r|nc|p|es of Ant|neop|ast|c Chemotherapy kes|stance to Ant|neop|ast|c Agents atterns of 1ox|c|ty 8|o|og|c kesponse Mod|f|ers |n Cancer 1herapy Safe nand||ng of Ant|neop|ast|c Chemotherapeut|c Agents C|ass|f|cat|on of Ant|neop|ast|c Chemotherapeut|c Agents
AnLlneoplasLlc chemoLherapy ls an lmporLanL componenL of small anlmal pracLlce and ls rouLlnely used for selecLed Lumors of horses and caLLle LffecLlve use of anLlneoplasLlc chemoLherapy depends on an undersLandlng of baslc prlnclples of cancer blology drug acLlons and LoxlclLles and drug handllng safeLy 1umor CrowLh and 8esponse Lo ChemoLherapy 1he fundamenLal blochemlcal and geneLlc dlfferences beLween cancer cells and normal cells are noL clearly undersLood none of Lhe emplrlcally developed anLlneoplasLlc drugs appears Lo acL on a process or componenL LhaL ls enLlrely unlque Lo cancer cells Cllnlcally useful drugs achleve a degree of selecLlvlLy on Lhe basls of cerLaln characLerlsLlcs of cancer cells LhaL can be used as pharmacologlc LargeLs 1hese characLerlsLlcs lnclude rapld raLe of dlvlslon and growLh varlaLlons ln Lhe raLe of drug upLake or ln Lhe senslLlvlLy of dlfferenL Lypes of cells Lo parLlcular drugs and reLenLlon ln Lhe mallgnanL cells of hormonal responses characLerlsLlc of Lhe cells from whlch Lhe cancer ls derlved eg esLrogen responslveness of cerLaln breasL carclnomas AspecLs of normal cell growLh and Lhe cell cycle provlde Lhe raLlonale for and are of ma[or lmporLance ln Lhe successful appllcaLlon of anLlneoplasLlc chemoLherapy ln Lhe S phase unA synLhesls occurs Lhe M phase beglns wlLh mlLosls and ends wlLh cyLoklnesls and Lhe C o phase ls a dormanL or nonprollferaLlve phase of Lhe cell cycle 1umor doubllng Llme ls relaLed Lo Lhe lengLh of Lhe cell cycle and Lhe growLh fracLlon (Lhe proporLlon of a populaLlon of cells undergolng cell dlvlslon) AnLlneoplasLlc agenLs can be classlfled accordlng Lo a number of schemes relaLlve Lo effecLs aL dlfferenL sLages of Lhe cell cycle ln Lhe slmplesL sense cycle nonspeclflc agenLs are consldered Lo be leLhal Lo cells ln all phases of Lhe cell cycle Cells are kllled exponenLlally wlLh lncreaslng drug levels and Lhe doseresponse curves follow flrsLorder klneLlcs hasespeclflc agenLs exerL Lhelr leLhal effecLs excluslvely or prlmarlly durlng one phase of Lhe cell cycle usually S or M Lhe greaLer Lhe raLe of cell dlvlslon Lhe more effecLlve Lhe drug 1he C o phase of Lhe cell cycle ls lmporLanL noL as a LargeL for chemoLherapeuLlc agenLs buL as a Llme durlng whlch dormanL Lumor cells can escape Lhe effecLs of drug Lherapy
rlnclples of AnLlneoplasLlc ChemoLherapy 1he declslon Lo use anLlneoplasLlc chemoLherapy depends on Lhe Lype of Lumor Lo be LreaLed Lhe sLage of mallgnancy Lhe condlLlon of Lhe anlmal and flnanclal consLralnLs ChemoLherapy can be used as an ad[uvanL Lo surgery and lrradlaLlon and can be admlnlsLered lmmedlaLely afLer or before Lhe prlmary LreaLmenL neoad[uvanL Lherapy ls admlnlsLered before surgery or lrradlaLlon and ls lnLended Lo lmprove Lhe effecLlveness of Lhe prlmary Lherapy by posslbly decreaslng Lumor slze sLage of mallgnancy or presence of mlcromeLasLaLlc leslons 8esponses Lo cancer chemoLherapy can range from palllaLlon (remlsslon of secondary slgns generally wlLhouL lncrease ln survlval Llme) Lo compleLe remlsslon (ln whlch cllnlcally deLecLable Lumor
cells and all slgns of mallgnancy are absenL) 1he percenLage and duraLlon of compleLe remlsslons are crlLerla for Lhe success of a parLlcular chemoLherapeuLlc proLocol LffecLlve cllnlcal use of anLlneoplasLlc drugs depends on Lhe ablllLy Lo balance Lhe kllllng of Lumor cells agalnsL Lhe lnherenL LoxlclLy of many of Lhese drugs Lo hosL cells 8ecause of Lhelr narrow LherapeuLlc lndlces dosages for anLlneoplasLlcs are frequenLly calculaLed based on body surface area (8SA) raLher Lhan body mass Powever evldence suggesLs LhaL small dogs and caLs may besL be LreaLed based on body welghL Lo avold overdosage 1hls ls especlally Lrue lf Lhe prlmary LoxlclLy ls bone marrow suppresslon ApparenLly 8SA does noL correlaLe well wlLh elLher sLem cell number ln Lhe bone marrow or resulLlng hemaLopoleLlc LoxlclLy CorrelaLlon ls beLLer beLween body welghL and Lhese LoxlclLles AnLlneoplasLlc agenLs are admlnlsLered by Lhe C lv SC Loplcal lnLracavlLary lnLraleslonal lnLraveslcular or arLerlal rouLes 1he rouLe chosen depends on Lhe lndlvldual agenL and ls deLermlned by drug LoxlclLy locaLlon slze and Lype of Lumor and physlcal consLralnLs AnLlneoplasLlc agenLs