1

Chapter3.ThePlatinumStory-version160805AWDrugsAgainstCancer:StoriesofDiscoveryandtheQuestforaCureKurtW.Kohn,MD,PhDScientistEmeritusLaboratoryofMolecularPharmacologyDevelopmentalTherapeuticsBranchNationalCancerInstituteBethesda,Marylandkohnk@nih.govCHAPTER3:ThePlatinumStory:FromImaginationtoaMajorNewAnticancerDrugTheprevious2chapterswereaboutalkylatingagents,anticancerdrugsthatdamageDNAbybindingtightly(covalently)toDNAbases,especiallytoguanine.Surprisingly,itturnedoutthatcertainmoleculescenteredonaplatinumatomcanbindanddamageDNAinamannerthatisrathersimilartothatofalkylatingagents,againespeciallybyattackingatguanines.Theanticanceractivityofplatinumcomplexeswasoneofthemostsurprisingandfar-reachingdiscoveriesinallofanti-cancerdrugresearch.Particularlyremarkableishowthatlandmarkdiscoverywasmade.Thefirstandstructurallysimplestoftheplatinumcomplexestobediscoveredwascisplatin,which,withitsmodifiedforms,isamainstayofmoderncancerchemotherapy.Cisplatinwouldnothavebeendiscoveredinthedrugscreeningprograms,becauseitisaninorganicchemical,whileallcancerdrugresearchhadbeenintherealmoforganicchemistry,whichisbasedoncarbonatoms.Cisplatinismadeupentirelyofanatomoftheheavymetal,platinum,2chlorineatoms,2nitrogenatoms,andafewhydrogens;thereisnotasinglecarbonatominit(Figure3.1).Norwouldithavebeendiscoveredbysearchingnaturalproductsmadebyanimals,plants,fungi,ormicroorganisms,becauseplatinumisnotfoundinanynaturalbiologicalsystem.Evenifheavymetalcomplexeshadbeenscreenedforanti-canceractivity,cisplatincouldeasilyhavebeenmissed,becausetheatomsandtheirconfigurationhavetobejustright.Forexample,cisplatinandtransplatinconsistofthesameatomsandbonds,differingonlyinwhetherthe2chlorinesarenexttoeachother(cis)oracrossfromeachother(trans),yetonlythecisconfigurationhasanti-canceractivity(Figure3.1).

2

3

Figure3.1.Chemicalstructuresofcisplatinandtransplatin.The2chlorides(Cl-)and2ammonias(NH3)arearrangedinaplanearoundtheplatinum(Pt++)atom.Theyarenexttoeachother(cis)incisplatinandacrossfromeachother(trans)intransplatin.Theplatinumatomhas2positivecharges,whilethechlorideshaveonenegativechargeeach;therefore.theseplatinumcomplexesareelectricallyneutral,whichallowsthemtoentercellseasily.BothcisplatinandtransplatinbindtoDNAatguanine-N7positions.ButonlycisplatinhasthegeometrytoformDNAcrosslinks,andonlycisplatiniseffectiveasananticancerdrug.DiscoverybyimaginationThecluetothediscoveryofcisplatincamefromanaccidentalandseeminglybizarreobservationbyanimaginativeandpersistentinvestigator.AsnotedbyPestko(Petsko,2002):“cisplatincamefromoutsidethebox-sofaroutsidethattheboxwasn'tevenvisible;itcamefromaplacenoonewouldhavedreamtoflookinginforananticancerdrug”.AsnotedbyA.Einstein,"Imaginationcanbeevenmoreimportantthanknowledge."BarnettRosenberg(1926-2009;hisfriendscalledhim"Barney")(Figure3.2)wasabiophysicist,workinginasmalllaboratoryatMichiganStateUniversitywithjustoneassistant.HehadgraduatedfromBrooklynCollegein1948andobtainedaPhDinphysicsfromNewYorkUniversityin1956.Asabiophysicist,anaturalwaytocombinebiologyandphysicsinthoseearlydayswastoexaminetheeffectsofelectriccurrentonthegrowthofbacteria;thetechniquesforsuchastudywerestraightforwardandeasilysetupinamodestlaboratory.Therewaslittlereasontoexpectanyinterestingfindings.

