Antineoplastic Agents 2011 Dental MARCH-1
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Transcript of Antineoplastic Agents 2011 Dental MARCH-1
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Pharmacology of Antineoplastic Agents
1
Outline of Lecture Topics:
• Antineoplastic Agents:
a. Cell Cycle Specific (CCS) agentsb. Cell Cycle Non-Specific (CCNS) agents
c. Miscellaneous (e.g. antibo!ies) agents
". Mechanisms of action an! si!e effects
#. $rug %esistance
&ishore 'ary Ph.$.
$ept Pharmacology
ary*uic.e!u
#+"-,+#-/"
http:00.ncbi.nlm.nih.go10pubme!health0
http:00.ncbi.nlm.nih.go10pubme!health0PM2333""450
http:00clinicaltrials.go10ct"0results6term7cancer
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"33 8stimate! 9S Cancer $eaths
ONS=Other nervous system.
Source: American Cancer Society, 200.
!en
22,"#0
$omen
2%,&00"4; reast
; Colon = rectum
4; Pancreas
; ?1ary
,; Non-2o!gin lymphoma
#; rain0?NS
"; All other sites
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Cancer
3
Cancer is a term use! for !iseases in hich abnormal cells !i1i!e ithout
control an! are able to in1a!e other tissues. Cancer cells can sprea! to other
parts of the bo!y through the bloo! an! lymph systems this process is calle!metastasis.
Categori@e! base! on the functions0locations of the cells from hich they
originate:
•Carcinoma - sin or in tissues that line or co1er internal organs. 8.g. 8pithelial
cells. /3-3; reporte! cancer cases are carcinomas.•Sarcoma - bone cartilage fat muscle bloo! 1essels or other connecti1e or
supporti1e tissue.•Leu'emia - 'hite bloo! cells an! their precursor cells such as the bone
marro cells causes large numbers of abnormal bloo! cells to be pro!uce! an!enter the bloo!.•Lymphoma - cells of the immune system that affects lymphatic system.•!yeloma - >-cells that pro!uce antibo!ies- sprea!s through lymphatic system.•Central nervous system cancers - cancers that begin in the tissues of the
brain an! spinal cor!.
(National Cancer nstitute NC)http:00.ncbi.nlm.nih.go10pubme!health0http:00.ncbi.nlm.nih.go10pubme!health0PM2333""450
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Cancer Therapeutic Modalities (classical)
4
• Surgery
• %a!iation
• Chemotherapy
+0# of patients ithout metastasis
%espon! to surgery an! ra!iation.
f !iagnose! at an early stage
close to 3; cancer
coul! be cure!.
3; patients ill un!ergo chemotherapy
to remo1e micrometastasis. 2oe1er
chemotherapy is able to cure only about +3-+;
of all cancer patients.
Cancer Chemotherapy
Chapter . >.B. &at@ung
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5Cancer Chemotherapy
Chapter . >.B. &at@ung
New types of cancer treatment
(ormonal Treatments: hese !rugs are !esigne! to pre1ent cancer cell groth by
pre1enting the cells from recei1ing signals necessary for their continue! grothan! !i1ision. 8.g. >reast cancer D tamoEifen after surgery an! ra!iation
Specific )nhi*itors: $rugs targeting specific proteins an! processes that are
limite! primarily to cancer cells or that are much more pre1alent in cancer cells.
Anti*o+ies: he antibo!ies use! in the treatment of cancer ha1e been
manufacture! for use as !rugs. 8.g. 2erceptin a1astin
iolo-ical esponse !o+ifiers: he use of naturally occuring normal proteins to
stimulate the bo!yFs on !efenses against cancer. 8.g. AbciEimab rituEmab
/accines: Stimulate the bo!yFs !efenses against cancer. Gaccines usually contain
proteins foun! on or pro!uce! by cancer cells. >y a!ministering these proteins
the treatment aims to increase the response of the bo!y against the cancer
cells.
