AnLlcancer agenLs

P8M 412
ancer and cancer chemoLherapy
Cne of Lhe mosL dlfflculL dlseases Lo LreaL
8esponslble for abouL 13 of all deaLhs
worldwlde
lncldence ls lncreaslng due Lo Lhe agelng of
populaLlon ln mosL counLrles buL speclally ln
Lhe developed ones
ancer and cancer chemoLherapy
ancer ls a dlsease ln whlch Lhe conLrol of
growLh ls losL ln one or more cells leadlng Lo a
solld mass of cells known as a Lumor
1he lnlLlal Lumor known as Lhe ptlmoty tomot
ofLen becomes llfeLhreaLenlng by obsLrucLlng
vessels or organs
ancer and cancer chemoLherapy
Powever deaLh ls mosL commonly caused by
spread of Lhe prlmary Lumor Lo one or more
oLher slLes ln Lhe body (by a process called
metostosls % whlch makes surglcal
lnLervenLlon lmposslble
CLher Lypes of cancers known as eokemlos
lnvolve a bulldup of large numbers of whlLe
cells ln Lhe blood
ancer and cancer chemoLherapy
haracLerlzed by Lhe loss of conLrol of Lhe
growLh dlvlslon and spread of a group of
cells leadlng Lo a prlmary Lumor LhaL lnvades
and desLroys ad[acenL Llssues
lL may also spread Lo oLher reglons of Lhe
body Lhrough a process known as meLasLasls
whlch ls Lhe cause of 90 of cancer deaLhs
ancer and cancer chemoLherapy
When prlmary Lumor cells meLasLaslze Lhe
new Lumor ls called a secondary or meLasLaLlc
Lumor and lLs cells are llke Lhose ln Lhe
orlglnal Lumor
1hls means for example LhaL lf breasL cancer
meLasLaslzes Lo Lhe lungs Lhe secondary
Lumor ls made up of abnormal breasL cells
noL of abnormal lung cells
1he Lumor ln Lhe lung ls Lhen called meLasLaLlc
breasL cancer noL lung cancer
AnLlcancer drugs
MosL anLlcancer drugs requlres Lhe
admlnlsLraLlon of a large LoLal dose Lo achleve
hlgh local concenLraLlons ln a Lumor
Cne of lLs maln assoclaLed problems ls Lhe
nonspeclflc LoxlclLy of mosL anLlcancer drugs
due Lo Lhelr blodlsLrlbuLlon LhroughouL Lhe
body
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1
1argeLed drug dellvery
Use of prodrugs
elecLlvely acLlvaLed ln Lumor Llssues Laklng
advanLage of some unlque aspecLs of Lumor
physlology such as selecLlve enzyme
expresslon hypoxla and low exLracellular pP
rug reslsLance
up Lo 30 of Lumors have elLher e oovo drug
reslsLance or oLherwlse develop reslsLance Lo
anLlcancer drugs afLer lnlLlal LreaLmenL
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2
rug reslsLance
AfLer Lhe developmenL of a reslsLance
mechanlsm ln response Lo a slngle drug cells
can dlsplay crossreslsLance Lo oLher sLrucLural
and mechanlsLlcally unrelaLed drugs a
phenomenon known as mulLldrug reslsLance
(M8%
Tumors can become resistant to
several, often unrelated, drugs
with different mechanisms of
action simultaneously.