4

Hereiswhathappened((Rosenbergetal.,1965),andfromwhathetoldme).BarneyhadacultureofE.colibacteriagrowinginagrowthmediuminwhichhehadinserted2electrodesconnectedupsoastopassanelectriccurrentthroughthemediumwhilethebacteriawereintheregrowinganddividing.Theelectrodesweremadeofplatinum,whichwasconsideredtobeaninertmetalthatwouldnotreactchemicallywithanythingintheculture.Oneday,accordingtoBarney,theculturedidn'tgrow.Hethoughthistechnicianmusthaveforgottentoinoculatethebacteriaintothebroth.Thetechnicianmayhaveknownthathedidindeedinoculateit,butthoughtthat,well,he'dinoculateitagaininthemorning.Butthebrothwasperfectlygood,hethought,sowhybotherpreparingitagaininthemorning,sohejustputitintotherefrigerator.Nextday,despiteafreshinoculumofbacteria,stillnothingseemedtobegrowinginthatoldmedium.Now,undersimilarcircumstance,manyaresearcherwouldhavejustdumpedtheoldmediumandstartedfresh.ButRosenbergwascurious,sohetookabitofthemedium,whichwasstillperfectlyclear,asifnothingwasgrowing--andlookedatitunderthemicroscope.Whathesawwasastonishing.(HxCaDrugDiscFigscisplatin160128g.pptx)

5

Figure3.3.Theplatinumcomplexpreventedthebacteriafromdividing,butallowedthemtogrowintolongfilaments.E.coligrownwithout(left)orwith(right)anactiveplatinumcomplex(X600)(Rosenbergetal.,1967a).E.colibacteriaarenormallyshortrods.ButwhatRosenbergsawunderthemicroscopewerelongfilaments(Figure3.3).ItseemedthattheE.coliweregrowinginlengthbutnotdividing.Itisimpossibletoknowexactlywhatwasgoingthroughhismindwhenhesawthat,butitmighthavebeensomethinglikethis:Thereissomethinginthismediumthatispreventingthebacteriafromdividing,eventhoughitisallowingthemtogrowinsubstance,therebyproducingthoselongthreads.Ithasrecentlybeenreported,hemighthavereasoned,thatx-raysandagentslikenitrogenmustarddoexactlythat:theyletthebacteriagrow,butinhibittheirabilitytodivide:theywerereportedtogrowintolongthreadsjustlikewhatisherenowinthismedium.Furthermore,xraysandnitrogenmustardhaveanticanceractivity.So,maybeananti-cancersubstancemightsomehowhavegottenintothemedium.Buthow?Theonlythingdifferentfromtheoriginalmediuminwhichthebacteriaweregrowingnormallyisthattherewerethinplatinumbars(theelectrodes)immersedinitandIhadpassedanelectriccurrentthroughthem.Butplatinummetalischemicallyinert.Orisit?Whatabouttheelectricitythatwasgoingthroughthoseplatinumelectrodes?Itmighthavecausedsomeplatinumatomstocomeoffandbindtotheammoniaorchlorideinthemedium.Sothatwasit!Followinguponthoseideas,Rosenbergorderedseveralplatinumcomplexesthatwereavailablefromachemicalsupplycompany.Hesoondiscoveredtheactivematerialthatpreventedthebacteriafromdividingwhileallowingthemtogrowintolongthreads:itwasindeedacomplexofplatinumwithammoniaandchloride(Rosenbergetal.,1967b);itwasinfactthedrugthatwenowcallcisplatin(Figure3.1).Inshortorder,itwastestedattheNationalCancerInstituteandattheChesterBeattyinEnglandforanti-canceractivityinmice.Andtheresultswerespectacular!Theanticanceractivityoftheplatinumcomplexwasastounding.Moreover,whencisplatinwascombinedwithotherdrugs,suchas