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6
Cancer Chemotherapy (Background)
A. Most of the recent progress using antineoplastic therapy is base! on:
+. $e1elopment of ne combination therapy of using eEisting !rugs.
". >etter un!erstan!ing of the mechanisms of antitumor acti1ity.#. $e1elopment of chemotherapeutic approaches to !estroying
micrometastases
,. 9n!erstan!ing the molecular mechanisms concerning the initiation of
tumor groth an! metastasis.
. %ecognition of the heterogeneity of tumors
. %ecently !e1elope! principles hich ha1e helpe! gui!e the treatment of
neoplastic !isease
+. A single clonogenic cell can pro!uce enough progeny to ill the host.
". 9nless a fe malignant cells are present host immune mechanisms !o
not play a significant role in therapy of neoplastic !isease.
#. A gi1en therapy results in !estruction of a constant percentage as
oppose! to a constant number of cells therefore cell ill follos first or!er
inetics.
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Cancer Chemotherapy
7
C. Malignancies hich respon! fa1orably to chemotherapy:
+. choriocarcinoma
". Acute leuemia
#. 2o!ginFs !isease
,. >urittFs lymphoma
. 'ilmsF tumor
4. esticular carcinoma
5. 8ingFs sarcoma
/. %etinoblastoma in chil!ren
. $iffuse histiocytic lymphoma an!
+3.%hab!omyosarcoma.
. Antineoplastic !rugs are most effecti1e against rapi!ly !i1i!ing
tumor cells.
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1. Boal of Antineoplastic Agents
S to eliminate the cancer cells ithout affecting normal tissues (the concept of
!ifferential sensiti1ity). n reality all cytotoEic !rugs affect normal tissues as
ell as malignancies - aim for a fa1orable therapeutic in!eE (aa therapeutic
ratio).
Therapeutic )n+e 7!5"#####
$!5"
A therapeutic in!eE is the lethal !ose of a !rug for 3; of the population (.B. &at@ung
%
http://en.wikipedia.org/wiki/LD50http://en.wikipedia.org/wiki/ED-50http://en.wikipedia.org/wiki/ED-50http://en.wikipedia.org/wiki/ED-50http://en.wikipedia.org/wiki/LD50http://en.wikipedia.org/wiki/LD50
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)nfre3uent sche+ulin- of
treatment courses.
4rolon-s survival *ut +oes not cure.
!ore intensive an+
fre3uent treatment.
5ill rate 6 -ro7th rate.
8ntreate+ patients
F. &he effects of tumor 'urden schedu*ng dos*ng and *n*t*at*on+durat*on of
treatment on pat*ent sur,*,a-
1arly sur-ical removal of the
primary tumor +ecreases the tumor
*ur+en. Chemotherapy 7ill remove
persistant secon+ary tumors.
Cancer Chemotherapy
Chapter . >.B. &at@ung
.
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1"
/enera rues of chemotherapy
Aggressive high-dose chemotherapy•Dose# *m*t*ng *s to0*c*ty towards norma ces
•Cyclic regimens # repeated adm*n*strat*ons w*th appropr*ate *nter,asfor regenerat*on of norma ces (e-g- 'one marrow ces)
•Supportive therapy - to reduce to0*c*ty
hematoto0*c*ty 'one marrow transpantat*on hematopo*et*cgrowth factors
2pec*f*c antagon*sts ant*foate (methotre0ate) foate(euco,or*n)
$2N # donor of 2 groups decreased uroto0*c*ty ofcycophospham*de- !eto0*fy*ng agent-
de0rao0ane cheates *ron reduced anthracyc*ne card*oto0*c*ty
am*fost*ne reduces hematoto0*c*ty ototo0*c*ty and neuroto0*c*tyof akyat*ng agents
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11
/enera rues of chemotherapy
•Com'*nat*on of se,era drugs w*th d*fferent mechan*sms of act*on
d*fferent res*stance mechan*sms d*fferent dose#*m*t*ng to0*c*t*es-
