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ANRV401-PA50-15 ARI 4December 2009 9:34 Circadian Timing in Cancer Treatments org Francis Le´vi,1,2,3 Alper Okyar,1,4 Sandrine Dulong,1,2 ews. Pasquale F. Innominato,1,2,3 and Jean Clairambault1,2,5 vi e alr 1INSERM,U776RythmesBiologiquesetCancers,HoˆpitalPaulBrousse,Villejuif,F-94807, u urnals.annuse only. 23FUArasnnsiicvsetaPnacreis-PSuubdl,iqUuMe-HR-oˆSp0it7a7u6x,dOerPsaayr,isF,-U91n4it0e´5d,eFrCanhcroenothe´rapie,De´partementde m arjosonal 4CIastnacne´bruolloUginei,vHerosˆiptyitaFlaPcuaultlyBorfoPuhssaer,mVaicllye,juDife,pFa-r9tm48e0n7t,oFfrPanhcaermacology,BeyazitTR-34116, wnloaded fro27/10. For per 5IepsImatNsaaqnRiulb:IauAflrle,a.RiTnnocuncirsoqk.mlueeeyvinni@caotionu@rseti,rnmDse.orfmrm,aa.fiorn,[email protected],[email protected],0ns5sae,[email protected],r,France; Do1/ 1. n 0 7-42unt o Annu.Rev.Pharmacol.Toxicol.2010.50:377–421 KeyWords 37co FirstpublishedonlineasaReviewinAdvanceon molecularclock,drugdelivery,chronotherapeutics,gender,mathematical ol. 2010.50:multi-site ac oNTnholeivneAemnabnteuprahl1aR7r,mev2ti0eow0x9.aofnPnhuaarlrmevaiceolwogs.yoarngdToxicologyis mAbodsterlsa,cctlinicaltrialmethodology,systemsbiology,personalizedmedicine xicM- Thisarticle’sdoi: Thecircadiantimingsystemiscomposedofmolecularclocks,whichdrive ToR 10.1146/annurev.pharmtox.48.113006.094626 macol. y INSE CAlolpryigrhigthstre(cid:2)cser2v0e1d0byAnnualReviews. 2D4N-hAcrheapnagier,sainpoxpetnoosbisi,oatincdmaentgaiboogleisnmesaisn.dTdheetocxeilfiluclaatriocnir,ccaedlliacnycclleoeckvesnatrse, arb coordinatedbyendogenousphysiologicalrhythms,sothattheytickinsyn- h P 0362-1642/10/0210-0377$20.00 chronyinthehosttissuesthatcanbedamagedbyanticanceragents.Asa v. e result,circadiantimingcanmodify2-to10-foldthetolerabilityofanticancer R u. medicationsinexperimentalmodelsandincancerpatients.Improvedeffi- n n A cacy is also seen when drugs are given near their respective times of best tolerability,dueto(a)inherentlypoorcircadianentrainmentoftumorsand (b) persistent circadian entrainment of healthy tissues. Conversely, host clocks are disrupted whenever anticancer drugs are administered at their mosttoxictime.Ontheotherhand,circadiandisruptionacceleratesexper- imental and clinical cancer processes. Gender, circadian physiology, clock genes,andcellcyclecriticallyaffectoutcomeoncancerchronotherapeutics. Mathematicalandsystemsbiologyapproachescurrentlydevelopandinte- gratetheoretical,experimental,andtechnologicaltoolsinordertofurther optimizeandpersonalizethecircadianadministrationofcancertreatments. 377 ANRV401-PA50-15 ARI 4December 2009 9:34 INTRODUCTION Theoutcomesofpatientsreceivinganticancertreatmentsremaincomplicatedbyunpredictable UGT: UDP- severetoxicitiesand/orpoorantitumorefficacy(1).Greaterthan10-foldinterindividualchangesin glucuronosyl drugexposureandpharmacokineticparametersaswellasthevariablestatusofgeneexpressionand transferase metabolismwithinthetumoritselflikelycontributetolargeinterpatientvariabilityintherapeutic 5-FU: 5-fluorouracil index(1,2).Whereasmappingthegeneticpolymorphismsindrugmetabolismanddetoxification Circadian: biological canpredictunduedrugtoxicity,theidentificationofmolecularsignaturesintumorcellscanpredict rhythmwithanabout efficacyofspecificanticancerdrugs(3,4).Recentresults,however,emphasizethattherelevance onedayperiod(circa, oftheUDP-glucuronosyl-transferaseUgt1a1∗28polymorphism,anFDA-approvedtestforthe about;dies,day) predictionofirinotecantoxicity,variesaccordingtogender,deliveryschedule,drugdoselevel, Chronotherapeutics: andassociatedgeneticpolymorphisms(5).Similarfindingsarereportedforthepolymorphisms org theadministrationof ofDpyd,whichencodesfordihydropyrimidinedehydrogenase,therate-limitingenzymeforthe s. treatmentsaccording w catabolismof5-fluorouracil(5-FU)(6). e