are commonly admlnlsLered ln varlous comblnaLlons of dosages and Llmlng Lhe speclflc reglmen ls referred Lo as a proLocol A proLocol may use 1 or as many as 3 or 6 dlfferenL anLlneoplasLlc agenLs SelecLlon of an approprlaLe proLocol should be based on Lype of Lumor grade or degree of mallgnancy condlLlon of Lhe anlmal and flnanclal consLralnLs references of lndlvldual cllnlclans for LreaLmenL of speclflc neoplasLlc condlLlons may also vary 8egardless of Lhe proLocol chosen a Lhorough knowledge of Lhe mechanlsm of acLlon and LoxlclLles of each lndlvldual LherapeuLlc agenL are essenLlal ComblnaLlon anLlneoplasLlc chemoLherapy offers many advanLages urugs wlLh dlfferenL LargeL slLes or mechanlsms of acLlon are used LogeLher Lo enhance desLrucLlon of Lumor cells lf Lhe slde effecLs of Lhe componenL agenLs are dlfferenL Lhe comblnaLlon may be no more Loxlc Lhan Lhe lndlvldual agenLs glven separaLely ComblnaLlons LhaL lnclude a cyclenonspeclflc drug admlnlsLered flrsL followed by a phasespeclflc drug may offer Lhe advanLage LhaL cells survlvlng LreaLmenL wlLh Lhe flrsL drug are provoked lnLo mlLosls and Lherefore are more suscepLlble Lo Lhe second drug AnoLher advanLage of comblnaLlon Lherapy ls Lhe decreased posslblllLy of developmenL of drug reslsLance Speclal conslderaLlons assoclaLed wlLh admlnlsLraLlon of anLlneoplasLlc drugs lnclude evaluaLlon of Lhe anlmal's quallLy of llfe medlcal and nuLrlLlonal supporL conLrol of paln and psychologlcal comforL for Lhe owner Many owners who choose Lo LreaL neoplasla ln Lhelr peLs have experlenced cancer Lhemselves or have been lnvolved wlLh lndlvlduals or famlly members who have had cancer ulscusslon of neoplasla ln peLs should be handled LacLfully and should provlde Lhe owners wlLh approprlaLe lnformaLlon for declslonmaklng
8eslsLance Lo AnLlneoplasLlc AgenLs lallure Lo respond or reslsLance Lo anLlneoplasLlc agenLs can be seen for several reasons harmacoklneLlc reslsLance ls seen when Lhe concenLraLlon of a drug ln Lhe LargeL cell ls below LhaL requlred Lo klll Lhe cell 1hls may be due Lo alLered raLes of drug absorpLlon dlsLrlbuLlon bloLransformaLlon or excreLlon ln addlLlon marglnal blood flow Lo a Lumor may noL provlde sufflclenL drug resulLlng ln lnadequaLe LherapeuLlc drug concenLraLlons and creaLlon of a populaLlon of qulescenL less suscepLlble cells CyLoklneLlc reslsLance ls seen when Lhe Lumor cell populaLlon ls noL compleLely eradlcaLed Lhls may be a resulL of dormanL Lumor cells dose llmlLlng hosL LoxlclLy assoclaLed wlLh drug Lherapy or Lhe lnablllLy Lo achleve a 100 klll raLe even aL LherapeuLlc drug dosages 8eslsLance can also develop vla blochemlcal mechanlsms wlLhln Lhe Lumor cell lLself LhaL block LransporL mechanlsms for drug upLake alLer LargeL recepLors or enzymes crlLlcal Lo drug acLlon lncrease concenLraLlons of normal meLabollLes
anLagonlzed by Lhe anLlneoplasLlc drug or cause geneLlc changes LhaL resulL ln proLecLlve gene ampllflcaLlon or alLered paLLerns of unA repalr Acqulred mulLldrug reslsLance can resulL from ampllflcaLlon and overexpresslon of a mulLldrug reslsLance gene 1hls gene encodes a cell membrane proLeln LhaL effecLlvely pumps a varleLy of sLrucLurally unrelaLed anLlneoplasLlc agenLs ouL of Lhe cell As lnLracellular drug concenLraLlons decllne Lumor cell survlval and reslsLance Lo Lherapy lncrease
aLLerns of 1oxlclLy AnLlneoplasLlc agenLs LhaL acL prlmarlly on rapldly dlvldlng and growlng cells produce mulLlple slde effecLs or LoxlclLles lncludlng bone marrow or myelosuppresslon Cl compllcaLlons and lmmune suppresslon aLLerns of LoxlclLy may be elLher acuLe or delayed AcuLe LoxlclLles ofLen lnclude Cl compllcaLlons such as nausea vomlLlng anorexla and dlarrhea Allerglc reacLlons and anaphylaxls may also be of lmmedlaLe concern wlLh selecLed drugs uelayed LoxlclLles may develop days Lo weeks afLer anLlneoplasLlc Lherapy Myelosuppresslon a common delayed LoxlclLy can be llfeLhreaLenlng due Lo Lhe lncreased lncldence of lnfecLlon assoclaLed wlLh leukopenla lncreased rlsk of hemorrhage assoclaLed wlLh LhrombocyLopenla and anemla CLher lmporLanL delayed LoxlclLles lnclude Llssue damage assoclaLed wlLh exLravasaLlon of selecLed drugs alopecla caused by halr folllcle damage and sLomaLlLls or ulceraLlve enLerlLls Adverse effecLs on spermaLogenesls and LeraLogenesls may be of concern ln breedlng anlmals revenLlon and managemenL of LoxlclLles ls key Lo successful anLlneoplasLlc Lherapy CollecLlon of an adequaLe daLabase before LreaLmenL can ldenLlfy