•Adjuvant therapy dd*t*ona cancer treatment g*,en after the pr*marytreatment to ower the r*sk that the cancer w* come 'ack- d8u,anttherapy may *ncude chemotherapy rad*at*on therapy hormone therapytargeted therapy or '*oog*ca therapy-
•!eoadjuvant therapy &reatment g*,en as a f*rst step to shr*nk a tumor
'efore the ma*n treatment wh*ch *s usuay surgery *s g*,en- $0ampes of
neoad8u,ant therapy *ncude chemotherapy rad*at*on therapy and
hormone therapy- 9t *s a type of *nduct*on therapy-
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1:
Al'ylatin- a-entsTopoisomeraseinhi*itors Antimeta*olites
!olecularlytar-ete+
busulfan !actinomycin cytarabine erlotinib
carboplatin !aunomycin clofarabine imatinib
carmustine !oEorubicin flu!arabine sorafenib
cisplatin etoposi!e gemcitabine sunitinib
cyclophosphami!e etoposi!e phosphate mercaptopurine tretinoin
!acarba@ine i!arubicin methotreEate 2erceptin
ifosfami!e irinotecan nelarabine !iscellaneous
lomustine liposomal !aunomycin thioguanine arsenic trioEi!e
mechlorethamine liposomal !oEorubicin Tu*ulin *in+ers asparaginase
melphalan mitoEantrone !ocetaEel bleomycin
oEaliplatin teniposi!e iEabepilone !eEamethasoneprocarba@ine topotecan 1inblastine hy!roEyurea
temo@olomi!e 1incristine mitotane
thiotepa 1inorelbine P8B-asparaginase
paclitaEel pre!nisone
Antineoplastic Agents
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13
Chemotherapy cass*f*cat*on 'ased on the
mechan*sm of act*on
Antimeta*olites: nterfere ith the formation of ey biomolecules
inclu!ing nucleoti!es the buil!ing blocs of $NA.
9enotoic ru-s: Alylate or intercalate the $NA causing the loss of itsfunction.
4lant+erive+ inhi*itors of mitosis: Pre1ent proper cell !i1ision byinterfering ith the cytoseletal components that enable the cell to !i1i!e.
4lant+erive+ topoisomerase inhi*itors: opoisomerases unin! orreligate $NA !uring replication.
Other Chemotherapy A-ents: nhibit cell !i1ision by mechanisms thatare not co1ere! in the categories liste! abo1e.
http://localhost/var/www/apps/conversion/Plocha/Dokumenty/index.cfm%3fpage=429http://localhost/var/www/apps/conversion/Plocha/Dokumenty/index.cfm%3fpage=482http://localhost/var/www/apps/conversion/Plocha/Dokumenty/index.cfm%3fpage=520http://localhost/var/www/apps/conversion/Plocha/Dokumenty/index.cfm%3fpage=1285http://localhost/var/www/apps/conversion/Plocha/Dokumenty/index.cfm%3fpage=1285http://localhost/var/www/apps/conversion/Plocha/Dokumenty/index.cfm%3fpage=520http://localhost/var/www/apps/conversion/Plocha/Dokumenty/index.cfm%3fpage=482http://localhost/var/www/apps/conversion/Plocha/Dokumenty/index.cfm%3fpage=429
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C8
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16
B3 7 resting phase
B+ 7 pre-replicati1e phase
B" 7 post-replicati1e phase
S 7 $NA synthesis
M 7 mitosis or cell !i1ision
!
S
9 9" + 2y!rocortisone
93
Cyclophosphami!e>leomycin Actinomycin $
Actinomycin $-Jluorouracil
Cytosine arabinosi!eMethotreEate
4-Mercaptopurine4-hioguanine
Purine antagonistsMethotreEateCyclophosphami!e-Jluorouracil
Cytosine arabinosi!e$aunom cin
GincristineGinblastine
PaclitaEel $ocetaEel
restin-
Ce cyce spec*f*c*ty of nt*#Neopast*c gents
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17Cancer Chemotherapy
Chapter . >.B. &at@ung
PA%
". Mechanisms of action#. Si!e 8ffects
#. $rug %esistance
;harmacoogy of nt*neopast*c gents
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1%Cancer Chemotherapy
Chapter . >.B. &at@ung
$NA
%NA
Protein
e.g. tubulin
Purines an!Pyrimi!ines
Aspara-inase
Tu*ulin *in+ers
Al'ylatin- a-entsTopoisomerase )nh.
