uhn 2013 anti cancer drugs

7/26/2019 Uhn 2013 Anti Cancer Drugs.

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Dr. Datten Bangun MSc,SpFK

Dept. Farmakologi dan Terapeutik,Fakultas KedokteranUniversitas HKBP Nomensen

Cancer Chemotherapy (1)


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SITOSTATIKA (CYTOSTATICS)

INTRODUCTION :

Cyto : CellsStatic : statis

Synonim : - Cancer chemotherapy

- Cytotoics- Antineoplastics


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The !iolo"y o# Cancer

Special characteristics o# cancer cells$

%$ Uncontrolle& proli#eration

'$ De&i##erentiation an& loss o##nction$

$ In*asi*eness

+$ ,etastasis


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The Cell Cycle and Cancer


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The cell cycle ' ey e*ents :

I$ S phase : Synthesis

o# DNA

II$ , phase : Di*ision o#

parent cell into t.o

&a"hter cells &rin"

mitosis$/%("ap) : Synthesis o# celllar

components nee&e& #or

DNA synthesis$

/' : Synthesis o# celllar

components #or mitosis


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I,0ORTANC1 O2 C133 CYC31 KIN1TICS

Based on informations of cell cycle cytotoxic

drugs are devided into two classes.

%$ Cell cycle - speci#ic a"ents 4 CCS - a"ents

CCS drugs most effective in :

- Haematologic malignancies

- Solid tumors which are proliferatingor are in "ro.th #raction$

'$ Cell cycle- Nonspeci#ic a"ents4CCNS -a"ents

CCNS drugs are useful in :- Low growth fraction solid tumors

Note : rowth fraction ! the ratio of the num"er of

cells that are proliferating to the total num"er

of cells in the tumor.


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DNA mutations disrupt the cell cycle.

Mutations maybe caused by:

1. radiation 2. smoking 3. Pollutants 4. chemicals

5. viruses


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Cells division

Normal Cell ivision

1. N! is re"licated

"ro"erly.2. Chemical signals

start and sto" thecell cycle.

3. Cells communicate#ith each other sothey don$t becomeovercro#ded.

Cancer Cells

1. Mutations occur inthe N! #hen it is

re"licated.

2. Chemical signals thatstart and sto" thecell cycle are ignored.

3. Cells do notcommunicate #itheach other andtumors %orm.


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General principles in the use:

cytostatics interfere with several different stages

of the cell cycle and so open the way to therational use of drug combinations.

Cycle non-specific drugsact at all stages inthe proliferating cell cycle

(but not in the G0resting phase)

Phase-specific drugsact only at a specific phase :

the more rapid the cell turnover the more effective

they are.


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&Chemothera"y&

# 'e%ers to the use o% conventional cytoto(ic

drugs in addition to hormonal and

endocrine thera"y.

# )riginally started in 1*41+ #hen ,oodman

and ,ilman -rst administered nitrogenmustard to "atients #ith lym"homa.

Cancer chemothera"y may be

# Primary# Palliative

# !duvant

# neoaduvant


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M

S

GG2 1 H y d r o c o r t i s o n e

o l c h i c i n e! i n c r i s t i n e! i n b l a s t i n e

G 0

y c l o p h o s p h a m i d e" l e o m y c i n# c t i n o m y c i n $

# c t i n o m y c i n $% & ' l u o r o u r a c i l y t o s i n e a r a b i n o s i d e( e t h o t r e ) a t e* & ( e r c a p t o p u r i n e

* & + h i o g u a n i n e

, u r i n e a n t a g o n i s t s( e t h o t r e ) a t e y c l o p h o s p h a m i d e% & ' l u o r o u r a c i l y t o s i n e a r a b i n o s i d e

$ a u n o m y c i n

The cell cycle and the phase specificity of some cytotoxic drugs.