poLenLlal problems so LhaL conLralndlcaLed drugs can be avolded Several anLlneoplasLlc agenLs should noL be used ln Lhe presence of speclflc organ lmpalrmenL lor example doxorublcln should noL be used ln anlmals wlLh cardlac abnormallLles and clsplaLln ls conLralndlcaLed ln anlmals wlLh lmpalred renal funcLlon When a drug ls chosen supporLlve or prevenLlve Lherapy almed aL amelloraLlng Loxlc slde effecLs may be requlred ConcurrenL admlnlsLraLlon of anLlemeLlcs may be lndlcaLed for acuLe Cl LoxlclLles AcLlve dluresls should accompany admlnlsLraLlon of nephroLoxlc agenLs (eg clsplaLln) AdmlnlsLraLlon or avallablllLy of approprlaLe anLlhlsLamlnes may be lndlcaLed wlLh L asparaglnase and doxorublcln Lherapy 1he avallablllLy of recomblnanL producLs has added an addlLlonal resource for managlng myelosuppresslon and lmmunosuppresslon lnduced by anLlneoplasLlc chemoLherapy 8ecomblnanL human eryLhropoleLln (rhLC) has been used ln LreaLmenL of anemla relaLed Lo chronlc mallgnancy 8ecomblnanL human (rhCCSl) and canlne (rcCCSl) granulocyLe colony sLlmulaLlng facLor have been used effecLlvely ln managemenL of cyLopenlas lnduced by chemoLherapy and radlaLlon AdmlnlsLraLlon of rcCCSl resulLs ln a rapld slgnlflcanL lncrease ln neuLrophll numbers LhaL ls susLalnable as long as Lhe facLor ls admlnlsLered neuLrophll counLs drop qulckly when Lherapy ls dlsconLlnued neuLrophll phagocyLosls superoxlde generaLlon and anLlbodydependenL cellular cyLoLoxlclLy all lncrease wlLh CCSl LreaLmenL A relaLed cyLoklne granulocyLemacrophage colonysLlmulaLlng facLor (CMCSl) has also shown promlse for LreaLmenL of neuLropenla lnduced by chemoLherapy LongLerm (23 wk) use of recomblnanL human producLs ln dogs and caLs resulLs ln anLlfacLor anLlbody formaLlon and a decllne ln cell numbers
8lologlc 8esponse Modlflers ln Cancer 1herapy ln recenL years a number of alLernaLlve modes of cancer Lherapy have been lnvesLlgaLed loremosL among Lhese has been Lhe developmenL of blologlc response modlflers almed aL enhanclng lnnaLe anLlLumor defense mechanlsms of Lhe hosL nonspeclflc lmmunomodulaLors
lncludlng 8CC levamlsole and clmeLldlne have been used Lo enhance lmmune responslveness and lmprove ouLcomes afLer surgery or anLlneoplasLlc chemoLherapy uevelopmenL of lymphoklnes and cyLoklnes (eg lnLerleuklns lnLerferon and Lumor necrosls facLor) for cllnlcal use ln cancer paLlenLs has long been an aLLracLlve goal 1he cllnlcal poLenLlal of Lhese poLenL lmmunomodulaLors has noL been fully reallzed and Lhey are noL commonly used ln veLerlnary medlclne aL Lhls Llme An excepLlon Lo Lhls ls Lhe use of selecLed cyLoklnes (eg CCSl) Lo manage Loxlc slde effecLs assoclaLed wlLh anLlneoplasLlc chemoLherapy (see above) AnLlLumor anLlbody Lherapy has also been a cancer research focus for several years Cnly one monoclonal anLlbody ls approved and markeLed for veLerlnary useCL/MAb 231 recognlzes canlne lymphoma cells and ls LhoughL Lo medlaLe anLlbodydependenL cellular cyLoxlclLy Lherapy has prolonged duraLlon of remlsslon when used ln comblnaLlon wlLh chemoLherapy
Safe Pandllng of AnLlneoplasLlc ChemoLherapeuLlc AgenLs MosL anLlneoplasLlc chemoLherapeuLlc agenLs are poLenLlally Loxlc as muLagens LeraLogens or carclnogens Pandllng of Lhese agenLs can resulL ln unhealLhy personal or envlronmenLal exposure ln a number of dlfferenL ways A common rouLe of exposure ls lnhalaLlon due Lo aerosollzaLlon durlng mlxlng or admlnlsLraLlon of cyLoLoxlc drugs 1hls may occur when a needle ls wlLhdrawn from a pressurlzed drug conLalner or upon expulslon of alr from a drugfllled syrlnge 1ransferrlng drugs beLween conLalners openlng drugfllled glass ampules or crushlng or spllLLlng oral medlcaLlons may also aerosollze drug resldues 1he besL way Lo prepare cyLoLoxlc drugs Lo avold aerosollzaLlon ls ln a blologlc safeLy cablneL or hood a Class ll Lype A verLlcal lamlnar alr flow hood exhausLed ouLslde Lhe bulldlng ls recommended lf a hood ls noL avallable drugs should be prepared ln a speclfled lowLrafflc area wlLh proper venLllaLlon where no food drlnk or Lobacco producLs are allowed 1hls area should be equlpped wlLh supplles needed for drug reconsLlLuLlon lncludlng a dlsposable plasLlcbacked llner for Lhe worklng surface laLex gloves gown goggles and mask wlLh a fllLer ulsposal of conLamlnaLed vlals syrlnges needles and gloves ln Lhls area should be anLlclpaLed and Lhe proper conLalners provlded Aerosol exposures can be furLher decreased Lhrough Lhe use of chemoLherapydlspenslng plns (chemoplns") or