Antimeta*olites
Chemotherapy echan*sms of ct*on
M K Cli i ll 9 f l Al l ti A tCancer Chemotherapy
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MaKor Clinically 9seful Alylating Agents
1.
>is(mechloroethyl)amines Nitrosoureas A@iri!ines
Cancer Chemotherapy
Chapter . >.B. &at@ung
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:"
Crosslin'in-: Loining to or more molecules by a co1alent bon!. his can
either occur in the same stran! (intrastran! crosslin) or in the opposite stran!s
of the $NA (interstran! crosslin). Crosslins also occur beteen $NA an!
protein. $NA replication is bloce! by crosslins hich causes replicationarrest an! cell !eath if the crosslin is not repaire!.
An 8Eample of $NA Crosslining
H2N
O
N
N
HN
N
HO
O
OP
O
NH2
O
N
NNH
N
OO
P
OH
O
N
R
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:1Cancer Chemotherapy
Chapter . >.B. &at@ung
kyat*ng gents (Co,aent !N '*nd*ng drugs)
+. he first class of chemotherapy
agents.". Stop tumor groth by cross-lining guanine nucleobases in$NA !ouble-heliE stran!s -!irectly attacing $NA.
#. his maes the stran!s unable touncoil an! separate.
,. As this is necessary in $NAreplication the cells can no longer!i1i!e.
. Cell-cycle nonspecific effect4. Alylating agents are also
mutagenic an! carcinogenic
A
C B
CB
B A
B C
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8.g. Mechlorethamine (Nitrogen Mustar!s)
::Cancer Chemotherapy
Chapter . >.B. &at@ung
h h d
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:3
Cycophospham*de
Cyclophosphami+e is an alylating agent. t is a i!ely use! as
a $NA crosslining an! cytotoEic chemotherapeutic agent.
•t is gi1en orally as ell as intra1enously ith efficacy.
•t is inacti1e in parent form an! must be acti1ate! to cytotoEic
form by li1er CI,3 li1er microsomaal system to ,-2y!roEycyclophami!e an! Al!ophosphami!e.
•,-2y!roEycyclophami!e an! Al!ophosphami!e are !eli1ere! to
the !i1i!ing normal an! tumor cells.
• Al!ophosphami!e is con1erte! into acrolein an!
phosphorami!e mustar!.
•hey crosslin $NAs resulting in inhibition of $NA synthesis
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:4
Cycophospham*de eta'o*sm
nacti1e
C h h *d
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:5
Cycophospham*de
Clinical Applications:
". >reast Cancer
#. ?1arian Cancer
,. Non-2o!gins
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:6
Cycophospham*de
MaKor Si!e effects
#. Nausea an! 1omiting
,. $ecrease in P>< count
. $epression of bloo! cell counts4. >lee!ing
5. Alopecia (hair loss)
/. Sin pigmentation
. Pulmonary fibrosis
Cancer Chemotherapy
Chapter . >.B. &at@ung
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:7
9fospham*de
echan*sms of ct*on
2*m*ar to cycophospham*depp*cat*on
,.Berm cell cancer
.Cer1ical carcinoma4.
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:%
". Mechanism o#
Action
$. Clinical application %. &oute '. Side e##ects
a. Nitrogen Mustards
A. echoretham*ne !N cross#*nksresut*ng *n
*nh*'*t*on of !N
synthes*s and
funct*on
odgk*n&neuro'astoma
=ray and 9-?- 2ame as a'o,e
C. Choram'uc* 2ame as a'o,e Chron*c ymphocyt*c
eukem*a
=ray effect*,e 2ame as a'o,e
D. ephaan 2ame as a'o,e ut*pe myeoma 'reast
o,ar*an
=ray effect*,e 2ame as a'o,e
. 9fosfam*de 2ame as a'o,e /erm ce cancer cer,*cacarc*noma ung odgk*ns
and non#odgk*ns
ymphoma sarcomas
=ray effect*,e 2ame as a'o,e
A. Al'ylatin- a-ents
Cancer Chemotherapy
Chapter . >.B. &at@ung
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:.
