Antineoplastic Agents 2011 Dental MARCH-1

8/16/2019 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


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


.


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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.

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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


PA%

". Mechanisms of action#. Si!e 8ffects

#. $rug %esistance

;harmacoogy of nt*neopast*c gents


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1%Cancer Chemotherapy


$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



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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


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


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



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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


. 9fosfam*de 2ame as a'o,e /erm ce cancer cer,*cacarc*noma ung odgk*ns

and non#odgk*ns

ymphoma sarcomas


A. Al'ylatin- a-ents

Cancer Chemotherapy



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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



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3"

d. Ethylenimines ". Mechanism o#

Action


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


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-


Cancer Chemotherapy


2


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31

2ummary

Cancer Chemotherapy



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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


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


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>


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


36/41

36Cancer ChemotherapyChapter . >.B. &at@ung

". 1n?ymes: Laspara-inase


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


".

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


$ *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


$ *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


41/41

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.

Antineoplastic Agents 2011 Dental MARCH-1

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