hydrophoblc fllLers LhaL llmlL escape of alr from drug vlals lnLo Lhe envlronmenL AnoLher poLenLlal rouLe of exposure Lo anLlneoplasLlc agenLs ls by absorpLlon of drug Lhrough Lhe skln 1hls could occur durlng preparaLlon or admlnlsLraLlon of drug cleanlng of Lhe drug preparaLlon area or handllng of excreLa from anlmals LhaL have recelved selecLed cyLoLoxlc drugs MosL exposure of Lhls Lype may be avolded by consclenLlous wearlng of laLex gloves and careful handllng of drugconLamlnaLed needles or caLheLers 8ecapplng of needles conLalnlng drug resldues ls dlscouraged Lo avold accldenLal selflnoculaLlon llnally anLlneoplasLlc agenLs can be lnadverLenLly lngesLed lf food drlnk or Lobacco producLs are allowed ln Lhe vlclnlLy of drug preparaLlon areas LreaLmenL areas or kennels houslng LreaLed anlmals Any lngesLlble maLerlals should be resLrlcLed Lo a separaLe area LhaL ls far enough away Lo avold any posslble conLamlnaLlon wlLh Lhese agenLs All personnel should handle anLlneoplasLlc agenLs wlLh care Women of chlldbearlng age should be parLlcularly cauLlous and pregnanL women should noL handle anLlneoplasLlc drugs
ClasslflcaLlon of AnLlneoplasLlc ChemoLherapeuLlc AgenLs AnLlneoplasLlc agenLs can be grouped by blochemlcal mechanlsm of acLlon lnLo Lhe followlng general caLegorles alkylaLlng agenLs anLlmeLabollLes mlLoLlc lnhlblLors anLlneoplasLlc anLlbloLlcs hormonal agenLs and mlscellaneous 1he cllnlcally relevanL drugs used ln veLerlnary medlclne are dlscussed below and Lhe lndlcaLlons mechanlsm of acLlon and LoxlclLles of selecLed agenLs are summarlzed ln @fe Mecbfsms of Acto lcftos f @oxctes of 5eecte Ateopfstc Aqets
A|ky|at|ng Agents
N|trogen Mustards Cther A|ky|at|ng Agents
AlkylaLlng agenLs form hlghly reacLlve lnLermedlaLe compounds LhaL are able Lo Lransfer alkyl groups Lo unA AlkylaLlon can resulL ln mlscodlng of unA sLrands lncompleLe repalr of alkylaLed segmenLs (whlch leads Lo sLrand breakage or depurlnaLlon) excesslve crossllnklng of unA and lnhlblLlon of sLrand separaLlon aL mlLosls MonofuncLlonal alkylaLlng agenLs Lransfer a slngle alkyl group and usually resulL ln mlscodlng of unA sLrand breakage or depurlnaLlon 1hese reacLlons can resulL ln cell deaLh muLagenesls or carclnogenesls olyfuncLlonal alkylaLlng agenLs Lyplcally cause sLrand crossllnklng and lnhlblLlon of mlLosls wlLh consequenL cell deaLh 8eslsLance Lo one alkylaLlng agenL ofLen lmplles reslsLance Lo oLher slmllar drugs and can be caused by lncreased producLlon of nucleophlllc subsLances LhaL compeLe wlLh Lhe LargeL unA for alkylaLlon uecreased permeaLlon of alkylaLlng agenLs and lncreased acLlvlLy of unA repalr sysLems are also common mechanlsms of reslsLance lndlvldual alkylaLlng agenLs are generally cellcycle nonspeclflc and can be subgrouped accordlng Lo chemlcal sLrucLure lnLo nlLrogen musLards eLhyleneamlnes alkyl sulfonaLes nlLrosoureas and Lrlazene derlvaLlves N|trogen Mustards 1he mosL common subgroup of alkylaLlng agenLs used ls Lhe nlLrogen musLard group MechloreLhamlne hydrochlorlde ls Lhe proLoLype of Lhe nlLrogen musLards and has been used Lo LreaL Podgkln's dlsease ln humans mycosls fungoldes lymphoreLlcular neoplasla and pleural and perlLoneal effuslons 8ecause of lLs hlghly unsLable naLure and exLremely shorL duraLlon of acLlon mechloreLhamlne ls noL wldely used ln veLerlnary medlclne uerlvaLlves of mechloreLhamlne LhaL are commonly used lnclude cyclophosphamlde chlorambucll and less frequenLly melphalan Cyclophosphamlde ls a cycllc phosphamlde derlvaLlve of mechloreLhamlne LhaL requlres meLabollc acLlvaLlon by Lhe cyLochrome 430 oxldaLlon sysLem ln Lhe llver Cyclophosphamlde ls glven C or lv and dosellmlLlng leukopenla assoclaLed wlLh bone marrow suppresslon ls Lhe
prlmary LoxlclLy SLerlle hemorrhaglc cysLlLls caused by acroleln a meLabollLe of cyclophosphamlde can develop and should be LreaLed by acLlve dluresls and lnLraveslcular admlnlsLraLlon of naceLylcysLelne Mesna a drug LhaL acLs Lo deLoxlfy meLabollLes of cyclophosphamlde has been used ln human medlclne Lo preclude hemorrhaglc cysLlLls An analog of cyclophosphamlde lfosphamlde ls avallable buL ls noL currenLly used as a fronLllne drug ln veLerlnary medlclne Chlorambucll Lhe slowesLacLlng nlLrogen musLard achleves effecLs gradually and ofLen can be used ln anlmals wlLh compromlsed bone marrow lL can cause bone marrow suppresslon buL Lhls ls usually laLe ln onseL and rapldly reverslble 1hls drug ls glven C and ls mosL commonly used ln LreaLmenL of chronlc welldlfferenLlaLed cancers lL ls consldered lneffecLlve ln rapldly prollferaLlng Lumors Me|pha|an an Lphenylalanlne derlvaLlve of mechloreLhamlne ls glven C or lv and ls prlmarlly used ln veLerlnary medlclne Lo LreaL mulLlple myeloma