". Mechanism o# Action $. Clinical application %. &oute '. Side e##ects
b. Alkyl Sulfonates
A. Busufan typ*ca akyat*ng agent- Chron*c granuocyt*c
eukem*a
=ray effect*,e Bone marrow depress*on
pumonary f*'ros*s and
hyperur*cem*a
c. Nitrosoureas ". Mechanism o# Action $. Clinical application %. &oute '. Side e##ects
A. Carmust*ne !N damage *t can
cross 'ood#'ra*n 'arr*er
odgk*ns and non#
odgk*ns ymphoma 'ra*n
tumors /-9- carc*noma
/*,en 9-?- must 'e
g*,en sowy-
Bone marrow depress*on
CN2 depress*on rena
to0*c*ty
. omust*ne omust*ne akyates and
cross*nks !N there'y
*nh*'*t*ng !N and @N
synthes*s- so
car'amoyates !N and
prote*ns resut*ng *n
*nh*'*t*on of !N and @N
synthes*s and d*srupt*on of
@N process*ng- omust*ne
*s *poph**c and crosses the
'ood#'ra*n 'arr*er
odgk*ns and non#
odgk*ns ymphoma
ma*gnant meanoma and
ep*dermo*d carc*noma of
ung
=ray effect*,e Nausea and ,om*t*ng
Nephroto0*c*ty ner,e
dysfunct*on
C. 2treptootoc*n !N damage pancreat*c cancer /*,en 9-?- Nausea and ,om*t*ng
nephroto0*c*ty *,er to0*c*ty
A. Al'ylatin- a-ents
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3"
d. Ethylenimines ". Mechanism o#
Action
$. Clinical application %. &oute '. Side e##ects
A. &r*ethyene
th*ophosphoram*de
(&h*o#&$;)
!N damage
Cytochrome
;45"
Badder cancer /*,en 9-?- Nausea and ,om*t*ng
fat*gue
. e0amethymeam*ne
()
!N damage d,anced o,ar*an tumor /*,en oray after
food
Nausea and ,om*t*ng ow
'ood counts d*arrhea
d. Triazenes ". Mechanism o#
Action
$. Clinical application %. &oute '. Side e##ects
A. !acar'a*ne (!&9C) Bocks !N @N and
prote*n synthes*s
a*gnant eanoma
odgk*ns and non#
odgk*ns ymphoma
/*,en 9-?- Bone marrow depress*on
hepatoto0*c*ty
neuroto0*c*ty 'eed*ng
'ru*s*ng 'ood cots sore
mouths-
A. Al'ylatin- a-ents
Cancer Chemotherapy
Chapter . >.B. &at@ung
2
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31
2ummary
Cancer Chemotherapy
Chapter . >.B. &at@ung
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3:
&u'u*n B*nd*ng gents
αα
ββ
Polymeri@ation
tubulin
$epolymeri@ation
e.g. Gincristine
Ginblastine Gin!esine
Ginorelbine: nhibition
of mitotic spin!le
formation by bin!ing to
tubulin.