tocircadianorother evi biologicalrhythms Thelargevariabilityintheoutcomeofpatientsonanticancertherapyisparalleledbythelimited nualr Biologicalrhythm: successrateofanticancerdrugdevelopment.Only5%oftheanticanceragentsselectedforclinical m arjournals.ansonal use only. seoPenselcdfri-oilsloguadetsi:ntoaoncinuyescdlbeiadonuldorgaitcioaln dp(cerievrTdcealihoc,tipsaiombrnoeeuvnoittfe;sswduaficeeecsmtey,spsdishfauayilds)liyeztnecimtsoifimitnehpgdal,teatcsteratenahaleltpmcmrleeiandniiintccattcaliambpulhyisneagscfehoswaraniitngnhdetienbbrerytuchopsemetev2ede4rr-caehllgifnoitsiilcmtdearelteshddceeavalteseo,lmoletphermdaabtiecinialsittt,iyo(c7nia)rsn.c.daPdotihaoner 1. Downloaded fron 01/27/10. For per Csbgrohyeiriosgynrtltaceoehnargmmaidistcimsea(asCinlnp∼sTthyc2isyemS4tsle)lii:uhmonloltagohutrghreayantd acrooninrdtciICeatnnudadmtineascneoaednrcr,dleom(fhWcfioukcsomsatrctablhydniaootHplfdoaaetrgnaiiievlcttneiahctltashfOnu(e9cnrse–gecr1atr4inaho)giyn.zetAasnhtdtimrosiesnscbpe)folanatcvyhtoomncirnicsorlccneuaaxoddnpgeicesareranrtipmhcphahretboanyn“ctseagthlshesimsefetisIonnwadtnmoeedlrrasknmraeatnmtdhiduoaactnilnesaisn(lc8svAau)on.grlTcevveniehvrscaeypcldaifironitscirercauRnadpntiesatcs.nieeoarndoricuosh-sf 7-42unt o aenndviraodnjumstesntthaelmcyctoles reuvpidteionnceis(1p5ro).bTabhluysc,atrhceinporgeveennictitoonhoufmciarncsa”diwanithdiasnruepsttiiomna,taenddr/ioskrtlehveerle2sAto,rtahtaiotnis,ocflfousnecttoiofnualll 7o 3c xicol. 2010.50:M-multi-site ac ctahldorjucoCksuhtsgm,rhoceontnhuoteltdohafecdtrormanepiasenttuimitstutierctnaesttniadoeienmwliosvofeabrttjyreeictamottimvpperhesoynvfstoiisnorgaltochgctehoirceraadpltienrouhgletyirttcoahsbm.bilisiotaylongdainctdha/leorrrheysttthohermaetsfifio(8nc,aoc1ry6t)h.oTfeimhnededuadiccteaiqotuinoanotesf ToR theserhythmscanimprovetherapeuticoutcomesincancerpatients(8,17). col. NSE Recentadvancesidentifycriticalmoleculareventsthatrhythmicallycontroldrugmetabolism may I and detoxification, cell cycle, molecular targets, DNA repair, apoptosis, and angiogenesis. The harb coordinationoftheseprocessesalongthe24-hperiodisensuredbythecircadiantimingsystem P v. (CTS),whosehierarchicalorganizationdetermineschronotherapeuticeffects.PhaseItoIIIclin- e R icaltrialsvalidatetherelevanceofcircadiantimingofcancertreatments.Moreover,translational u. n studiesidentifypotentialkeydeterminantstooptimallyshapecircadiandrugdeliverypatternsin n A agivenpatient.Data-basedcomputationalmodelsareprovidingnovelinsightsintotheinterac- tionsbetweencircadianclocks,cellcycle,andanticancerdrugpharmacology.Theynowreveal severalcriticaldynamiceventsforthesuccessofcancerchronotherapeuticsthroughthedesignof patient-tailoredchronomodulateddeliveryofanticancermedications. THECIRCADIANTIMINGSYSTEM OverallOrganization TheCTScoordinatesphysiologyandcellularfunctionsovera24-hperiod.Environmentalsyn- chronizerssuchasthealternationofdaysandnights,socio-professionalroutines,andmealtimes 378 Le´vietal. ANRV401-PA50-15 ARI 4December 2009 9:34 Circadian timing system Sleep/ wakefulness Environment • Day/night 12 Suprachiasmatic • Social 9 3 nuclei • Familial 6 Rest-activity rhythm • Meal g Core body ws.or timing Hrhoyrmthomnsa l temrhpyethramtu re Fpeaetdteinrng e vi e ualr Sympathetic/ urnals.annuse only. parassyysmtepmatshetic m arjosonal • Cell cycle, apoptosis, wnloaded fro27/10. For per Cionri rgpcaeanrdisipahne crlaol cks 9 162 93 162 93 162 93 162 93 162 3 •• aaADnnnrddugg idDo meNgteAeontx raeiefibspciosaaliitrsiomn Do1/ 21. on 0 Figure1 7-4unt SchematicrepresentationoftheCTS.TheCTSiscomposedof(a)ahypothalamicpacemaker,the 7o ol. 2010.50:3multi-site acc scdsuyleonptcocrkahxscirfihoincinaaitstzhmieoedanct,wiecclieltnslhluoctcfiylmaeclileleSp,cCeuarpNeiosp,php(terboo)rsavailisnd,tieaDsdrsrNubaeyyAs.olriMfgepShoaCtl-ierdNc,aua-rlngkaedrcncyaelncrolgaectiskoesadgnrechdniyreoctshtaihsdmeoiairvcneeanrlplvyhaiyrc2soo4inno-mhtloropegnleyrtxoaieolundftoa.pbcTutitoohstr,eisca.CnCmdTier(Stcca)aibsdmoialoinlsemcualnard