6

cyclophosphamide,theanti-cancereffectswereevenmoreimpressive(RosenbergandVanCamp,1970)(Woodmanetal.,1973).Howitworks:cisplatinandnitrogenmustardarechemicalcousins.Thechemicalstructuresofcisplatinandnitrogenmustardmaylookverydifferent(Figure3.4).NeverthelesstheybothworkbycrosslinkingDNA(Zwellingetal.,1981).ThefavoredsiteofattackonDNAisthesameforcisplatinandnitrogenmustard:thenitrogenatposition7ofguanine.Theonlysimilaritybetweenthetwostructuresisthateachhas2chlorineatoms,whichindeedisthekeytothesimilarityintheirchemicalactions.Inbothdrugs,eachchlorinecancomeoff,leavingbehindareactivesitecapableofformingacovalentbondwithDNAorproteins.Bothdrugshave2reactivesiteswherebyDNAcanbecomecrosslinked.Althoughcisplatin,likenitrogenmustard,canproduceinterstrandcrosslinks(Zwellingetal.,1981),cisplatindiffersinthatitmorefrequentlyproducesDNA-disablingintra-strandcrosslinks(Figure5).Crosslinkrepairisparamounttothedrug-treatedcell'ssurvival.ThecellhashighlyeffectiveDNArepairmechanisms,whichhoweverarenotfoolproof.SometimesitleavestherepairedDNAwithmissingbases,thusproducingmutations.Howevertherewasapuzzleaboutcisplatin:thepowerfulantitumoractionofcisplatinwascompletelyabolishedifthe2chlorineatomswereacrossfromeachother(transconfiguration)ratherthannexttoeachotherasincisplatin(cisconfiguration).(Figure3.4).LeonardZwelling,whowasthenaClinicalAssociateinmylaboratory,decidedtoinvestigatethispuzzleusingtheDNAfilterelutionmethodswehadbeendevelopingatthattimetomeasurebothDNAinter-strandandDNA-proteincrosslinks(Kohn,1996).Len'sresultswerequiteremarkable:heshowedthatthetranscompoundproducedalmostexclusivelyDNA-proteincrosslinks,andlackedthepotentcell-killingandmutation-producingactionsofcisplatin(Zwellingetal.,1979a;Zwellingetal.,1979b).Evidently,havingtheactivechlorinesacrossfromeachother(transgeometry)wasunsuitedforDNAcrosslinking,whereasiteasilycrosslinkedbetweenDNAandproteins.Wewerethenabletomeasuretheratesofformationandrepairofbothtypesofcrosslinks.Thetrans-platinumcompoundthenwasalsousefulinourdevelopingamethodtoquantifyDNA-proteincrosslinks(KohnandEwig,1979),amethodthatprovedkeytothediscoveryoftopoisomerase-targetedanti-cancerdrugs(seeChapter8).

7

Figure3.4.Thechemicalstructuresofcisplatinandnitrogenmustardlookdifferent,buttheirkeychemicalreactionsaresimilar.Nitrogenmustardhas2carbonsseparatingtheClfromtheN;thatarrangementfacilitatesthelossoftheCl,leavingbehindareactivegrouponthemolecule(seeChapter1).Cisplatintooismadereactivebythelossofachloride,whichisfacilitatedbyanabundanceofwatermoleculesthatreplacetheCl–.Inbothmolecules,twochlorinesareessential,becausethedepartureofeachoneleavesbehindanactivecenter,thusallowing2reactionstoformacrosslink;the2chlorinesincisplatinhavetobenexttoeachotherforthegeometrytoallowcrosslinkingofDNA.(HxCaDrugDiscFigscisplatin160128g.pptx)

Figure3.5.Afterits2chlorineionshavecomeoff(andreplacedby2watermolecules),cisplatincanbindto2guaninesonthesameDNAstrand.Theresultingintra-strandcrosslinkdistortstheDNA,whichhastoberepairedbeforetheDNAcancontinuetofunction;butiftherepairfails,thecrosslinkhaslethalpotential.Cisplatin’splatinumatom(Pt)bindstothesamenitrogenatomonguanines(GN7)

