Circadian Timing in Cancer Treatments

47 Pages·2010·1.55 MB·English

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,
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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
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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
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ws.or timing Hrhoyrmthomnsa l temrhpyethramtu re Fpeaetdteinrng
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urnals.annuse only. parassyysmtepmatshetic
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21. on 0 Figure1
7-4unt SchematicrepresentationoftheCTS.TheCTSiscomposedof(a)ahypothalamicpacemaker,the
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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
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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,
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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
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Clock
Npas2
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FBXL3
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or C B N B
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om arjoersonal Cry1,2
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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
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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.