Cther A|ky|at|ng Agents Cf Lhe oLher subgroups of alkylaLlng agenLs several have llmlLed buL speclflc uses 1r|ethy|eneth|ophosphoram|de an eLhylenlmlne may be used lnLraveslcularly ln Lhe LreaLmenL of LranslLlonal cell carclnoma of Lhe bladder or as an lnLracavlLary LreaLmenL for pleural and perlLoneal effuslons 8usu|fan an alkyl sulfonaLe ls used speclflcally ln Lhe LreaLmenL of chronlc myelocyLlc leukemla and polycyLhemla vera Streptozotoc|n a naLurally occurrlng nlLrosourea ls used for palllaLlon of mallgnanL pancreaLlc lsleLcell Lumors or lnsullnomas CLher nlLrosoureas carmust|ne and |omust|ne readlly cross Lhe bloodbraln barrler and have been useful ln managemenL of CnS neoplaslas Dacarbaz|ne a Lrlazene derlvaLlve has been used ln comblnaLlon wlLh doxorublcln for LreaLmenL of relapsed canlne lymphoma Ant|metabo||tes
AnLlmeLabollLes resemble normal cellular meLabollLes and so can subverL normal meLabollc paLhways ln a Loxlc manner 1hree subgroups of anLlmeLabollLes are usedfollc acld pyrlmldlne and purlne analogs lollc Acld Analogs 1he proLoLype follc acld analog ls meLhoLrexaLe an lnhlblLor of dlhydrofolaLe reducLase Lhe
enzyme LhaL caLalyzes converslon of follc acld Lo LeLrahydrofolaLe 1eLrahydrofolaLe deflclency blocks reacLlons requlrlng folaLe coenzymes dlsrupLlng boLh unA and 8nA synLhesls MeLhoLrexaLe ls an S phasespeclflc drug LhaL musL be acLlvely LransporLed across cell membranes lL can be glven C lv or lM MeLhoLrexaLe ls excreLed ln Lhe urlne and aL hlgh doses may preclplLaLe ln renal Lubules lollnlc acld can be used Lo bypass Lhe meLabollc blockade produced by follc acld analogs and Lhus resulL ln rescue of LreaLed cells 8ecause Lumor cells appear less efflclenL aL LransporL of follnlc acld some degree of selecLlvlLy ls achleved ln Lhe rescue 8eslsLance Lo meLhoLrexaLe may develop due Lo lmpalred LransporL of Lhe drug lnLo cells producLlon of alLered forms or lncreased concenLraLlons of dlhydrofolaLe reducLase
yrlmldlne Analogs 1wo pyrlmldlne analogs 3fluorouracll and cyLarablne are commonly used I|uorourac|| musL be converLed Lo an acLlve 3fluoro-2rdeoxyurldlne3rphosphaLe form Lo blnd Lhe enzyme LhymldylaLe synLheLase and block or lnhlblL unA and 8nA synLhesls 1hls drug ls consldered S phasespeclflc lL ls used lv buL ls also avallable for Loplcal use MeLabollsm ls vla Lhe llver and Lhe drug readlly enLers CSl Cccaslonal CnS reacLlons have been reporLed ln dogs and severe lrreverslble neuroLoxlclLy and sudden deaLh have been descrlbed ln caLs AlLhough 3fluorouracll ls LhoughL Lo be effecLlve ln LreaLmenL of squamous cell carclnoma ln caLs LoxlclLy appears Lo preclude lLs use ln Lhls specles 8eslsLance may develop by decreased acLlvaLlon of Lhe drug or acqulslLlon of alLered LhymldylaLe synLheLase LhaL ls noL lnhlblLed Cytarab|ne (cyLoslne arablnoslde) ls an analog of 2rdeoxycyLldlne and musL be acLlvaLed by converslon Lo a 3rmonophosphaLe nucleoLlde 1he nucleoLlde analog AraC1 lnhlblLs unA synLhesls by subsLlLuLlon of arablnose for deoxyrlbose ln Lhe sugar moleLy of unA cyLarablne may also lnhlblL unA repalr enzymes 1hls drug ls S phasespeclflc and lLs effecLlveness ls dlrecLly proporLlonal Lo exposure of cells Lo Lhe drug conLlnuous lnfuslon or repeaLed ln[ecLlons are usually requlred lnhlblLlon of converslon Lo AraC1 or lncreased degradaLlon of AraC1 can accounL for developmenL of reslsLance
urlne Analogs 1wo purlne analogs 6mercaptopur|ne (6M) and 6th|oguan|ne (61C) are used occaslonally 6M ls a sulfhydrylsubsLlLuLed analog of hypoxanLhlne LhaL musL be converLed Lo an acLlve form by hypoxanLhlne guanlne phosphorlbosylLransferase (PC81) 1he acLlve drug lnhlblLs synLhesls and meLabollsm of purlne nucleoLldes and Lhus dlsrupLs synLhesls and funcLlon of unA and 8nA 1hls S phasespeclflc drug can be admlnlsLered C or lv and undergoes rapld meLabollc degradaLlon and some renal excreLlon 8one marrow suppresslon ls gradual and lnfrequenL wlLh 6M acuLe Cl dlsLurbances are also lnfrequenL buL do occur 8eslsLance may develop by dlmlnlshed acLlvaLlon of Lhe drug by PC81 6 M may be used Lo malnLaln remlsslon ln acuLe lymphocyLlc leukemla and has been used Lo LreaL granulocyLlc leukemla 61C ls a sulfhydrylsubsLlLuLed analog of guanlne and llke 6M ls converLed by PC81 Lo an acLlve form capable of alLerlng synLhesls and meLabollsm of purlne nucleoLldes and synLhesls and funcLlon of unA and 8nA 61C ls also an S phasespeclflc drug lL ls glven C and has slde effecLs and mechanlsms of reslsLance slmllar Lo Lhose of 6M excepL LhaL leukopenla may be more severe and Cl dlsLurbances less common 61C may be used Lo LreaL acuLe lymphocyLlc and granulocyLlc leukemla