rug reslsLance
eoce lottoceoot toq cooceottotloos
1hls may resulL from enhanced drug efflux or
decreased cellular peneLraLlon
AnLlcancer drug LhaL produce reslsLance by
Lhls meLhod vlnca alkalolds dacLlnomycln
rug reslsLance
obooce toq looctlvotloo
or Lhe alkylaLlng agenLs gluLaLhlone
Lransferase producLlon may lncrease whlch
caLalyzes Lhelr covalenL lnLeracLlon wlLh
gluLaLhlone raLher Lhan -A
rug reslsLance
ecteose octlvotloo of toq
erLaln anLlmeLabollLes LhaL musL be
enzymaLlcally converLed Lo nucleoLldes ln
order Lo exerL Lhelr effecLs
1he acLlvaLlon process may be affecLed by
cancer cell
rug reslsLance
,olfle ptooctloo of o teceptot ot eozyme
(le qeoe omplflcotloo)
MeLhoLrexaLe (anLlmeLabollLe%
AmpllflcaLlon of dlhydrofolaLe reducLase can
occur ln reslsLanL Lumors so LhaL lncreaslngly
hlgher concenLraLlons of drug are requlred for
a slmllar effecL
omblnaLlon chemoLherapy
LarLed Lo use ln early 1960s
ommonly used ln cllnlcal pracLlce Loday
Lxample
1emozolomlde + LomeguaLrlb
LomeguaLrlb
1emozolomlde
,ecboolsm of eqtootloo of temozoomle to fotm tbe -
metbyotloq metby specles
PydrolyLlc
cleavage
hyslologlcal pP
1emozolomlde
1emozolomlde ls a prodrug
1ransporL a meLhylaLlng agenL (Lhe
meLhyldlazonlum lon% Lo guanlne bases wlLhln
Lhe ma[or groove of -A
omblnaLlon chemoLherapy
@emozoomle
AlkylaLlng agenL (metbyotloq oqeots)
omeqoottlb
lnhlblLs Lhe meLhyl Lransferase enzyme
C
6
alkylguanlne-AalkylLransferase LhaL
removes Lhe meLhyl groups added Lo -A
by Lemozolomlde
LxperlmenLal model
lnally a ma[or problem ln Lhe developmenL
of anLlcancer drugs ls Lhe large gap from
promlslng flndlngs ln precllnlcal lo vltto and lo
vlvo models Lo Lhe resulLs of cllnlcal Lrlals
1he problems found ln Lhls LranslLlon arlse
because experlmenLal cancer models greaLly
dlffer from paLlenLs who very ofLen suffer
from a much more complex LherapeuLlc
slLuaLlon
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3
-aLural producLs ln cancer
chemoLherapy
Maln source of cyLoLoxlc anLlcancer agenLs
slnce Lhe beglnnlng of chemoLherapy
lanLs (largely explored%
Mlcoorganlsms (sLlll very low%
Marlne organlsms (largely unexplored%
-aLural producLs ln cancer
chemoLherapy
Around half of Lhe drugs currenLly ln cllnlcal
use as anLlcancer drugs are of naLural producL
orlgln
lL has been esLlmaLed LhaL abouL 60 of new
chemlcal enLlLles (-Ls% lnLroduced ln Lhe
19812002 perlod ln Lhls fleld were naLural
producLs or were derlved from a naLural lead
compound
-aLural producLs ln cancer
chemoLherapy
upply problems of naLural producLs make Lhe
developmenL of synLheLlc rouLes necessary
CfLen long and dlfflculL Lo scaleup owlng Lo
Lhelr sLrucLural complexlLy
-aLural producLs ln cancer
chemoLherapy
ln general naLural producLs have several
funcLlonal groups whlch are locaLed lnLo a
preclse Lhreedlmenslonal poslLlon provldlng
speclflc lnLeracLlons wlLh LargeL molecules
lL ls ofLen assumed LhaL secondary
meLabollLes ln naLure organlsms have been
opLlmlzed Lhrough evoluLlon Lo exerL Lhelr sLlll
noL welldeflned effecLs
-aLural producLs ln cancer
chemoLherapy
onsequenLly Lhey may be consldered as
hlghly advanced lead compounds lead compounds ln whlch
furLher opLlmlzaLlon of acLlvlLy ls dlfflculL
-aLural producLs ln cancer
chemoLherapy
LrucLural modlflcaLlon of naLural producLs ls
ofLen dlrecLed Lo flnd Lhe slmplesL porLlon
LhaL malnLalns mosL of Lhe blologlcal acLlvlLy
LhaL ls lLs pharmacophorlc unlL
Pelps Lo obLaln slmple analogs wlLhouL
conslderable loss of acLlvlLy
yLoLoxlc marlne compound
Pallchondrln 8
evelopmenL of Lhe anLlLumor
agenL
LacLone
rlng
evelopmenL of Lhe anLlLumor
agenL
eleLlon of a large porLlon of Pallchondrln 8
8eplacemenL of Lhe unsLable lacLone by a
keLone funcLlon yleld L7389
o noL affecL lLs anLlmlLoLlc properLles
AnLlLumor agenL L7389
hase lll cllnlcal Lrlals
evelopmenL of Lhe anLlLumor
agenL
LacLone
8lng replaced by keLone