M-phase of the cell
cycle.
e.g. PacliteEal: bin!s
to tubulin promotes
microtubule formation
an! retar!s
!isassembly results in
mitotic arrest.PacliteEal (taEol)
Gincristine
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. !atural *roducts
33
". Mechanism o# Action $. Clinical application %. &oute '. Side e##ects
A. ?*ncr*st*ne Cytoto0*c 9nh*'*t*on of
m*tot*c sp*nde format*on
'y '*nd*ng to tu'u*n-
#phase of the ce cyce-
etastat*c test*cuar cancer
odgk*ns and non#odgk*ns
ymphoma Aapos*
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34
". Mechanism o# Action $. Clinical application %. &oute '. Side e##ects
A. toposide B*nds to and *nh*'*ts
&opo*somerase 99 and *ts
funct*on- ragmentat*on of
!N ead*ng to ce death
apoptos*s-
&est*cuar cancer sma#ce
ung carc*noma odgk*n
ymphoma carc*noma of
'reast Aapos*
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35Cancer ChemotherapyChapter . >.B. &at@ung
#. Anti*iotics CCS>
". Mechanism o# Action $. Clinical application %. &oute '. Side e##ects
a. Dactinomycin
(ACT+!,MC+! D)
9t '*nds to !N and *nh*'*ts
@N synthes*s *mpa*red
m@N product*on and
prote*n synthes*s
@ha'domyosarcoma and >*mDs
tumor *n ch*dren
chor*ocarc*noma (used w*th
methotre0ate
9-?- Bone marrow depress*on nausea
and ,om*t*ng aopec*a
/9 d*stur'ances and ucerat*ons of
ora mucosa
. Daunoruicin
(C&/+D+!)
Do0oruicin
(AD&+AMC+!)
*nh*'*t !N and @N
synthes*s
cute ymphocyt*c+granuocyt*c
eukem*as treatment of
cho*ce *n nonympho'ast*c
eukem*a *n aduts when
g*,en w*th cytara'*ne
9-?- 2*de effects 'one marrow
depress*on /9 d*stur'ances and
card*ac to0*c*ty (can 'e pre,ented
'y de0rao0ane)
*nh*'*t !N and @N
synthes*s
cute eukem*a odgk*nDs
d*sease non odgk*nDs
ymphomas (BC=; reg*men) C
of 'reast E o,ary
sma ce C of ung sarcomas
'est a,a*a'e agent
for metastat*c thyro*d C
9-?- Card*ac to0*c*ty !o0oru'*c*n
ma*ny affects the heart musces
ead*ng to t*redness or 'reath*ng
trou'e when c*m'*ng sta*rs or
wak*ng swe*ng of the feet -
c. leomycin
(1!,2A!)
fragment !N cha*ns and
*nh*'*t repa*r
/erm ce tumors of testes and
o,ary e-g- test*cuar
carc*noma (can 'e curat*,e when
used w*th ,*n'ast*ne E c*spat*n)
sFuamous ce carc*noma
/*,en
9-?- or
9--
ucosocutaneous react*ons and
pumonary f*'ros*s 'one
marrow depress*on much ess than
other ant*neopast*cs
nhibit $NA an! %NA syntheses
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36Cancer ChemotherapyChapter . >.B. &at@ung
". 1n?ymes: Laspara-inase
". Mechanism o# Action $. Clinical application %. &oute '. Side e##ects
1-asparaginase ydroyes #asparag*ne (to
#aspart*c ac*d) an
essent*a am*no ac*d to
many eukem*c ces
cute ymphocyt*c eukem*a
*nduct*on of rem*ss*on *n acute
ympho'ast*c eukem*a when
com'*ned w*th ,*ncr*st*ne
predn*sone and anthracyc*nes
9-?- or
9--
Nausea and ,om*t*ng ;oor
appet*te 2tomach cramp*ng
outh sores ;ancreat*t*s- ess
common 'ood cott*ng
MO
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37
C. Antimeta*olites
%e!uce!
Jolate
Carrier
protein
MO
&ills cells
!uring
S-phase
(Jolic aci! analog)polyglutamates
Are selecti1ely
retaine!
n tumor cells.
Jolic aci! is a groth factor that pro1i!es single
carbons to the precursors use! to form the
nucleoti!es use! in the synthesis of $NA an!
%NA. o function as a cofactor folate must be
re!uce! by $2J% to 2J-
Cancer ChemotherapyChapter . >.B. &at@ung
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3%Cancer ChemotherapyChapter . >.B. &at@ung
". Mechanism o# Action $. Clinical application %. &oute '. Side e##ects
".