8

asnitrogenmustarddoes,althoughnitrogenmustardmoreoftenformsinter-strandcrosslinks(Figure3.5).Althoughitmayseemsurprising,the2DNAcrosslinkingdrugs,cisplatinandcyclophosphamide(aderivativeofnitrogenmustard),sometimesaremoreeffectivewhenusedtogether(synergistic)thaneitherofthemusedalone(Woodmanetal.,1973).ThereasonmaybethatthecrosslinksproducedbythetwodrugsproducedifferentalterationsinDNAstructure,suchasintra-versusinter-strandcrosslinks,whicharerepairedbydifferentmolecularsystems.Sometumorcellsmayhaveahighabilitytorepaironeortheothertypeofcrosslink,whilerelativelyfewcouldrepairbothtypeswell.FromcisplatintocelldeathThereisjoywhenapatient’scancerrespondstochemotherapy.Thefactorsthatdeterminewhetherthecancerwillrespondhoweverwerecomplicatedandnotverywellunderstood.Muchattentionwaspaidonidentifyingfactorsthatgavesomedegreeofpredictabilityofresponse.Someofthemwereempiricalclinicalfactorsandsomewerephysiology-ormolecular-basedandallweregivenmuchattentionaschemicalandmoleculardetailswereelucidated.AgeneralideaofwhatisinvolvedisshowninFigure3.7,whichisanoverviewofsomeofthemainfactorsthatwerethoughttodeterminewhetheracisplatin-treatedcellwillliveordie.Asthestepsgoverningcancercellkillingwereelucidated,thatinformationwasusedtohelpimprovetheclinicaleffectivenessoftheplatinumdrugs(Galluzzietal.,2014;Kelland,2007;O'Gradyetal.,2014).Themainreactionstepsthatwerefoundtoaffectthedeathorsurvivalofcisplatin-treatedcellsarediagrammedinFigure3.7:First,cisplatinhastopassthroughthecell’splasmamembranetogetintothecell,whichoccursinpartbywayofspecificchannelsinthemembranethatnormallyallowessentialcoppercompoundstoenter.Particularlyimportanthoweverareotherchannels,whichactivelypumpcisplatin(normallycopper)outofthecell.Theintakeandexportchannelsaffecthowmuchcisplatinisinsidethecell(aandbinFigure3.7).(Whenthoseparticularexportpumpsaredefective,copperisknowntoaccumulateincellsandcauseWilson’sdisease.OnemightexpectthatcisplatinwouldalsoaccumulateinthecellsofWilson’sdiseasepatients,therebymakingthosecells,whethernormalorcancerousmoresensitivetothedrug.)Onceinsidethecell,cisplatinbecomesactivatedbyitsplatinum-boundchloridesbeingreplacedbywatermolecules(cinFigure3.7).Thereasonthatthisreplacementactivatescisplatinisthattheplatinum-waterbondisweak,andtheplatinumatomwouldmuchratherbindtoanitrogenatom,suchas,forexample,theoneatposition7ofguanineinDNA.Thatwouldbethefirstbondinaprospective

9

DNAcrosslink.Themainreasonthatthischloride-waterreplacementoccursinsidethecell,butnotoutside,isthattheconcentrationoffreechlorideismuchlowerinsidethecellthanoutsideintheblood.Whencisplatinhasbeenwater-activated(seemsoddtoputitthatway,soscientistsinsteadsay“aquated”),whathappensnext?SometimestheaquatedcisplatinwillbindtoN7ofDNAguanine,asmentionedabove;thattoxicreactionhoweverisrelativelyrareoverall,butitsimpactoverridesitsrarity.Moreoften,theaquatedcisplatinwillbecomeinactivatedbybindingtightlytooneofthemanysulfurcompoundsinthecell(suchasglutathione,acommonsulfhydrylcompound,ortometallothione,ametal-bindingproteinthathasalargenumberofexposedsulfhydrylgroups)--platinumlovessulfur(dinFigure3.7).TheaquatedsiteontheotherarmofcisplatincanthenproceedtoformDNAcrosslinks(einFigure3.7).TheresultingDNAdamageisdetectedbyasurveillancesystems,whichsignaltothecell’smolecularresponsesystemsthatdangerisafoot(finFigure3.7).ThesignalsactivearemarkablenetworkoflogicallyintegratedcomponentsthatcausethecelltodelayDNAreplicationandcelldivisioninordertogivemoretimeforthecelltoadaptandtorepairthedamagebeforethereplicationmachinerybogglesbytryingtoreplicatethroughacrosslink,orthechromosomesscrambleifthecelltriestomitosewhileitsgenomeisunrepaired.Italsoputsthecell’sDNArepairmachineryonhighalert(gandhinFigure3.7).Afterallthat,ifDNAcrosslinksstillremainasthecelltriestomoveforwardinthecelldivisioncycle,alethaleventmayoccurwhentheDNAreplicationmachineryencountersacrosslink(iinFigure3.7).Anotherprocessthatdetermineslifeordeathforthecellcomesasanoutputfromthe damage detection and response network. If the damage persists too long, thesystemtakesnochancesandactivelysuicidesthecell--aficionadoscallit“apoptosis”(fromGreek“fallingoff,”asinfallingoffofleaves)(jinFigure3.7).Thishelpsavoidthe production of mutated cells that could lead to cancer. However, apoptosis ofcancer cells obviously is desirable and is a positive factor for chemotherapeuticresponse.