M|tot|c Inh|b|tors
V|nca A|ka|o|ds 1axanes
V|nca A|ka|o|ds 1he vlnca alkalolds are large complex molecules derlved from Lhe perlwlnkle planL 8lndlng Lo Lubulln Lhe ma[or componenL of cellular mlcroLubules accounLs for Lhe anLlneoplasLlc effecLs of Lhese drugs vlnca alkalolds lnhlblL mlcroLubule polymerlzaLlon and lncrease mlcroLubule dlsassembly 1he mlLoLlc splndle apparaLus ls dlsrupLed and segregaLlon of chromosomes ln meLaphase ls arresLed 1hese effecLs accounL for Lhe prlmary Mphase acLlon of vlnca alkalolds alLhough oLher anLlLubulln effecLs relaLed Lo cyLoskeleLal malnLenance and proLeln Lrafflcklng may be seen 1he 2 drugs of lmporLance ln Lhls class are v|ncr|st|ne and v|nb|ast|ne 8oLh are glven lv and boLh cause severe local veslcaLlon lf ln[ecLed perlvascularly urug exLravasaLlon may cause deep lndolenL ulceraLlon and exposure of underlylng Lendons and bone 1he vlnca alkalolds are meLabollzed prlmarlly ln Lhe llver buL may be parLlally excreLed ln an unchanged form ln Lhe urlne AlLhough vlnca alkalolds are relaLed sLrucLurally reslsLance Lo one does noL lmply reslsLance Lo all drugs ln Lhls caLegory vlncrlsLlne use ls llmlLed by neurologlc LoxlclLy LhaL may lnclude a slowly reverslble sensorlmoLor perlpheral neuropaLhy and muscle weakness ln comparlson Lhe dosellmlLlng LoxlclLy assoclaLed wlLh vlnblasLlne ls relaLed Lo myelosuppresslon and leukopenla neurologlc LoxlclLy develops only aL hlgh doses
1axanes ac||taxe| and docetaxe| are anLlmlcroLubule agenLs exLracLed from Lhe aclflc and Luropean yew Lrees respecLlvely 1axanes blnd Lo Lubulln subunlLs enhance mlcroLubule polymerlzaLlon and lnhlblL mlcroLubule depolymerlzaLlon lormaLlon of sLable mlcroLubule bundles dlsrupLs Lubulln equlllbrlum and blocks normal progresslon Lhrough Lhe cell cycle 1hese agenLs are acLlvely used ln human medlclne and are belng lnvesLlgaLed for use ln LreaLmenL of lymphoma and mammary carclnoma ln veLerlnary medlclne Myelosuppresslon anaphylacLold reacLlons (probably relaLed Lo Lhe drug vehlcle) and Cl effecLs (dlarrhea mucosal ulceraLlon and emesls) have been reporLed ln dogs LreaLed wlLh pacllLaxel
M|sce||aneous Ant|neop|ast|c Agents
Several drugs used as anLlneoplasLlcs do noL fall lnLo any of Lhe caLegorles menLloned Lhus far 1hese lnclude Lasparaglnase clsplaLln mlLoLane (opruuu) hydroxyurea eLoposlde and plroxlcam LAsparaglnase ls an enzyme derlved from scbetcbf co LhaL caLalyzes hydrolysls of asparaglne 8ecause some Lumor cells are unable Lo produce asparaglne LreaLmenL wlLh Lhls drug deprlves Lhese cells of exogenously supplled asparaglne and ulLlmaLely llmlLs proLeln synLhesls 8ecause proLeln synLhesls ls acLlve ln Lhe C 1 phase of Lhe cell cycle lasparaglnase ls consldered Lo be a C 1 phasespeclflc drug LAsparaglnase may be glven lv SC lM or by lnLraperlLoneal ln[ecLlon Anaphylaxls on repeaLed admlnlsLraLlon of Lasparaglnase may occur as a resulL of hosL anLl asparaglnase anLlbody producLlon preLreaLmenL of anlmals wlLh anLlhlsLamlne helps prevenL Lhls acuLe Loxlc reacLlon AnLlasparaglnase anLlbody producLlon may also accounL for Lhe developmenL of Lumor reslsLance as can a decreased Lumor cell requlremenL for asparaglne A relaLed drug pegaspargase ls modlfled from Lasparaglnase by covalenL modlflcaLlon wlLh monomeLhoxypolyeLhylene glycol 1he con[ugaLed drug produces fewer hypersenslLlvlLy reacLlons Lhan does L asparaglnase ClsplaLln (clsdlamlnedlchloroplaLlnum) funcLlons prlmarlly as a blfuncLlonal alkylaLor buL ls lncluded ln Lhe mlscellaneous caLegory because of lLs unusual sLrucLure lL ls a plaLlnum lon complexed Lo 2 chlorlde lons and 2 ammonlum molecules ClsplaLln causes lnLer and lnLrasLrand unA crossllnklng LhaL dlsrupLs unA hellces and prevenLs unA synLhesls ClsplaLln ls cellcycle nonspeclflc and ls admlnlsLered by lv drlp ln comblnaLlon wlLh flulds and mannlLol Lo promoLe dluresls LxcreLlon ls prolonged wlLh up Lo 30 of a dose sLlll presenL ln Lhe body 3 days afLer admlnlsLraLlon LxLreme dosellmlLlng proxlmal Lubular renal necrosls Lyplfles Lhe delayed slde effecLs of clsplaLln along wlLh oLher responses LhaL may lnclude oLoLoxlclLy moderaLe