课件-chapter45.anticancer drugs p抗代谢药

Anticancer

DrugsYE

ShaojianAlsocalled:oplastic

DrugsCancer

chemotherapeutic

drugs§1

Basic

Pharmacology

ofAnticancer

DrugsI.

Classification

of

anticancer

drugs1.

according

tostructureAlkalyting

agent(烷化剂)tabolites（抗代谢药）AntitumorantibioticsPlant

alkaloidsHormonalagentsOthers2.

according

to

mechanism

of

actionDrugs

affecting

biosynthesis

of

nucleic

acidDrugs

destroying

DNA

structureandfunctionDrugs

interfering

with

transcription

and

blockingRNA

synthesisDrugs

affecting

protein

synthesisHormonalagentsAccording

to

Effect

on

cell

proliferation

kineticsTumor

cell

phaseG0

phaseCell

cycle:

G1→S→

G2

→Mgrowth

fraction，GFAnticancer

drugsCell

cycle

nonspecific

drugs(

CCNS)Cell

cycle

specific

drugs(CCS)II.

Mechanisms

of

anticancer

drugs1.

mechanism

of

cytotoxic

anticancerdrugsCell

cycle

nonspecific

drugs(

CCNS)Cell

cycle

specific

drugs(CCS)2.

mechanism

ofnon-cytotoxic

agentsBalance

hormones

in

the

bodyInduce

cancer

celldifferentiationInduce

apoptosis

of

cancer

cellsSuppress

the

vascular

growth

of

cancerIII.

Mechanisms

of

drugG0

cellP-glucoprotein§2

Cytotoxic

anticancer

drugsI.

Drugs

affecting

nucleic

acidsynthesis(

tabolites)Methothrexate

(MTX,

甲氨蝶呤)

CCS SphaseMechanism:

inhibit

dihydrofolate

redu e

(DHFR，二氢叶酸还原酶),interfering

synthesis

of

thymidylate,

purinenucleotidesClinical

uses:childhood

acu ymphoblastic

leukemia

andchorioepithelioma（绒毛膜上皮癌）Toxicity:

myelosuppressionFluorouracil

（5-Fu,

氟尿嘧啶）Pyrimidine

antagonistsMechanism:

convert

to

5F-dUMP

andinhibit

thynidylate

synthase,block

thesynthesis

of

dTMPClinical

uses:

good

effect

on

cancer

ofdigestive

tract,

breast

cancerToxicity

:

myelosuppression

and

mucositisMercaptopurine

（6-MP,巯嘌呤）Mechanism:

metabolized

by

HGPRTtothionosinate

(T-IMP)

and

inhibitsynthesisof

AMP

and

GMP

from

IMPClinical

uses:

childhood

acu

eukemiaToxicity

:

myelosuppression

andgastrointestinal

symptomsHydroyurea

(Hu,羟基脲)Inhibit

ribonucleotide

redu

eClinical

uses:

chronic

granulocytic

leukemiaToxicity:

bone

marrow

depression,

nausea,vomitingCytarabine

（Ara-C,阿糖胞苷）Ara-C

→Ara-CMP

→→Ara-CTP,competitively

inhibit

DNApolymeraseClinical

uses:

acute

granulocytic

leukemia,mononuclearcy

eukemiaToxicity:

severe

myelosuppression

,

nauseaetcII.

Drugs

destroying

DNA

structureandfunctionCCNSAlkylating

agentsAntitumor

antibioticsCisplatin（顺铂）

and

carbaplatinCamptothecins(喜树碱)1.

Alkylating

agentsCyclophosphamide

(CTX，环磷酰胺)CTX →aldophosphamide

→phosphoramide

mustardClinical

uses:

malignant

lymphoma,acuteleukemiaToxicity:

bladderitis（

炎）,alopecia（ ）,

nausea,

vomiting,myelosuppressionThiotepa(

TSPA,

噻替派)Clinical

uses:

breast

cancer,

ovarian

cancer,liver

cancer

etcToxicity:

myelosuppressionBusulfan(myleran,

白消安)Good

effect

on

chronic

granulocyticleukemiaToxicity:

myelosuppressionNitrosoureas(亚硝基脲)Drugs:carmustine(BCNU,卡氮芥),lomustine(CCNU,)Highlylipid-soluble,

can

crossBBBTreatment

of

brain

tumor2.

Cisplatin(顺铂)&

CarbaplatinClinical

uses:Genitourinary

cancers,

particular

ovarian

andbladdercancerTesticular

cancer:

in

combination

with

vinblastineandbleomycinToxicityAcute

toxicity:

nausea,

vomitingRenal

toxicity:

hydration

with

saline

infusion

&diureticsMyelosuppression3.