10

Figure3.7.Simplifiedschemeshowingfactorsthatwwerethoughttogoverntheeffectsofcisplatinoncells.aChannelsallowcisplatintoenterthecell.bChannelsthatpumpcisplatinoutofthecell.cCisplatinbecomesactivatedinsidethecellbyitschloridesbeingreplacedbywatermolecules(favoredinsidethecell,wherechlorideconcentrationislow).dCisplatincanreactwithsulfur-containingmoleculesinsidethecelltoforminactiveproducts.eCisplatinproducesDNAcrosslinks.fDNAcrosslinksstimulatethecell’sDNAdamagedetectionandresponsesystems.gDNArepairmachineryofthecellrepairsthecrosslinks.hDNAdamageresponsesystemstimulatesthecell’sDNArepairmachinery.iUnrepairedDNAcrosslinksleadtodeathofthecell.jIftheDNAdamagerepairsystemfails,itinducesthecelltosuicidebyapoptosis(Galluzzietal.,2014)(O'Gradyetal.,2014).DaC'16Fig7cisptpharkinscheme150126dCisplatindamagesthekidneyThemaintoxicitythatlimitedhowmuchcisplatincouldsafelybegivenwasdamagetothekidneys(Figure3.8).Cisplatinisactivelytakenupbycellsofthekidneytubules,resultingindeleteriousdrugconcentrationsinthecells(Yaoetal.,2007).Althoughtheproblemwasnotfullysolved,thekidneytoxicitywasreducedbygivingpatientslotsoffluidanddiureticsinordertoincreaseurineflowthatwouldreducetheconcentrationofthedrugintheurineasitflowsthroughthekidney.

11

Figure3.8.Damagetocellsofthekidneytubulesafteracourseofcisplatintreatmentinmice(Krugeretal.,2016).TheyellowarrowspointtosomeofthecellnucleithathavesustainedextensiveDNAdamage(asrevealedbystainingwithantibodytogamma-H2AX:seeChapter10).Aftercisplatintreatment(right),thenumberofDNAdamagedcellsincreased6-foldcomparedwithuntreatedcells(left).Whysomepatientsrefusedtotakecisplatin.Cisplatin-containingtherapymademostpatientssonauseousthatmanycouldnotstandit.Evenenteringthehospitalwherethedrugwasgivenwassometimessufficienttotriggernausea.Manychemotherapeuticdrugscancausenausea,butcisplatinstoodoutasanextremecase,andthevomitingitinducedwassometimesalarming.Thecausemightbeadirectactiononcertaincentersinthebrain,butdrugstointerferewiththatdirectactionwerenotyetavailable.Ordinaryavailablemedicationscontrolednauseathatoccuredshortlyafterthedrugwasadministered.Howevernauseaoccuredlater(perhapsafterthedrughadenteredandaffectedcertainneuronsinthevomitingcenterinthebrainstem),atwhichtimeitwasnoteasilycontrolled(DeJongheetal.,2016;Ishidoetal.,2016;Shietal.,2016).TreatmentofcancerpatientswithCisplatinandrelateddrugs.Thetestingofcisplatinintumor-bearingmice,whichbeganin1968,producedresultsthatweresoencouragingthatonly3yearslaterthefirstclinicaltrialwasbegun.Thatwasaremarkablyshorttimebetweenfindinganti-tumoractivityinmiceandapprovalforclinicaltrial.Notonlywastherestrongevidenceofantitumoractivity,butthetoxicityanddose-levelswerewellenoughunderstoodtotrythedrugonhumanpatients.Substantialantitumoreffectwasfirstreportedin1974fortesticularandovariancancer,andseveralsubsequentclinicaltrialsreportedincreasedsurvivalalsoinlungcancerpatients(LebwohlandCanetta,1998).Moreover,cisplatinwasunusualbecauseitwasnottoxictotheblood-formingcells