G0 resting phase

G! prereplicati"e phaseG# postoperati"e phase

S $%& synthesis

M mitosis or cell di"ision


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CANC1R C51,OT51RA0Y

$. Concepts

%$ Cell cycle inetics : Cell cycle-specific %CS& drugsact on tumor cells during the mitotic cycle and are

usually phase specific. 'ost anticancer drugs are cell

cycle-nonspecific %CCNS&( )illing tumor cells in "oth

resting and cycling phases.'$ 3o" ill : $ntitumor drug treatment )ills a fixed

proportionof a cancer cell population rather than a

constant num"er of cells. $ *-log-)ill dose of a drug

reduces cancer cell num"ers "y three orders ofmagnitude.

$ Resistance :+sta"lished mechanisms of tumor cell

resistance to anticancer drugs.

,. oxicities : rug-specific toxicities.


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Principles of chemotherapy

N! synthesis

$ntimeta"olites$ntimeta"olites

N$

N$ transcription N$ duplication

'itosis

$l)ylating agents$l)ylating agents

Spindle poisonsSpindle poisons

/ntercalating agents/ntercalating agentsCelllar le*elCelllar le*el

Action sites of cytotoxic agents


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6-MERCAPTP!R"NE

6-T#"$!AN"NE

MET#TRE%ATE

&-'(!R!RAC"(

#)DR%)!REA

C)TARA*"NE

0URIN1 SYNT51SIS0URIN1 SYNT51SIS 0YRI,IDIN1 SYNT51SIS0YRI,IDIN1 SYNT51SIS

RI!ONUC31OTID1SRI!ONUC31OTID1S

D1O6YRI!ONUC31OTID1SD1O6YRI!ONUC31OTID1S

DNADNA

RNARNA

0ROT1INS0ROT1INS

,ICROTU!U31S,ICROTU!U31S1N7Y,1S1N7Y,1S

L-$S0$1$/N$S+

2/NC$ $L3$L4/S

$54/S

$L36L$/N $+NS

$N/B/4/CS

+404S/+

Action sites of cytotoxic agents


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CYTOTO6IC DRU/S

%$ ,echanisms o# action :he alylatin"

a"ents are CCNS drugs.a.hey interact covalently with N$ "ases(

especially at the N-7 position of guanine.

".Nucleic acid functions are disrupted dueto cross-lin)ing( a"normal "ase pairing(

and N$ strand "rea)age.

A$ Alylatin" A"ents

! & ' ( ) ' & T * % G &G+%TS! & ' ( ) ' & T * % G &G+%TS C i


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!. & ' ( ) ' & T * % G &G+%TS:!. & ' ( ) ' & T * % G &G+%TS:Cyclophosphamide,*fosphamide, Chlorambucil, %itrosoureas

Cell- cycle-nonspecific drugs

-combine ith $%& of both malignant and normal cells and

thus damage not only malignant cells but also di"iding normal

cells the bone marro and the G*T/

-mechanisms: the alyl groupings ethyleneimine ions and

positi"ely charged carbonium ions/ are highly reacti"e, so that

combine ith susceptible groups in cells and in tissue fluids

S1, P23/

The alylating action on $%& leads toabnormal baseabnormal base

pairing or intra and interstrand links with DNA moleculepairing or intra and interstrand links with DNA molecule

-cytotoxic, mutagenic and teratogenic effects may result

from interaction ith $%&


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#

$ #

+

G

G

G#+

G

#

G

#

+

G

G

+

i . e .# l / y l a t i n ga g e n t

( e c h a n i s m o f i n t r a m o l e c u l a r b r i d g i n g o f $ # b y a l / y l a t i n g a g e n t s .

