Ant|neop|ast|c Agents Introduct|on

1umor Growth and kesponse to Chemotherapy

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

Io||c Ac|d Ana|ogs
yr|m|d|ne Ana|ogs
ur|ne Ana|ogs


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