xicM- physiologyoutputscanalsoserveasCTSbiomarkers. ToR col. NSE entrain and calibrate at precisely 24 h, the period of the CTS (Figure 1). Endogenous circa- may I arb dian rhythms with periods differing from precisely 24 h characterize all aspects of mammalian h P physiology(10,18,19).Inhumanbeingssynchronizedwithusuallight-dark,socio-professional, v. e andfeedingsynchronizers,motoractivityishighatdaytimeandlowatnight,bodytemperature R u. reaches a maximum in the early evening, cortisol secretion by the adrenal gland rapidly rises n An fromanadirnear2:00a.m.toamaximumnear8:00a.m.,andmelatoninsecretionbythepineal glandmostlyoccursatnight,withamaximumnear2:00a.m.(18,19).Thiscircadianphysiology isgeneratedorcontrolledbyacentralpacemaker,thesuprachiasmaticnuclei(SCN),inthehy- pothalamus.ThecircadianperiodoftheSCNneuronsiscalibratedto24hthroughtheperception ofsynchronizationsignals,namelylightanddarknessviatheretino-hypothalamictractusingglu- tamateandpituitary-adenylate-cyclase-activatingpeptide(PACAP)asneuromediatorsandother brainareasvianeuropeptideYfibers(18).TheSCNgeneratescircadianphysiologythroughdif- fusiblesignals,includingtransforminggrowthfactorα,epidermalgrowthfactor,prokineticin-2 (PK-2),cardiotrophin-likecytokine,andneuroanatomicsympatheticandparasympatheticpath- ways(20–22).Circadianphysiologyandothersignalsdirectlyorindirectlyemanatingfromthe SCNcoordinatemolecularclocksineachcell(18,23).Inturn,themolecularclockrhythmically www.annualreviews.org • CancerChronotherapeutics 379 ANRV401-PA50-15 ARI 4December 2009 9:34 controlsmanycellularfunctionsthatarerelevantforcancertreatmentincludingdrugmetabolism anddetoxificationaswellascellularproliferation,DNAdamagesensingandrepair,apoptosis,and angiogenesis(24). Clock: circadian Theperiodicresettingofthecircadiantimestructurebyexternal24-hcyclesallowsforthe locomotoroutput cycleskaput predictionoftimesofthepeaksandtroughsofcircadianrhythmsinrodentsandinhumans.This appliestotherhythmsthatregulateanticancerdrugpharmacologyandcellularproliferation(23, Bmal: brainand musclearyl 24).Conversely,alackofexternalsynchronizers,thatis,adefectintheperceptionofenvironmental hydrocarbonreceptor timecuesthroughblindness,forinstance,oranalterationofthecircadianphysiology,molecular nucleartranslocator clock, or clock-controlled pathways, results in the deregulation of the circadian time structure Per: period(geneor (19,25,26).Inturn,relevant24-hrhythmsbecomedamped,ablated,orphaseshifted,withan protein) unpredictabletimingofthepeaksandtroughsifthecircadianperiodislengthened,shortened,or org Cry: cryptochrome shifted.Insuchcases,melatonin,glucocorticoids,orotherchronobioticagentscanrestoreproper ws. DBP: albumin circadiancoordination(26,27). e vi D-bindingprotein Healthy human subjects can display different CTS phasing, despite exposure to the same e alr TEF: thyrotroph environmentalsynchronizers.Suchdistinctchronotypesaredefinedwithquestionnairesonliving u urnals.annuse only. eHlemuLkbFer:ymohinaeipfcaafctaticoctror hpaatbtietrsn,ws(h2i8ch).reflectdistincttimingofcircadianbehavior,physiology,andclockgeneexpression m arjosonal CircadianClockMechanisms oer wnloaded fr27/10. For p ATulhadteooszreeygnleosnopepescsaifitrhecaictnlvroeocslkuvelgtdeininnestthrcaeonngssectnriitepurttaieotintohaneloacnfodrthepeoofsctittrhrcaeandmsicaornliepoctsiuoclinalrlaalctialoocnctikvianintiionmndaiavmniddmuiaanllshmi(bFaiitmgioumnraerlei2ag)n-. Do1/ cells.Inparticular,theCLOCK-BMAL1orNPAS2-BMAL1proteindimersplayakeyroleinthe 1. n 0 molecularclockthroughtheactivationofthetranscriptionoftheclockgenesPerandCry(23,27). 