# a d e n i n e c y t o s i n eG g u a n i n e

+ t h y m i d i n e


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Cyclophosphamide

4 an inacti"e prodrug

4 can be gi"en orally

is acti"ated by the C)P350 in li"er as ell as in tumors.

ith time, the acti"e metabolite and also acrolein areformed. The latter compound is responsible for

bladder toxicity chemical hemorrhagic cystitis/.

a ide spectrum antitumor and immunosuppressi"eacti"ity used as a part of combination therapy

regimens to treat lymphoma, breast cancer, bladder

cancer, o"arian cancer

and "arious children malignancies


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T o x i c i t i e s:

bone marro depression, granulocytopenia,

thrombocytopenia.

urotoxicity appears ith chronic therapy -M e s n a 6 dimesna

#-mercaptoethane sulfonate sodium/ protects the

urinary tract against the irritant effects by supplying

sulfhydryl groups to form a stable thioether ithacrolein. Mesna is gi"en by *7 in8ection or by mouth

The nitrosoureas:Carmustine and 'omustine are potebone marro toxins. 1epatotoxicity and nephrotoxicity.

9road spectrum of acti"ity solid tumors, in particular

brain tumors/.

! A ti t 8 lit


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!$ Antimeta8olites

8. ,echanisms o# action: $ntimeta"olites are CCSdrugs.

a. hey are structurally similar to endogenouscompounds.

". $nticancer and immunosuppressive actions resultfrom interference with the meta"olic functions of

folic acid( purines( and pyrimidines.9. ,ethotreate (,T6)is an analog of folic acid that

inhi"its dihydrofolate reductase and otherenymes in folic acid meta"olism.

a. /t is used %orally and intravenously& in acuteleu)emias( "reast cancers( and non-Hodg)in;s and-cell lymphomas.

8$ 2olinic aci& (leco*orin) is used to reverse '5

toxicities and full hydration is needed to preventcr stalluria.

* , t i (9 ,0) i hi"it i t " li


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*. ,ercaptoprine (9-,0) inhi"its purine meta"olismfollowing its activation "y hypoxanthine guaninephosphori"osyl transferase %H01&.

a. 1esistant cells may lac) H01.".


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C$ 0lant Alaloi&s (CCS Dr"s)

8. 1toposi&eandteniposi&e act in late S and

early 9phases( inhi"iting topoisomerases.a.hey are used in regimens for lung %small

cell&( prostate( and testicular cancers.

".hese agents cause myelosuppression.

9. 0aclitael and &ocetael act in the ' phaseto "loc) mitotic spindle disassem"ly.

a. hey are used in advanced "reast andovarian cancers.

". Significant myelosuppression occurs( "utperipheral neuropathy is distinctive.


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*. ;in8lastine and *incristine act in the '

phase to "loc) mitotic spindle assem"ly.

a. hey are widely used in com"ination

regimens for acute leu)emias( Hodg)in;s and

other lymphomas( 3aposi;s sarcoma(

neuro"lastoma( and testicular cancer.

". 2incristine is neurotoxic

c. 2in"lastine suppresses "one marrow.


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D$ Anti8iotics

8. !leomycin is a glycopeptide mixture %CCS&

that alters nucleic acid functions via free

radical formation.

a./t is used in regimens for Hodg)in;s and otherlymphomas and suamous cell and testicular

cancers.

".0ulmonary toxicity( s)in thic)ening( and "yhypersensitivity reactions are distinctive.


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9. Door8icin and &anor8icin are

anthracyclines %CCNS& that intercalate with

N$( inhi"it topisomerases( and form free

radicals.

a.oxoru"icin is widely used in "reast(

endometrial( lung( and ovarian cancers and in

Hodg)in;s lymphoma.

".aunoru"icin is used in leu)emias.

c. 'yelosuppression is mar)ed( "utcardiotoxicity is dose limiting.


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$ Other anti8iotics incl&e &actinomycin

an& mitomycin$

a.actinomycin %CCNS& inhi"its N$-

dependent 1N$ synthesis and is used in

melanoma and ilms;tumors.