Antitumor

antibioticsBleomycin

（BLM,博莱霉素）Clinical

uses

:

treatment

of

squamous

cellcarcinoma

of

the

neck,

cervix,skin,penis

,rectum

and

in

combination

therapyfor

lymphomasToxicity:Severe:

pulmonary

fibrosisCommon:

anorexia,alopecia,

blisteringand

hyperkeratosis

of

paMitomycin

C(丝裂霉素)Clinical

uses:

adenocarcinomas

of

thestomach,

pancreas,lung

andbreastToxicitySevere:

myelosuppressionCommon:

nausea,

vomiting

andanorexia4.Topoisomerase

inhibitors(拓扑异构酶抑制剂)Camptothecins(喜树碱类)Drugs:

topotecan(TPT),

irinotecan(CPT-11)Mechanism:

interfere

with

the

activity

oftopoisomerase

ⅠClinical

uses:

cancer

of

lung,

stomach,

colon

etcNo

cross with

otheranticancer

drugsToxicityCommon:

nausea,

vomiting,alopeciaDose-limiting

effect:

neutropenia,thrombocytopeniaCPT-11:diarrheaPodophyllotoxins(鬼臼毒素衍生物)Etopsid(vepesid,

VP-16,鬼臼乙叉苷)Combined

with

microtubule

protein

and

inhibittheir

polymerization,

CCSTeniposide(VM-26,

泊苷)Inhibit

the

activity

of

topoisomerase

II,

CCNSIII.

Drugs

interfering

withtranscriptionDactinomycin(放线菌素D

)Doxorubicin

(ADM,多柔比星)Darnorubucin

(DNR,柔红霉素)Dactinomycin(放线菌素D

)Mechanism

bind

tightly

to

double-stranded

DNAthrough

interaction

between

adjacentguanine-cytosine

base

pair,

and

inhibitallforms

of

DNA-dependent

RNAsynthesisClinical

uses:

narrow-spectrum

In

combination

with

surgeryandvincristine(长春新碱）

intheadjuvanttreatment

of

Wi

tumorToxicity

:

evident

myelosuppressionDoxorubicin

(ADM,多柔比星)&Daunorubicin(DNR,柔红霉素

)MechanismBind

with

high

affinity

to

DNAthroughintercalation

and

thenblock

thesynthesisof

DNA

and

RNAClinicalusesADM:

one

of

the

most

important

anticancerdrugs

,

treatment

of

carcinoma

of

thebreast,

endometrium,

ovary,

testicle,thyroid,

lung

and

many a,

acuteleukemia,

Hodgkin’sdiseaseDaunorubicin:

acu

eukemiaAdverse

reactionsCardiac

toxicity:

most

severe

and

irreversiblySevere

or

total

alopecia

: at

standard

dosageMyleosuppression

:

short

duration

andrapidrecoveryIV.

Drugs

affecting

protein

synthesisVinblastine(VLB)

&

Vincristine(VCR)Podophyllotoxins

:

teniposide（VM-26）

andetoposide（VP-16）Taxanes

:

taxol

&

taxotereHarringtonine

&

Ho

rringtonineL-asparaginaseVinblastine（VLB,长春碱）&vincristine（VCR,

长春新碱）Mechanism

of

action

bind

specifically

to

the

microtubular

protein

tubulin（微管）

indimeric

form,

terminate

assembly

of

microtubules（抑制微管

）and

result

in

mitotic

arrest

（有丝

阻滞）at

metaphase（中期）,cause

dissolution

of

the

mitotic

spindle

（纺锤体溶解）and

finallyintefere

with

chromosome

segregationClinicalusesVLB:

systemic

Hodgkin’s

disease

and

other

lymphomaVCR:

acu eukemia

in

children

(

combination

with

predinisone)ToxicityVLB:

nausea,

vomiting,

alopecia（ ）,

myelosuppressionVCR:

neurotoxicity,include

muscle

weakness,peripheral

neuritis

andareflexia（无反射）Etoposide（VP-16）MechanismInhibit

topoisomerase

Ⅱ,

result

in

DNAdamage

through

strand

breakageClinical

usesVP-16:

lungandtesticularcancerVM-26:

brain

cancer

andlymphomaToxicity

nausea,

vomiting,

alopecia

andmyelosuppressionTaxol(紫杉醇)&

taxotereMechanismEnhance

tubulin

polymerization

and

promotemicrotubule

assemblyClinical

uses:

choice

for

ovarian

and

advancedbreastcancerToxicityHypersensitivityPeripheral

neuropathyNeutropenia

（WBC减少）,thrombocytopeniaHarringtonine(三尖杉生物碱类)

&Ho

rringtonineMechanismInhibit

thestart

stage

ofprotein

synthesis,pose

theribosomeClinical

use:Acute

granulocytic

leukemia

andacutemononuclear

leukemiaToxicityNausea,

vomiting,

leukopenia

and

heart

toxicityL-asparaginase

（

酰胺酶）MechanismDepletion

of

serum

asparagineandinhibitprotein

synthesis

in

neoplastic

cellsClinical

usesChildhood

acu

eukemia§3

Rationale

for

combination

ofoplastic

drugsCell

proliferating

kineticsThe

mechanism

of

the

drugsToxicity

of

the

combinational

drugsAnti-cancer

spectrumMethod

of

administering

drugsToxicity

of

the

anticancer

drugsAcute

toxicityCommon

toxicityMyleosuppressionGastrointestinal

disturbanceAlopeciaSpecific

toxicityCardiac

toxicity:

daunorubicinLiver

toxicity:

CTX,

dactinomycinBladder

toxicity:

CTXNeurotoxicity:

VCRHypersensitivity:

taxolChronic

toxicity:

infertility,

teratogenesis,

carcinogenesis§4

Non-cytotoxic

drugsI.

Hormonal

agentsAdrenal

corticosteroidsActue

leukemia,

lymphoma

and

m