrugsaredesignedtobindto
thesemRNAs.OnceboundtothemRNA,subsequentproteinproductionisst
opped.
DetailsAboutGenasense’sMechanismofAction
GenasenseblockstheproductionofBcl-2,aproteinmadebycancercells
thatisthoughttoblockchemotherapy-inducedcelldeath.Byreducingt
heamountofBcl-2incancercells,Genasensemayenhancetheeffectiven
essofcurrentanticancertherapy.
ThefiguresbelowshowhowBcl-2preventschemotherapy-inducedcelldeat
handhowBcl-2blocksthispathway,thusallowingcelldeath.
Inanimalstudies,whenGenasenseisusedincombinationwithotheranti
cancertreatments,includingchemotherapy,radiation,andimmunotherapy,
thereappearstobeasynergistic(additive)killingeffect.Asasingl
e-agent,Genasensealsoappearstohavesomedirectkillingeffectsonm
yelomacellsandmayinhibitangiogenesis(thegrowthofnewbloodvesse
ls).
HowItIsAdministered
Genasenseisgivenasacontinuousintravenousinfusionusingaportable
pump,typicallyovertheperiodof5to7days,followedby1to3week
soff.Inclinicaltrials,a3-weekcycleiscommonlyusedandmaybere
peatedformanymonths,dependingonthetrial.
PotentialSideEffects
Since1995,morethan1,000patientshavebeentreatedwithGenasense.T
hemostcommonsideeffectsobservedinclinicaltrialshavebeenlow-gr
adefeverandfatigue.Thrombocytopenia(lowplateletcounts)hasbeeno
bservedinsomepatientswhoarealsoreceivingmyelosuppressive(bonem
arrow-suppressing)drugs.
Genasenseincreasestheincidenceofsideeffects,particularlyfever.I
talsoincreaseslaboratoryabnormalities,particularlylowneutrophilc
ounts(neutropenia)andthrombocytopenia.Mostoftheincreasesaremild
tomoderateinseverityandreturntobaselineornearbaseline.Thety
pesofsideeffectsseenweresimilartothoseseenwithchemotherapy(e
g,lowbloodcounts,nausea,orvomiting).Noneworuniquesideeffects
werenoted.Catheter-relatedcomplications,suchasinfection,mayalso
occur.Despiteanincreasedincidenceofserioustreatment-emergentadv
erseeventsobservedwiththecombinationofGenasenseandchemotherapy,
thepercentageofpatientswhodiedorwerediscontinuedduetoadverse
eventswascomparabletothatobservedwithchemotherapyalone.
PreclinicalStudies
Inthelaboratory,Genasensehasbeenshownto&n