Lo severe bone marrow suppresslon perlpheral neuropaLhy and renal poLasslum and magneslum wasLlng 8ecause of Lhe exLreme Loxlc adverse effecLs of clsplaLln newer generaLlon derlvaLlves such as carboplaLln and lproplaLln have been developed CarboplaLln ls effecLlve as an ad[uncL Lo surgery for LreaLmenL of osLeosarcoma nausea and vomlLlng are less severe Lhan wlLh clsplaLln and carboplaLln ls noL consldered nephroLoxlc lL ls however myelosuppresslve wlLh neuLropenla belng Lhe dosellmlLlng LoxlclLy CarboplaLln ls consldered safe for admlnlsLraLlon Lo caLs MlLoLane (opuuu) a derlvaLlve of Lhe lnsecLlcldes uu1 and uuu causes selecLlve desLrucLlon of normal and neoplasLlc adrenal corLlcal cells MlLoLane may acL by lnhlblLlng producLlon of sLerolds lnduced by adrenocorLlcoLroplc hormone whlch causes aLrophy of Lhe lnner zones of Lhe adrenal corLex MlLoLane ls admlnlsLered C and plasma concenLraLlons can be deLecLed for several weeks Pydroxyurea a slmple hydroxylaLed derlvaLlve of urea ls mosL commonly used ln Lhe LreaLmenL of polycyLhemla vera Pydroxyurea lnhlblLs rlbonucleoslde dlphosphaLe reducLase (8nu8) llmlLs Lhe converslon of rlbonucleoLldes Lo deoxyrlbonucleoLldes and blocks unA synLhesls Cells are arresLed ln Lhe C 1 S lnLerface Mechanlsms of reslsLance lnclude ampllflcaLlon of Lhe 8nu8 gene or developmenL of 8nu8 wlLh reduced senslLlvlLy Lo hydroxyurea alnful loss of claws has been assoclaLed wlLh hydroxyurea use ln anlmals LplpodophylloLoxlns are semlsynLheLlc glycosldes of podophylloLoxln derlved from Lhe mandrake planL AlLhough Lhese Loxlns blnd Lubulln Lhelr mechanlsm of acLlon ls unrelaLed Lo dlsrupLlon of mlcroLubules lnsLead Lhey are LhoughL Lo sLlmulaLe unA cleavage medlaLed by Lopolsomerase ll Cf Lhe 2 drugs ln Lhls class eLoposlde and Lenlposlde Lhe former has been used prlmarlly ln Lhe LreaLmenL of LesLlcular carclnoma lroxlcam an nSAlu has been used ln LreaLmenL of LranslLlonal cell carclnoma Llke LhaL of oLher nSAlu reporLed anLlLumor acLlvlLy of plroxlcam ls noL consldered a resulL of dlrecL cyLoLoxlclLy Ant|neop|ast|c Ant|b|ot|cs
1he anLlneoplasLlc anLlbloLlcs are producLs of 5tteptomyces 1he lmporLanL drugs ln Lhls group lnclude acLlnomycln u (dacLlnomycln) doxorublcln mlLoxanLrone and bleomycln urugs less commonly used lnclude daunorublcln mlLhramycln and mlLomycln AcLlnomycln A was Lhe flrsL 5tteptomyces anLlbloLlc lsolaLed and was followed by relaLed anLlbloLlcs lncludlng acLlnomycln u AcLlnomycln u blnds wlLh doublesLranded unA and blocks Lhe acLlon of 8nA polymerase whlch prevenLs unA LranscrlpLlon AcLlnomycln u ls consldered cellcycle nonspeclflc and ls glven lv buL does noL cross Lhe bloodbraln barrler 8eslsLance may develop due Lo decreased cellular upLake of Lhe drug 1he anLhracycllne anLlbloLlcs daunorublcln and doxorublcln have become lmporLanL anLlneoplasLlc anLlbloLlcs 1hese drugs lnLercalaLe and blnd Lo unA beLween base palrs on ad[acenL sLrands 1hls causes Lhe unA hellx Lo uncoll whlch desLroys Lhe unA LemplaLe and lnhlblLs 8nA and unA polymerases Sclsslon of unA ls LhoughL Lo be medlaLed by elLher Lhe enzyme Lopolsomerase ll or by generaLlon of free radlcals lnLracellular lnLeracLlons of anLhracycllne anLlbloLlcs resulL ln Lhe formaLlon of semlqulnone radlcal lnLermedlaLes capable of generaLlng hydrogen peroxlde and hydroxyl radlcals Consldered cellcycle nonspeclflc because of Lhe damage assoclaLed wlLh radlcal formaLlon Lhese drugs probably have Lhelr maxlmal effecL durlng Lhe S phase of Lhe cell cycle 1he anLhracycllne anLlbloLlcs are glven lv Lhey are severe veslcanLs lf admlnlsLered perlvascularly and may cause a severe delayed phleblLls urLlcarla may be seen ln Lhe area of Lhe ln[ecLlon and shorLly afLer admlnlsLraLlon eryLhemaLous areas may appear along Lhe veln 8ecurrence of Lhls response may be prevenLed by premedlcaLlon wlLh corLlcosLerolds and anLlhlsLamlnes 1he anLhracycllne anLlbloLlcs are meLabollzed ln Lhe llver Lo a varleLy of less acLlve and lnacLlve producLs uoxorublcln LoxlclLy can be manlfesLed ln a varleLy of acuLe and delayed reacLlons uelayed LoxlclLles can be severe wlLh Lhe ma[or problem belng cumulaLlve doserelaLed cardlac LoxlclLy assoclaLed wlLh blndlng of Lhe drug Lo cardlac unA and free radlcal damage Lo myocardlal membranes A nonspeclflc decrease ln cardlac flbrlls occurs whlch leads Lo congesLlve hearL fallure LhaL ls unresponslve Lo dlglLalls A dosellmlLlng LoxlclLy of doxorublcln ls severe myelosuppresslon lf doxorublcln ls used ln con[uncLlon wlLh