12

inthebonemarrow.By1978,thebenefittocancerpatientswaspromisingenoughtomakecisplatinavailableforgeneraloncologypractice.Modifyingthechemicalstructureofcisplatininsearchforbetterdrugs.Manyvariationsonthecisplatinstructureweretestedinasearchforcompoundswithincreasedeffectivenessagainstagreatervarietyoftumors,withlesstoxicity,orwithlackofcross-resistancetocisplatin(LebwohlandCanetta,1998).Twostructuralrelativesbecamewidelyused:carboplatinandoxaliplatin(Figure3.9).Incarboplatin,thetwochlorineatomsarereplacedbyachemicalgroupthathastwocarboxyl(COO-)groupsattachedtotheplatinumatom(Figure3.9).Thecarboxylgroupsactivatetheplatinuminthesamewaythatthechloridesdo,thatis,bybeingreplacedbywatermolecules;however,carboplatinisactivatedmoreslowlythancisplatin.Anotherfeatureisthatthetwocarboxylgroupsarepartofastructuralunitthatwouldfavorbothcarboxylscomingoffatthesametime;thusthetwoplatinumsiteswouldbeaquatedtogether,settingthestageforefficientcrosslinkproduction.CarboplatinformsthesamekindsofDNAcrosslinksascisplatin,butformsthem10-timesmoreslowly,and30-timeshigherdrugconcentrationsareneeded.Theclinicalbenefitintermsofincreasedsurvivaltimehoweverwasnotverydifferentfromcisplatin;themainbenefitofcarboplatinwasthatitislesstoxic;itdidnotdamagethekidneys,andsparedthegastrointestinaltractandcentralnervoussystem;itsdose-limitingtoxicity,instead,wassuppressionofplateletandwhitebloodcellproductioninthebonemarrow(Kelland,2007;LebwohlandCanetta,1998).Inoxaliplatin,likecarboplatin,thechloridesarereplacedbycarboxylgroupsinastructuralunit.Unlikecisplatinandcarboplatin,however,thetwoaminogroupsarelinkedtogetherviaa6-memberedring,acyclohexylgroup(Figure3.9).Oxaliplatin-mediatedDNAcrosslinksthereforeretainthiscyclohexylstructure,whichmightimpairthebindingofsomeDNArepairproteinstothedamagesite.Anotablefindingintheclinicalexperiencewithoxaliplatinwasthat,unlikecarboplatin,itsometimeswaseffectiveinpatientswhosetumorshadstoppedrespondingtocisplatin(Kelland,2007).

13

Figure3.9.Theupperrowshowsthechemicalstructuresofcisplatinanditstworelativesthatweremostcommonlyused:carboplatinandoxaliplatin.ThebottomrowshowsthestructuresoftheDNAintra-strandcrosslinksformedbyeachofthedrugs.TheDNAcrosslinkproducedbyoxaliplatindiffersfromthekindproducedbycisplatinorcarboplatininthatishasanadditional6-memberedring(cyclohexylgroup)stickingoutfromtheDNA;thismayblockthebindingofsomeDNArepairproteins,andmaybewhyoxaliplatinsometimesworksagainsttumorsthatareresistanttocisplatinorcarboplatin(Chaneyetal.,2005;Kelland,2007)..CisplatinandthecureofadvancedtesticularcancerThegreatestbenefitofcisplainwasforpatientswithtesticularcancer:cisplatinproducedlastingremissionsinnearly80%ofthecases,andmostofthepatientswhohavethecommongermcelltypeoftesticularcancerwerecuredwithadrugcombinationbasedoncisplatin(Figure3.10).Germcellcancerofthetestis,althoughrelativelyrare,wasoneoftheveryfewtypesofcancersthatcouldbecuredbychemotherapyafterhavingspread(metastasized).Whatmadethatpossiblewastheadditionofcisplatintothepreviousdrugcombinationsthatbythemselvesweremuchlesseffective(Einhorn,1997;Einhorn,1981;Hintonetal.,2003).Thesusceptibilityoftesticularcancertochemotherapywasinpartduetoarelativelyrapidcellproliferationratecomparedtoothercancers,andtothefactthattesticularcancersrarelybecomedormant.Tumorswithactivecelldivisiontendedtobesusceptibletochemotherapy,aswasthecaseforacuteleukemiasandchoriocarcinoma,andthesetumorswereoftencured(seeChapter…).Alsocontributingtotheirbeingcurable,maybethattesticularcancersarenearlyunabletorepairtheDNAdamagecausedbythedrug.(Kelland,2007).