2o 7-4unt Thefunctionalityofthemolecularclockinperipheraltissuesincludingmalignanttumorscanbe 7o 3c estimatedthroughtherelativephaserelationsofcircadianexpressionpatternsofthreecoreclock ol. 2010.50:multi-site ac greegnTuelshawteehsCoRLseeOvt-CrearKnbαs-cBraMinpdtAioPLne1ri2st,rraaenngdsualPcatetirev2datdbiooynwonncreoemagnupollaethtxeesarl:RsRoeverv-he-reybrtαbhαmadnicodawliltnysroecwogunnltartrtoealsnssBtchmreiaplmt1io,RBnNm(2Aa3l1,tr2ua4np)--. xicM- scriptionofproline-acidicaminoacid–richbasicleucinezipper(PARbZip)transcriptionfactors, ToR macol. y INSE ilneuclkuedminiagfaaclbtourm(iHnLDF-)b(i2n9d)i.nTghpersoetterianns(DcrBipPti)o,nthfaycrototrrosprehguemlatberymoonsitcpfaatchtworay(TstEhFat),haannddlehexpeantoic- arb bioticmetabolismanddetoxificationinliver,intestine,andkidneythroughtherhythmiccontrol h v. P ofC-androstanereceptor,P450oxydo-reductases,and5-amino-δ-levulinicacidsynthetase(Alas1) e (23,29).Furthermore,posttranslationalmodificationsregulatetickingofthemolecularclock(30). R u. TheCLOCK-BMAL1dimeralsogatescellcyclephasetransitionsthroughtherepressionof n n A c-Mycandp21,twoimportantplayersincellularproliferationandapoptosis,theactivationofp53, aproapoptoticgene,andthatofWee1,whoseproteingatestransitionfromG2tomitosis(24,31, 32).Circadianclocksfurtherregulateapoptosisthroughtherhythmicexpressionsofantiapoptotic BCL-2 protein and proapoptotic BAX protein (33); DNA damage sensing through molecular interactionsofataxiatelangiectasiamutated(ATM)orATMandrad3-relatedinteractingprotein (ATRIP)withclockproteinsPERs,CRYs,andTIM(32,34);andDNArepairthroughrhythmic activitiesorlevelsofO -methylguanineDNAmethyltransferase,aproteinthatexciseslethalDNA 6 alkylatedlesionsproducedbynitrosoureas(35),aswellasTip60,Xpa,andpossiblyErcc1,which repairplatinum-inducedDNAadducts(36–38). Theintrinsicsustainabilityofmolecularclockshasbeenshowninsynchronizedcellcultures. Thus,celllinesarepotentialmodelsforinvitrostudiesofcircadianclocksandclock-controlled 380 Le´vietal. ANRV401-PA50-15 ARI 4December 2009 9:34 ROR α,β,γ Clock Npas2 Bmal1 FBXL3 g or C B N B s. w CRY1,2 e SIRT1 evi CK2α REV-ERBα,β ualr SIRT1 WDR5 PER1,2 NONO n urnals.anuse only. Per1,2 CK1δ,ε GSK3β om arjoersonal Cry1,2 Downloaded fr1/27/10. For p DEC1,2 RevD-eEcr1b,α2,β EZH2 1. n 0 2o 7-4unt Figure2 37co Simplifiedhypotheticalmammaliancircadianclock.Themolecularoscillatoristhoughttobebasedonmolecularfeedbackloopswithin ol. 2010.50:multi-site ac aRpSrIpEoRoVtTse-ii1tEnivsiRneCBtleiLαmr.aObcTCt(hwCKeiLtt(hrCOat)nChoseKcrsr,eNiNphPtePiAotAenSrS2oo2d(f,NiPBm)eM.reTraAsnhLaden1Cpd)oartnlyhydegcreoaenmbneyebsgfipaasrtcaoiivcltietetiiavlnitametEetbZdh(eHPbiryE2ahRacestatiweonrnedol.lCdTaiRmshYceea)rasstcehbcianuettmkwairuneeleaaisntneiotB2enMr(caCoAnKnLdn21ae)cc(atBtinev)ddiatysvniidloaefnethPicteiEhnneRgruiaconnlffedotahrrCmeoRtarwYptihoopanrrneorlrteaeegticeunedlspaattoorerr xicM- alsoinfluencedbyphosphorylationbyproteinkinases(CK1δ,ε),byubiquitinationviaacomplexcontainingtheF-boxproteinFBXL3 col. ToNSER (DspEeCci1ficanfodrDCERCY2s)c,obmyptheetehwisittohnBeMmAetLh1yl--CtrLanOsCfeKra/sNe-PbAinSd2inhgetperrootdeiimneWrsDfoRr5E,-abnodxbbyinNdOinNgaOn,datnhRerNebAy-raendducDeNEA-b-obxin-mdiendgiaptreodtein. may I transactivation.Anaccessoryfeedbackloop,employingthenuclearorphanreceptorsRORα,RORβ,andRORγasactivators,and harb REV-ERBαandREV-ERBβasrepressors,regulatesthecircadiantranscriptionofBmal1.