Methotre0ate
*nh*'*ts format*on
of 4
(tetrahydrofoate)
from fo*c
ac*d 'y *nh*'*t*ng
the enyme
d*hydrofoate
reductase (!@)s*nce 4 transfers
methy groups
essent*a to !N
synthes*s and
hence !Nsynthes*s 'ocked-
Chor*ocarc*noma
acute
ympho'ast*c
eukem*a
(ch*dren)
osteogen*c
sarcoma Burk*ttDs
and other non#odgk*nGs
ymphomas cancer
of 'reast o,ary
'adder head E
neck
=ray
effect
*,e as
we
as
g*,en
9-?-
'one marrow
depress*on
*ntest*na es*ons
and *nterference
w*th
em'ryogenes*s-
!rug *nteract*on
asp*r*n andsufonam*des
d*space
methotre0ate
from pasma
prote*ns-
C. Antimeta*olites
-
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3.
". Mechanism o#
Action
$. Clinical application %. &oute '. Side e##ects
$ *yrimidine Analogs
Cytosine Arainoside
*nh*'*ts !N
synthes*s
most effect*,e agent for *nduct*on of
rem*ss*on *n acute myeocyt*c
eukem*a aso used for *nduct*on of
rem*ss*on acute ympho'ast*c eukem*a
non#odgk*nDs ymphomas usuay used
*n com'*nat*on chemotherapy
=ray
effect*,e
'one marrow
depress*on
". Mechanism o#
Action
$. Clinical application %. &oute '. Side e##ects
$ *urine analogs
3-Mercaptopurine (3-M*) and Thioguanine
Bocks !N synthes*s
'y *nh*'*t*ngcon,ers*on of
9; to ;2 and to
H; as we as
'ock*ng con,ers*on
of ; to
!; aso 'ocks f*rst
step *n pur*ne
synthes*s-
eed'ack *nh*'*t*on'ocks !N synthes*s
'y *nh*'*t*ng
con,ers*on of 9; to
H; as we as /;
to /!; aso 'ocks
f*rst step *n pur*ne
synthes*s 'y
feed'ack *nh*'*t*on
most effect*,e agent for *nduct*on of
rem*ss*on *n acute myeocyt*ceukem*a aso used for *nduct*on of
rem*ss*on acute ympho'ast*c eukem*a
non#odgk*nDs ymphomas usuay used
*n com'*nat*on chemotherapy
=ray
effect*,e
'one marrow
depress*on
-
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4"Cancer ChemotherapyChapter . >.B. &at@ung
6- !rug @es*stance
?ne of the fun!amental issue in cancer chemotherapy is the !e1elopment
of cellular !rug resistance. t means tumor cells are no longer respon! to
chemotherapeutic agents. Jor eEample melanoma renal cell cancerbrain cancer often become resistant to chemo.
A fe7 'no7n reasons:
.Mutation in p# tumor suppressor gene occurs in 3; of all tumors.
his lea!s to resistance to ra!iation therapy an! i!e range of
chemotherapy.
5.$efects or loss in mismatch repair (MM%) en@yme family. 8.g. colon
cancer no longer respon! to fluoropyrimi!ines the thiopurines an!
cisplatins.
.ncrease! eEpression of multi!rug resistance M$%+ gene hich
enco!es P-glycoprotein resulting in enhance! !rug effluE an! re!uce!
intracellular accumulation. $rugs such as athracyclines 1inca alaloi!s
taEanes campothecins e1en antibo!y such as imatinib.
2ummary
-
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2ummary+. he main goal of anti-neoplastic !rug is to eliminate the cancer cells
ithout affecting normal tissues. 8arly !iagnosis is the ey.
". ecause chemotherapeutic agents target not only tumor cells but also
affect normal !i1i!ing cells inclu!ing bone marro hematopoietic an!
B epithelium. &no hat the si!e effects are.
• $rug resistance is often associate! ith loss of p# function $NA
mismatch repair system an! increase! M$%+ gene eEpression.