14

Figure3.10.Acancercure.Patientswithtesticularcancerthathadalreadyspreadweretreatedwithacisplatin-baseddrugcombination.Thethreecurvesareforpatientswhowerejudgedatthebeginningoftreatmenttohaveagood,intermediate,orpoorprognosis,basedonhowadvancedtheirdiseasewasatthetime.Theresultsshowedthatpatientswhosediseasewasnothighlyadvancedhadgreaterthan80%chanceofremainingaliveafter10years;evenhighlyadvancedcaseshada50%chance(Hintonetal.,2003).Thecurvesleveledoffwithtime,showingthatpatientswhosurvivedthefirstfewyearswereunlikelytodieofthediseaseintheyearstocome.(HxCaDrugDiscFigscisplatin160128g.pptx)SummaryCisplatin,whichbecameoneofthemostusefulanticancerdrugs,wasdiscoveredastheresultofanaccidentaleventinaverymodestlaboratory.ItsdiscoverywasduetoboldthinkingbyBarnett(Barny)Rosenberg.Thestoryisremarkable,becausetherehadbeennocluethataheavymetalcompound,suchascisplatin,couldhaveanticanceractivity,andthemajordrugdiscoveryprogramshadneverconsideredtestingsuchcompounds.Cisplatintherapywassopromisingthatgreateffortwasmadetoovercomethedrug’stoxicities,andthoseeffortshadsignificantsuccess.Cisplatinwashighlyeffectiveandenabledthecureoftesticularcancer.Theaimthenwastomodifycisplatin-typetherapysoastofindtreatmentsthatwouldbeaseffectiveforthecommoncancersascisplatinwasfortesticularcancer.Onepossibilitywasthat

15

higherdrugdosescouldbeusediftoxicitywerecontrolled.Anotherpossibilitywastodevelopbetterplatinumdrugsorbetterdrugcombinations.Themajortoxicityofcisplatinwaskidneydamage,whichhoweverwaslargelyovercomebyincreasedhydrationofthepatient.Manyvariationsofthecisplatinstructurewereputinclinicaltrial,butnothingwasfoundbetterthantheoldstandbys:cisplatin,carboplatin,andoxaliplatin.Unfortunately,manycancerpatientswerenothelpedbyanyplatinumregimensorotheravailablechemotherapy.Whentumorregressionoccurred,itwasoftenbriefandsurvivalwasextendedforbutafewmonths.Butcompletedurableremissiondidsometimesoccur,whichgavereasonforhope,especiallyiftheexactreasonsfortheeffectivenessagainsttesticularcancercouldbeworkedout.ReferencesChaney,S.G.,Campbell,S.L.,Bassett,E.,andWu,Y.(2005).Recognitionand

processingofcisplatin-andoxaliplatin-DNAadducts.Criticalreviewsinoncology/hematology53,3-11.

DeJonghe,B.C.,Holland,R.A.,Olivos,D.R.,Rupprecht,L.E.,Kanoski,S.E.,andHayes,M.R.(2016).HindbrainGLP-1receptormediationofcisplatin-inducedanorexiaandnausea.Physiology&behavior153,109-114.

Einhorn,E.H.(1997).Testicularcancer:anoncologicalsuccessstory.Clinicalcancerresearch:anofficialjournaloftheAmericanAssociationforCancerResearch3,2630-2632.

Einhorn,L.H.(1981).Testicularcancerasamodelforacurableneoplasm:TheRichardandHindaRosenthalFoundationAwardLecture.Cancerresearch41,3275-3280.

Galluzzi,L.,Vitale,I.,Michels,J.,Brenner,C.,Szabadkai,G.,Harel-Bellan,A.,Castedo,M.,andKroemer,G.(2014).Systemsbiologyofcisplatinresistance:past,presentandfuture.Celldeath&disease5,e1257.

Hinton,S.,Catalano,P.J.,Einhorn,L.H.,Nichols,C.R.,DavidCrawford,E.,Vogelzang,N.,Trump,D.,andLoehrer,P.J.,Sr.(2003).Cisplatin,etoposideandeitherbleomycinorifosfamideinthetreatmentofdisseminatedgermcelltumors:finalanalysisofanintergrouptrial.Cancer97,1869-1875.

Ishido,K.,Higuchi,K.,Azuma,M.,Sasaki,T.,Tanabe,S.,Katada,C.,Yano,T.,Wada,T.,andKoizumi,W.(2016).Aprepitant,granisetron,anddexamethasoneversuspalonosetronanddexamethasoneforprophylaxisofcisplatin-inducednauseaandvomitinginpatientswithuppergastrointestinalcancer:arandomizedcrossoverphaseIItrial(KDOG1002).Anti-cancerdrugs.