(AdaptedfromU.Schibler,with v. P permission.) e R u. n n pathways(39).Two-hourexposureofculturedcellsto50%horseserum,dexamethasone,orother A compoundssynchronizesthecircadianclocksinculturedcellswhoseinternaltimingisotherwise drifting at a different pace (39, 40). Circadian transcription has been demonstrated for at least threefullperiodsinsynchronizedculturesofcelllinesandexvivocellularpreparationortissue explantsfromrodentsorhumans,includingSCN,liver,lung,kidney,intestine,andadiposetissue (41–43).TheuseofaPERIOD2-LUCIFERASEfusionproteinasareal-timereporterofcircadian dynamicsdemonstratesthatperipheraltissuesfrommiceself-sustaincircadianoscillationsfor>20 cyclesinisolation,withtissue-specificdifferencesincircadianperiodandphase(44).Repeatserum shocksat3-dayintervalsor24-hcyclesinexternaltemperatureavoidthedesynchronizationofin vitrotranscriptioncircadianrhythms(39,45).Thepropertiesofsynchronizedcellculturesthus supporttheirrecentuseaspotentialmodelsforcellularchronopharmacology. www.annualreviews.org • CancerChronotherapeutics 381 ANRV401-PA50-15 ARI 4December 2009 9:34 THEEXPERIMENTALCHRONOPHARMACOLOGY OFANTICANCERAGENTS ZT: Zeitgebertime TheRelevanceofCircadianTimingforTreatmentTolerability (equivalenttohours afterlightonset) Circadian timing largely modifies the extent of toxicity of 40 anticancer drugs, including cyto- statics,cytokines,andtargetedbiologicalagents,inmiceorrats(Table 1).Apotentiallylethal doseofanyoftheseagentsresultsin2-foldtomorethan10-foldchangesintheincidenceoftoxic deathsand/ormaximumbodyweightlossasafunctionofcircadiantimingofdrugadministration. Suchlargedifferencesoccurirrespectiveofdeliveryroute—oral,intravenous,intraperitoneal,or intra-arterial—orthenumberofdailyorweeklyadministrations(23).Themethodologyusedto demonstratethe24-hchangesinanticancerdrugtolerabilityinvolvesthesynchronizationofnoc- org turnallyactivemiceorratswithanalternationof12hoflightand12hofdarkness(LD12:12).The ws. samedrugdoseisadministeredtodifferentgroupsofratsormice,witheachgroupcorrespond- e vi ingtoadifferentcircadianstage,alsocalledZeitgebertime(ZT).Usually,sixcircadianstages, e alr occurring4hapart,aretested.TimeusuallyisexpressedinZThoursorinhoursafterlightonset. u urnals.annuse only. Dgatreotdhuiepcsamtoeofdsatcnhcimroonanvlsoebnloiioceanlottegtdiicmoanensdim(i4faf6el)rf.eaFncitilgiitsuioerlseaat3elldodwsehpseielcvttuesspt,hlsieoghttihtmaotendssieoftffealrteetanhsttectdiorexcsiaicrdietidayntaisnmtdaegbfeoesnraedrfieiftfteefrrsoetenmdt om arjoersonal oppertaimtuarlecrihrcyatdhimanfotirm1i6nagn,triecfaenrcrienrgdtrougesxitnermnaalleLBD6Dsy2nFch1rmonicizee(rfeamndaleinCte5r7nBalLa/v6er×agmebaloedDyBteAm2-) wnloaded fr27/10. For p itonhfesmt2ua4di-nihetsappregererioftodorrmagnaedndcsaaftnoonruotrotlxbaiebcioptyrra.etCdoiircrytcea(d4d7ita–hn6u3rsh)f.yaTrthhbmyesothipnetitkmhneaoltwcoillreecdraagdbeiialointfytpiohmfairanmngtasiccaaornelocsgetriacgdcgrleuargsessdoparelrtoshniasgtt Do1/ inrodentskeptinconstantdarknessorinconstantlight,whichdemonstratestheirendogenicity 21. on 0 (64). 7-4unt Evenwhencombined,chemotherapeuticagentsdisplaytheleasttoxicityneartheirrespective 7o ol. 2010.50:3multi-site acc to(d5ixem6ate,leirs6pmo5laf–itnb6inae7ns)ot.trstTogalhefetmeersarcebietifixlaipnbtoydinsianues-rgscesiinstsgopullpetahptaieognerfiitnnrtstBsht,ea6anDsptsei2hcrFoas1niwsctmneernficocaereg,deaoonnfxtd,othdaruetoblcceeiiactrsiacntxa-wedclihi-asdenponlaxcttoohirnneutirblnaoitcLltieoonrfuiinarsanCgttisi3v,cHeiarnni/ncHneoeretaemdrcratiuhncgee- ToxicRM- timeofbesttolerability. col. NSE armaby I CircadianControlofMetabolism,Detoxification,andPharmacokinetics h v. P Most anticancer agents with circadian tolerability undergo oxidation, reduction, or hydrolysis Re underphaseImetabolism,mainlyintheliverand,toalesserextent,intheintestine(1,2).The u. CTScontrolsbothphaseImetabolismandphaseIIdrugdetoxificationandeliminationthrough n n A redundant processes involving rhythmic physiology and circadian clock signaling (Figure 4) (23,29,68,69). Theactivityofmostmicrosomaloxidasesarehighestbyseveralfoldduringthedark(activity) span and lowest during the light (rest) span in the liver of rats and mice (29, 68, 70). Twenty- four-hourrhythmsfurthercharacterizetheactivitiesofseveralCYPisoenzymes(23,71).Two-to