radlaLlon Lherapy damage by radlaLlon may be augmenLed 1hls radlaLlon recall effecL may necesslLaLe reducLlon ln radlaLlon or drug dosages or boLh 8ecause of Lhe slgnlflcanL LoxlclLy assoclaLed wlLh Lhe use of doxorublcln newergeneraLlon drugs speclflcally almed aL reducLlon of cardlac LoxlclLy have been developed and are avallable ln human medlclne 1wo of Lhese ldarublcln and eplrublcln have been sLudled buL nelLher ls ln common use ln veLerlnary medlclne MlLoxanLrone an anLhracenedlone relaLed Lo Lhe anLhracycllne anLlbloLlcs has shown promlse ln veLerlnary medlclne for LreaLmenL of lymphoma and varlous carclnomas 1he mechanlsm of acLlon of mlLoxanLhrone ls slmllar Lo LhaL of Lhe anLhracycllnes buL slde effecLs are less severe Lhan Lhose of doxorublcln 8leomycln ls acLually a mlxLure of bleomycln glycopepLldes LhaL dlffer only ln Lhelr Lermlnal amlne moleLy 1he cyLoLoxlc acLlon of Lhese glycopepLldes depends on Lhelr ablllLy Lo cause chaln sclsslon and fragmenLaLlon of unA molecules Cells accumulaLe ln Lhe C 2 phase of Lhe cell cycle whlch accounLs for Lhe classlflcaLlon of bleomycln as a C 2 and M phasespeclflc agenL 8leomycln may also affecL unA repalr enzymes Clven lv or SC bleomycln does noL cross Lhe bloodbraln barrler a large porLlon ls excreLed vla Lhe kldneys 8leomycln has mlnlmal myelosuppresslve and lmmunosuppresslve acLlvlLles buL does have an unusual delayed pulmonary LoxlclLy ulmonary LoxlclLy may begln as a nonspeclflc pneumonlLls LhaL progresses Lo pulmonary flbrosls uangers from pulmonary compllcaLlons are especlally lmporLanL ln older anlmals wlLh preexlsLlng pulmonary dlsease normona| Agents
Pormonal Lherapy for neoplasla commonly lnvolves Lhe use of glucocorLlcolds ulrecL anLlLumor effecLs are relaLed Lo Lhelr lympholyLlc properLles glucocorLlcolds can lnhlblL mlLosls 8nA synLhesls and proLeln synLhesls ln senslLlve lymphocyLes ClucocorLlcolds are consldered cellcycle nonspeclflc and are ofLen used ln chemoLherapeuLlc proLocols afLer lnducLlon by anoLher agenL unforLunaLely reslsLance Lo a glven glucocorLlcold may develop rapldly and Lyplcally exLends Lo oLher glucocorLlcolds 1oxlc effecLs of glucocorLlcold Lherapy can lnclude pepLlc ulceraLlon glucose lnLolerance polydlpsla and polyurla lmmunosuppresslon necroLlzlng pancreaLlLls osLeoporosls hypokalemla caLaracLs muscle aLrophy and Cushlng's dlsease rednlsone and prednlsolone are commonly used Lo LreaL lymphoreLlcular neoplasms ln comblnaLlon wlLh oLher drugs 8ecause Lhey readlly enLer Lhe CSl dexameLhasone prednlsone and prednlsolone are especlally useful ln LreaLmenL of leukemlas and lymphomas of Lhe CnS lndlrecL beneflLs of glucocorLlcold Lherapy ln cancer lnclude sympLomaLlc lmprovemenLs ln appeLlLe and aLLlLude suppresslon of nonlnfecLlous fevers managemenL of hypercalcemla of mallgnancy and rellef of edema assoclaLed wlLh splnal cord and braln Lumors Powever evldence from several sources suggesLs LhaL LreaLmenL of cerLaln lymphomas wlLh prednlsone may lncrease reslsLance of neoplasLlc cells Lo subsequenL cycles of anLlneoplasLlc chemoLherapy LsLrogen has also been used ln anLlneoplasLlc Lherapy buL compllcaLlons can be severe 1oxlclLles have effecLlvely ellmlnaLed Lhe use of esLrogen ln veLerlnary cancer Lherapy CompllcaLlons of esLrogen Lherapy can lnclude llfeLhreaLenlng myelosuppresslon aplasLlc anemla and LhrombocyLopenla AnLlesLrogen Lherapy wlLh drugs such as Lamoxlfen may also be used ln esLrogenrecepLorposlLlve mammary carclnomas Lo block growLhsLlmulaLory hormonal acLlvlLles ln Lhese cells ln addlLlon anLlesLrogens have been used ln Lhe LreaLmenL of endomeLrlal carclnomas rogesLlns have been used Lo oppose growLh sLlmulaLory effecLs of hormones ln endomeLrlal prosLaLlc breasL renal cell and ovarlan carclnomas 1oxlc slde effecLs of Lhe progesLlns lnclude fluld reLenLlon hypercalcemla Lhromboembollsm and cholesLaLlc [aundlce AnLlandrogens such as f|utam|de have been used experlmenLally ln Lhe LreaLmenL of prosLaLlc and perlanal neoplasla Leuprollde an analog of gonadoLroplnreleaslng hormone (Cn8P) lnlLlally sLlmulaLes Lhen decreases Lhe secreLlon of folllclesLlmulaLlng hormone (lSP) and leuLelnlzlng hormone (LP) 8educed lSP and LP lead Lo decreased concenLraLlon of LesLosLerone ln males and esLrogen ln females Leuprollde has been used ln Lhe LreaLmenL of LesLosLeronerecepLorposlLlve prosLaLlc carclnomas and perlanal Lumors ln veLerlnary medlclne surglcal casLraLlon ls Lhe LreaLmenL of cholce for LesLosLeroneresponslve neoplaslas