Kelland,L.(2007).Theresurgenceofplatinum-basedcancerchemotherapy.NaturereviewsCancer7,573-584.

Kohn,K.W.(1996).DNAfilterelution:awindowonDNAdamageinmammaliancells.BioEssays:newsandreviewsinmolecular,cellularanddevelopmentalbiology18,505-513.

16

Kohn,K.W.,andEwig,R.A.(1979).DNA-proteincrosslinkingbytrans-platinum(II)diamminedichlorideinmammaliancells,anewmethodofanalysis.Biochimicaetbiophysicaacta562,32-40.

Kruger,K.,Ziegler,V.,Hartmann,C.,Henninger,C.,Thomale,J.,Schupp,N.,andFritz,G.(2016).Lovastatinpreventscisplatin-inducedactivationofpro-apoptoticDNAdamageresponse(DDR)ofrenaltubularepithelialcells.Toxicologyandappliedpharmacology292,103-114.

Lebwohl,D.,andCanetta,R.(1998).Clinicaldevelopmentofplatinumcomplexesincancertherapy:anhistoricalperspectiveandanupdate.EurJCancer34,1522-1534.

O'Grady,S.,Finn,S.P.,Cuffe,S.,Richard,D.J.,O'Byrne,K.J.,andBarr,M.P.(2014).TheroleofDNArepairpathwaysincisplatinresistantlungcancer.Cancertreatmentreviews40,1161-1170.

Petsko,G.A.(2002).Achristmascarol.Genomebiology3,COMMENT1001.Rosenberg,B.,Renshaw,E.,Vancamp,L.,Hartwick,J.,andDrobnik,J.(1967a).

Platinum-inducedfilamentousgrowthinEscherichiacoli.Journalofbacteriology93,716-721.

Rosenberg,B.,VanCamp,L.,Grimley,E.B.,andThomson,A.J.(1967b).TheinhibitionofgrowthorcelldivisioninEscherichiacolibydifferentionicspeciesofplatinum(IV)complexes.TheJournalofbiologicalchemistry242,1347-1352.

Rosenberg,B.,andVanCamp,L.(1970).Thesuccessfulregressionoflargesolidsarcoma180tumorsbyplatinumcompounds.Cancerresearch30,1799-1802.

Rosenberg,B.,Vancamp,L.,andKrigas,T.(1965).InhibitionofCellDivisioninEscherichiaColibyElectrolysisProductsfromaPlatinumElectrode.Nature205,698-699.

Shi,Q.,Li,W.,Li,H.,Le,Q.,Liu,S.,Zong,S.,Zheng,L.,andHou,F.(2016).Preventionofcisplatin-basedchemotherapy-induceddelayednauseaandvomitingusingtripleantiemeticregimens:amixedtreatmentcomparison.Oncotarget.

Woodman,R.J.,Sirica,A.E.,Gang,M.,Kline,I.,andVenditti,J.M.(1973).Theenhancedtherapeuticeffectofcis-platinum(II)diamminodichlorideagainstL1210leukemiawhencombinedwithcyclophosphamideor1,2-bis(3,5-dioxopiperazine-1-yl)propaneorseveralotherantitumoragents.Chemotherapy18,169-183.

Yao,X.,Panichpisal,K.,Kurtzman,N.,andNugent,K.(2007).Cisplatinnephrotoxicity:areview.TheAmericanjournalofthemedicalsciences334,115-124.

Zwelling,L.A.,Anderson,T.,andKohn,K.W.(1979a).DNA-proteinandDNAinterstrandcross-linkingbycis-andtrans-platinum(II)diamminedichlorideinL1210mouseleukemiacellsandrelationtocytotoxicity.Cancerresearch39,365-369.

Zwelling,L.A.,Bradley,M.O.,Sharkey,N.A.,Anderson,T.,andKohn,K.W.(1979b).Mutagenicity,cytotoxicityandDNAcrosslinkinginV79Chinesehamstercellstreatedwithcis-andtrans-Pt(II)diamminedichloride.Mutationresearch67,271-280.

Zwelling,L.A.,Michaels,S.,Schwartz,H.,Dobson,P.P.,andKohn,K.W.(1981).DNAcross-linkingasanindicatorofsensitivityandresistanceofmouseL1210

17

leukemiatocis-diamminedichloroplatinum(II)andL-phenylalaninemustard.Cancerresearch41,640-649.