eight-foldcircadianchangesinmRNAexpressionarefoundforcytochromeP-450oxidoreductase inliverandintestine,withamaximumatZT12;forCyp2b10(testosterone16-α-hydroxylase),with amaximumatZT16inliverandintestine;andforCyp2c50,withamaximumatZT20inmouse liver(29).However,Cyp3a13mayescapefromclockregulation(72). ThecircadianrhythminCyp3alikelycontributestothechronotolerancepatternofseliciclib, docetaxel,irinotecan,mitoxantrone,andvinorelbine,whichundergooxidativemetabolism.On 382 Le´vietal. ANRV401-PA50-15 ARI 4December 2009 9:34 Table1 Anticancerdrugswithdocumentedrelevanceofcircadiantimingfortolerability,pharmacokinetics,and/or antitumorefficacyinlaboratoryrodents Endpointmodifiedbycircadiantiming[reference(s)] Pharmacologicclass Drug Tolerance Pharmacokinetics Efficacy Antimetabolite D-actinomycin (219) Methotrexate (220,221) (99,221) (99) 5-fluorouracil (88,222,223) (86,224) (88,225) Floxuridine (226,227) (226,228) Arabinofuranosylcytosine (229) (229,230) Gemcitabine (56) (56) L-alanosine (55) (55) g Top1inhibitor Irinotecan (48,77,82) (77,82) (66) or s. Topotecan (95) (95) w e 9-aminocamptothecin (231) (231) vi alre Top2inhibitor Mitoxantrone (54) (54) nu Etoposide (52) m arjournals.ansonal use only. DNAintercalator DDDThaoouexxpnoorrrouuurbbbuiiibccciiiicnnnin-liposomes (64(4,667,((225,2333327,23))3,283)4) (234) (65,67((22,2333795)),236) oer Epirubicin (240) wnloaded fr27/10. For p Mitoticinhibitor VVViiinnncborlraiesslttbiininneee (6((322,441128))2) (182) Do1/ Docetaxel (58,67) (58,67) 21. on 0 Alkylator Cyclophosphamide (72,91) (72) (230,236,243–245) 7-4unt Ifosfamide (246) 7o 3c Melphalan (235,247) (235) ol. 2010.50:multi-site ac PMCeiisptpotlimacthyiencmini-oC (47,((556912,))212) (47,248) (56,65,249) xicM- Carboplatin (47,60,103) (47,59) ToR Oxaliplatin (59,61) (59,61,87,250) (66) col. NSE B-85-0040 (251) (251) may I Nedaplatin (252) (252) harb Nitrosourea Cystemustine (57) (57) P v. Cytokines rHu-interferonα (253) (253) e R rMu-interferonγ (253) (253) u. n Interferonβ (98) (98) (98) n A Tumornecrosisfactorα (254) (255) Interleukin-2 (50) (256) CDKI Seliciclib (49) (49) (94) Cox-2inhibitor Celecoxib (96) (96) VEGFinhibitor TNP-470 (97) (97) (97) SU1498 (100) BB2516 (100) www.annualreviews.org • CancerChronotherapeutics 383 ANRV401-PA50-15 ARI 4December 2009 9:34 Antimetabolites Gemcitabine HALO 0 L-alanosine Topoisomerase inhibitors 222000000%%% Irinotecan ent 21 m 3 Mitoxantrone e v Etoposide pro m Intercalating agents I 000%%% Theprubicin Alkylating agents Peptichemio Cisplatin org Carboplatin 18 35.0°C 6 ws. Oxaliplatin e vi Nitrosoureas or related e alr Mitomycin-C u n Cystemustin urnals.anuse only. MitoDtoicce stapxienldle poisons 37.5°C m arjosonal CytoViknionreelsbine 15 9 wnloaded fro27/10. For per SmaSInleltl eikcriilcenluiabksine- 2inhibitors 12 Do1/ Figure3 21. on 0 Relevanceofcircadiantimingforthetolerabilityofanticancerdrugs.Circadiantimingassociatedwithbest 7-4unt tolerability,inZT(orhoursafterlightonset,rangingfrom0to24)andrelativemagnitudeofsurvivalbenefit 37co fromoptimaltoworsttiming,rangingfrom0to200%.Thediagramillustrateschronotolerancefor16 ol. 2010.50:multi-site ac aceninrtdciaocdagnieacnneorruhdsyrrtuehgfmesrseitnnucdbeioefddoyrintoepomtuiprmelraaalbtdourrruaetgoistriysmhioinnwgmn(asileneeBthT6eaDbin2letFe11rnmfaolirccecir,ocsrlyreenascpnhodrnopdnriionzvegiddreewsfietarheCnLTcDeSs1)b2.i:o1m2.aTrkheer,aavnerage xicM- ToR macol. y INSE tchirecaodthiaenrhtoalnedra,bniolintyrhoyfthcmycilcoCphypo3sap1h3a,mrhidyeth(m29i,c7C2y)p.2Ibn10c,oanntdrapsto,s5si-bFlyUCaynpd2c2g9empacrittaicbiipnaet,ewinhothsee arb toxicityalsodependsuponcircadiantiming,undergorapidlivercatabolismthroughdihydropy- h P rimidinedehydrogenase(DPYD)andcytidinedeaminaseactivities,respectively(73–75). v. Re ThecarboxylesterasesCes1andCes2arerhythmicallycontrolledbothbythecircadianclock