".'itomycin %CCNS& is "iotransformed to an

al)ylating agent and is used for hypoxic

tumors.

c. Both of these agents cause "one marrow

suppression.D


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2$ ,iscellaneos Anticancer A"ents$

%$ Aspara"inase depletes serum asparagine and

is used in auxotrophic -cell leu)emias andlymphomas. /t causes "leeding( hypersensitivity

reactions( and pancreatitis.

'$ Inter#eronsinclude interferon-alfa( which is used

in early-stage chronic myelogenous leu)emia(hairy cell cancers( and -cell lymphomas.

/nterferons cause myelosuppression and

neurotoxicity.

$ ,onoclonal anti8o&ies$

a$ /emt


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8$ Ritima8 interacts with a surface protein of

non-Hodg)in;s lymphoma cellsF toxicities include

myelosuppression and nypersensitivity reactions.

c$ Trast


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. P'&T*%M C2MP2%$S

Cisplatincis-diaminedichlorplatinum/ is an inorganicplatinum complex.

mechanism of action:$%& synthesis by formationof intra-and interstrand cross-lins ith $%& molecule.

&d"erse effects, toxicity:

se"ere "omiting

nephrotoxicity is dose-relatedacute distal tubular necrosis/.

Prevention:the patients is fully hydrated by *7 infusion

combined ith manitol and furosemide.

hypomagnesemia

ototoxicity de"elops in up to ;0


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Cisplatinis the most effecti"e single agent

in testicular teratomas, but is usually gi"en

in combination ith other cytotoxic drugs.

Cisplatin has been used ith some succes in head and nec

and bladder cancers -*7 .

Carboplatinis less toxic renal toxicity or ototoxicity/,

neuropathy is rare and "omiting although common,

is less se"ere than after cisplatin.

2xaliplatin

5 12=M2%+S and antagonists


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5. 12=M2%+S and antagonists1ormon can cause remission in certain types of cancer

breast and prostate/.

>ays in hich hormones can affect malignant cells: a direct cytotoxic action on the malignant cells.

This is liely if cancer cells that are normally dependent

on a specific hormone are exposed to a high concentration

of a hormone ith the opposite effect if a carcinomaarises from cells of the prostate that are testosterone

dependent, 6.estrogens in large doses are cytotoxic

to the cancer/

a hormone may suppress production of the hormonesby a feedback mechanism.

+strogensare used in the management of prostaticand breast carcinoma


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Progestogens: megesteron,

medroxy-progesteron acetate:

*ndication: -adenocarcinoma of the body of the uterus

- in ad"anced breast cancer,

- carcinoma of the idney.

G l u c o c o r t i c o s t e r o i d s:

are cytotoxic to lymphoid cells

are usedith combination ith other cytotoxic agents in treating:

lymphomas, myeloma and

to induce a remission in acute lymphoblastic


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1 o r m o n e a n t a g o n i s t s:- &nti-estrogens:

tamoxifen- in breast tissue competes ithendogenous estrogens for the estrogen receptors

and inhibits the transcription of estrogen-responsi"e

genes.

is remarably effecti"e in some cases of

hormone-dependent breast cancer

- &nti-androgens:

flutamideis used in prostate tumors- &drenal hormone synthesis inhibitors:inhibitsex hormone synthesis. &minoglutethimide.


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&minoglutethimide

inhibits adrenal synthesis of estrogens,

glucocorticoids and mineralocorticoids

by inhibition of the en?yme producing

their common precursor- pregnandione

inhibits tissue aromatase blocing con"ersion

of androgens to estrogens.

2"arian aromatase is resistant to

this inhibition, so aminoglutethimide is onlyuseful in postmenopausal omen.

Ph i i


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Pharmacoinetics:polymorphic acetylation to an inacti"e %-acetyl

metabolite. @ast acetylators - slo acetylators.

&d"erse effects:

di??iness, lethargy are common on starting treatment

but decline during chronic dosing

probably due to en?yme induction/.

sage:

&. is effecti"e in about ;0< of postmenopausal patients

ith best effects on sin and breast disease.The response of bone metastases is also good.