u. and by clock-controlled Dbp, Tef, and Hlf in the liver and gastrointestinal tract (29, 76). Ces1 n n A andCes2circadianexpressioncanaccountfortheincreasedbiotransformationofirinotecaninto SN-38duringthelight(rest)spanofmaleICRmice(77).DpydmRNAexpressionandactivity displaysignificantrhythmsintheliverofmaleB6D2F1mice,withan∼15-htimelagbetween their peaks. Peak DPYD activity occurs near the middle of the light span, when the animals rest(78).Alltheenzymaticactivitiesthatgeneratethecytotoxicformsof5-FU,suchasorotate phosphoribosyltransferase,uridinephosphorylase,anddeoxythymidinekinase,arehighestduring thedark(activity)spanofratsormice,when5-FUismosttoxictohealthytissues(23). Rhythmic phase II detoxification by reduced glutathione (GSH) is a critical determinant of the toxicities of platinum complexes and other cytostatics. Liver and jejunum GSH contents GSH: reduced are approximately threefold higher in the second half of the dark span in mice and rats com- glutathione pared with mid-light, and the pharmacologic suppression of GSH synthesis with buthionine 384 Le´vietal. ANRV401-PA50-15 ARI 4December 2009 9:34 Circadian timing system Drug metabolism and target Cell cycle, DNA repair, and apoptosis Active compound Wee1 CycB1 G0 CDK1 cMyc CES Top1 DNA repair M TK Bioactivation Target TS ATM CYP3A4 AGT G2 Drug P53 G1 UGT1A1 Metabolism and DPYD org detoxification GSH Apoptosis S views. Drug AAABBBCCCBCG122 BBaclx2 CCCyDyccKED2 e alr p21 u n urnals.anuse only. Metabolites m arjosonal oer wnloaded fr27/10. For p 1. Don 01/ Chronotherapeutics 2o 7-4unt Figure4 37co Maincellulardeterminantsofcancerchronotherapeutics.TheCTS(top)determinestheoptimalcircadiantimingofanticancer Toxicol. 2010.50:RM-multi-site ac maschecheevcrldepooriunccanooalttpncifheosotlanlrrr-sumctc(hybtaceocoltecotp-ohdtrmriyemon)l.naaatTomlepcdhihhceesarvCoroemnTfnoaatSmcsnocttoilhocodanagutntylrgacootaeletrfsedaddGndrrutru1iugcg/gsaStn(rdorcaeiernglrishGvpate)2ogr./reyTMtn,shtcbstehiraoeartadencclusaetilittlevilisouoa,tnlnaiwsosr,i,nbtath,eistsdpwsweurteeoeoelp,lxnaeiafinrcschdpDarawtoNrionahAmnoo,pleremheteoaperrratsmgia.rabanaocnilosidmksmianlp,eeottvaipecrtlsgsoeas(tnilessdf,,twa)c.nhhTdricohehnelioamCpcichTnoaaSurtmniaotlasnfco,oowrrdethyghniucealhmateicss macol. y INSE sulfoximide profoundly alters the chronotolerance pattern of cisplatin and oxaliplatin in mice arb (79,80). h P UGT1Acatalyzesthedetoxificationofseliciclib,irinotecan,andSN-38.HighestUGTactivity v. e isreportedduringthedark(activity)spanofrats(70).However,meanandcircadianexpressionof R u. Ugt1a1differaccordingtospecies,strain,andgender,withrelevantconsequencesforirinotecan n n A chronotolerance (81, 82). Circadian clocks control the transcription of ATP-binding cassette familymembers,includingAbcb1aandAbcb1b(Mdr1),Abcc2(Mrp2),andAbcb4(Mdr2)inmouse liverandintestine(29,69,83–85).TheAbcb1aandAbcb1bmRNArhythmstranslateintoa30% increase of permeability glycoprotein (P-gp) activity at ZT17–19 compared with ZT5–7 in rat jejunumandileum(B.Lemmer&A.Okyar,unpublisheddata). Themultiplecircadiancontrolsofdrugabsorption,distribution,metabolism,andelimination (ADME)accountfordosingtimedependenciesinthepharmacokineticsof17anticancerdrugs ofallclassesinmice,rats,andevenpigs(Table1).Eventhecontinuousdeliveryof5-FUbyan implantedpelletresultsincircadianchangesinplasmadrugconcentrations,withhighvaluesat P-gp: permeability daytime,duringtherestspanofthemice(86).Circadiantimingmostlyaffectstheinitialdistribu- glycoprotein tionphase(Cmax,t1/2α,Vdi),theareaundertheconcentrationxtimecurve(AUC),andtheplasma www.annualreviews.org • CancerChronotherapeutics 385 ANRV401-PA50-15 ARI 4December 2009 9:34 clearanceofanticanceragents.Highcircadiandrugexposureofhealthytissues,basedonplasma PKanalysis,isrelatedtothehighcircadiantoxicityofmethotrexate,mitoxantrone,interferon-α, andtheantiangiogenicagentTNP-470inmice(Table1).However,noconsistentrelationships TS: thymidilate arefoundbetweenbloodchronopharmacokineticsandchronotoleranceforirinotecan,cyclophos- synthetase phamide,cisplatin,carboplatin,oxaliplatin,interferonβ,orseliciclib.Forinstance,highestVdi Top: topoisomerase andeliminationareobservedinmicedosedwithcarboplatinatZT8andwithoxaliplatinatZT16, despite both drugs being least toxic at ZT16 (87). Highest platinum content is found in 12/18 tissues24hafterasingledoseofoxaliplatinatZT8,whenthisdrugismosttoxic(61).However, noconsistentrelationshipisfoundinthetissuesofmicetreatedatZT24,whenthetoxicityof oxaliplatin is intermediate, or at ZT16, when it is least toxic (61). The plasma and liver phar- macokineticsoforallygivenseliciclibdiffersignificantlyaccordingtocircadiantiming.Seliciclib g AUCis25%greateratZT3thanatZT19inplasma,and80%lessatZT3thanatZT19inliver, or s. whenthedrugproducesthefewestliveralterations(49).Takentogether,theresultsbothempha- w e vi sizeandqualifytherelevanceofchronopharmacokineticsasmechanismsofchronotolerancefor e alr anticancermedications. u n urnals.anuse only. CircadianControlofCellCycle,DNARepair,Apoptosis,andMolecularTargets om arjoersonal Cfreeqlluceynctletaervgeenttssfaorretchoeotrodxiincaittyedoaflcoanngcethretr2e4a-thmpeenrtiso(d24in).hPeraoltphoyrbtioonnesmofaSr-roawn,dgGut2,/aMnd-pskhians,ethcerelles wnloaded fr27/10. For p itonhvceerrteotahtsaeel2bb4oy-n∼he5pm0e%rairoridon,wtwhoietfhmseaacmloenaBdx6ihmDaul2fmFo1fadtmeaiarckrelny(e3lsi3sg,,h5wt8.h)A.eInrneoatpshpGiso0tsii-stGseup1ea,ctBetleClrsLnp2crhepdarrooamtcetiiennraeitzxeepdsrpuesrrsoiniaogpnolitpgrithpotlteiincs Do1/ BAX,withafivefold24-hchangeandapeakatZT15(33).Thetemporaryarrestofcyclingcellsin 1. n 0 G0-G1,thehighBCL2,andlowBAXexpressionsduringthelightspanwhenmiceresthelpexplain 2o 7-4unt thebestcircadiantimingforthetolerabilityof5-FU,gemcitabine,irinotecan,anddocetaxelin 7o 3c male B6D2F1 mice (48, 56, 58, 67, 73). However, the circadian control of drug metabolism ol. 2010.50:multi-site ac amonfod5l-edFceuUtloadxruitfiracirnagtgeiottshneaarlelisgouhstpusrapollafyonucrnleodsculkyltrsmefgoroudmliafiteethsdet(hc7ei7r,cca8ed8lli)ua.nlFarpoereaxiknposintsauDnrcePeY,totDhtehaceintsiecvrimetyaesiedndicliadvteeitoronaxsni,fidwcoahtthoioesner xicM- healthycells(73,78).ItthusaddsuptothereducedproportionsofS-phasecellsinbonemarrow, ToR macol. y INSE gacutti,viatnydofsktihny,maisdailamteecsyhnatnhisemtasfeo(rTimS)p,rwohviecdhcpirrocavdidiaenthteoluenraiqbuileityde(7n3o)v.oBsootuhrctreaonfsctrhiypmtioidnilaanted, arb are linked to early S-phase in proliferating tissues (89). Consistently, bone marrow TS activity h P peaks near mid-dark in coincidence with the greatest hematologic toxicity of 5-FU in female v. e CD2F1mice(88). R u. WhereascircadianPhaseIandIImetabolismpartlydeterminesirinotecanpharmacologyover n n A the24-hperiod,topoisomerase1(Top1),themainproteintargetofthisdrugismostlyatwork duringlateS-phase.Thus,thecircadiangatingofthecellcycleandpossiblythedirectcontrol ofTop1bythemolecularclockalsocontributetothebetterhematologictolerabilityofirinotecan duringtherestspanofmaleICRmice(77,90). TheRoleofMolecularClocksandClock-Controlled PathwaysinChronotolerance TheCLOCK-BMAL1transactivationcomplexrepressescyclophosphamidetoxicitymechanisms andpartlydeterminesthechronotolerancepatternofthisdrug.Cyclophosphamidewasbesttoler- atedatZT10-ZT14intwostudiescarriedout∼30yearsapartinfemalewtC57Bl6mice(72,91). 386 Le´vietal.

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in Cancer Treatments. Francis Lévi,1,2,3 Alper Okyar,1,4 Sandrine Dulong,1,2. Pasquale F. Innominato,1,2,3 and Jean Clairambault1,2,5. 1INSERM
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