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5ormones

%$ /lcocorticoi&s include pre&nisone= which

is used in com"ination regimens forHodg)in;s lymphoma and leu)emias.

'$ /ona&al hormones include the palliative use

%rare& of androgens in estrogen dependentcancers in women and the use of estrogens

in prostate cancer.

$ /ona&al hormone anta"onistsinclude

estrogen receptor "loc)ers %tamoi#en andtoremi#ene& and the androgen receptor

"loc)er #ltami&e$hey are used for tumors

responsive to gonadal hormones.


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+$ /ona&otropin-releasin" hormone analo"s

include leproli&e and na#erelin( which

decrease follicle-stimulating hormone %@SH&

and luteiniing hormone %LH& if used in

constant doses.

$ Aromatase inhi8itorsinclude anastro


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Princi"les o% chemothera"y

INCREASED EFFICACYINCREASED EFFICACY

ifferent mechanisms of action Compati"le side effects

ifferent mechanisms of resistance

ACTI;ITYACTI;ITY SA21TYSA21TY

Aim of combination therapy


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Problems With Cancer Chemotherapy

# Drug Resistance

# Drug Toxicity


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Mesna+, mercaptoethanesulfonate+

forms a comple/ 0ith acrolein1the

meta2olite of cyclophosphamide that causes

2ladder

to/icity$era1oane2bloc/s the formation of free radicalsthat are responsible for the cardiotoicity of doo

rubicin

'olinic acid is used to reverse +3 toicity


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Drug Resistance

De novo Resistance# Acquired Resistance

# Multidrug Resistance (MDR)

$e no"o resistance:

$e no"o resistance can be de no"o genetic i.e. the cells

are initially inherently resistant/, or

can arise because drugs are unable to reach the target

cells because of permeability barriers such as the blood-

brain barrier.


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Drug Resistance

Acquired Resistance:# Acquired drug resistance may result from

genomic mutations, such as the induction ordeletion of enzymes involved in drug inactivationor drug activation, resectively!

Multidrug Resistance (MDR):"#glycorotein transorts many naturally

occurring drugs out of neolastic cells, and itsinduction may lead to multidrug resistance!As scientific understanding of the mechanismsof drug resistance increases, ne$ treatments

may %e develoed to counteract resistance!


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=+S*ST&%C+

primary: non-responsi"e tumors/

aAuired:

- reduced uptae of drugs

- deletion of en?yme to acti"ate drug- increased detoxication of drug- increased concentration of target en?yme

- rapid repair of drug-induced lesion

- decreased number of receptors for drug- increased efflux



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/0'!C/!'/0'!C/!' N'!C/!'N'!C/!'

AT0AT0

0/00/0%>?%>? AT0AT0

Dr"Dr"

Dr"Dr"

0lasma0lasma

,em8rane,em8rane

Drug resistance

h i f ll l d i


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echanisms of cellular drug resistance

reduced uptaeof drugs

deletion of en?yme

to acti"ate drug

increased

detoxication of drug

acti"e

metabolite

inacti"ated

cytotoxic drug

increased effluxmultidrug resistance/

C

increased

concentration

of target molecules

+& cellular target

4+ & gene amplification

BT

T

rapid repair of drug-

induced lesion

defecti"e cellular target

,U3TIDRU/ R1SISTANC1 (,DR)


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,U3TIDRU/ R1SISTANC1 (,DR)

Resistance to mltiple anticancer &r"s

may occr #rom increase& epression o#the ,DRI (,DR Type I) "ene #or cell

sr#ace "lycopreteins (0-"lycoproteins)

in*ol*e& in &r" e##l$ Sch &r" transporters (not limite& to

cancer cells) se AT0 to &ri*e &r"

molecles ot o# a cell a"ainst a

concentration "ra&ient$ ;erapamil (a calcim channel anta"onist)

inhi8its these &r" transporters$

Ta8el Resistance to anticancer &r"s


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Ta8el$ Resistance to anticancer &r"s$

Mechanisms of Resistance Anticancer Drugs Affected

/ncreased N$ repair $l)ylating agents

@ormation of trappingagents

$l)ylating agents

Changes in target enymesor receptors

+toposide( gonadalhormones( methotrexate(vincristine( vin"lastine.

ecreased activation ofprodrugs


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Drug Toxicity

The most common toxicities of antineolastic

drugs result from inhi%ition of cell

relication in the %one marro$,

gastrointestinal eithelium, and hair follicles!

Many antineolastic drugs also stimulate thechemorecetor trigger zone in the medulla

and there%y elicit nausea and vomiting!


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oxicities( which can "e severe( include

alopecia( gastrointestinal distress( neutropenia(

throm"ocytopenia( and possi"le sterility.

/n addition( patients on the $B2 regimen may

suffer the pulmonary toxicity of "leomycin and a

delayed cardiomyopathy caused "y doxoru"icin.

Ta8el$ Anticancer &r"-speci#ic toicities$


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Ta8el$ Anticancer &r" speci#ic toicities$

Drug Specific Toxicities

Bleomycin; 0ulmonary fi"rosis( fevers( s)in hardening and

"listers( anaphylaxis.Cisplatin; Nephrotoxicity( acoustic and peripheral neuropathy.

Cyclophosphamide

Hemorrhagic cystitis-mesna is protective %trapsacrolein&F ifosfamide is similar to cyclophosphamide.

oxoru"icinanddaunoru"icin

Cardiomyopathy %eg( delayed heart failure&-dextraoxane is protective %decreases free radicalformation&F liposomal forms are less cardiotoxic.

'ethotrexate

%'5&

'yelosuppression %use >leucovorin rescue?& and

mucositisF crystalluriaF toxicity is enhanced "y drugsthat displace '5 from plasma proteins %eg(salicylates( sulfonamides&.

2incristine; 0eripheral neuropathy %autonomic( motor( andsensory&F vin"lastine is less neurotoxicF paclitaxel

also causes sensory neuropathy.


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Mucositis

Nauseavomiting

iarrhea

Cystitis

6terility

Myalgia

Neuro"athy

$lopecia

0ulmonary fi"rosis

Cardiotoxicity

Local reaction

1enal failure

'yelosuppression

0hle"itis

Side effects of chemotherapy


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&d8u"ant therapy:

courses of cytostatic drugs are gi"en hen the cancer has

apparently been destroyed by surgery or radiotherapy.

*ts ob8ecti"e is to eradicate micrometastases.

%eoad8u"ant therapy:is defined as a preoperati"e cytostatic treatment,

in patients ith locally ad"anced solid tumors

the aims of neoad8u"ant chemotherapy B radiotherapy are:-the potentiality of curati"e resection,-the reduction of surgical measures, and

-an increase in life span.


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M * S C + ' ' & % + 2 S &G+%TS

Procarba?inedepresses $%& synthesis. *ts main use is in treating1odginDs disease.

* % T + = @ + = 2 % Shairy cell leuemia, lograde non-1odginDs

lymphoma, chronic myeloid leuemia.

T51 A!;D R1/I,1N IN 5OD/KIN@S DIS1AS1


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T51 A!;D R1/I,1N IN 5OD/KIN S DIS1AS1

Chemotherapy in cancer commonly involves the

use of drug com"inations to enhance antitumoractions and to prevent development of

resistance.

he A!;D re"imen includes &oor8icin(A&riamycin)= 8leomycin= *in8lastine= and

&acar8a


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*t is easy to ill cancer cells,but

the challenge is eeping thepatient ali"e at the same

time6..E


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hank you %or the


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hank you %or the

uhn 2013 anti cancer drugs

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