Ungthu

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i hc Y DcThnh ph H Ch Minh

TS. Thi Khc Minh

B Mn Ha Dc

https://sites.google.com/site/thaikhacminh/daihocwww.facebook.com/thaikminh

[email protected]

Ken Thai (thaikminh)

THUC IU TR UNG TH

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Mt s nh ngha

- Khi u, ung th (neoplasms): mt dng pht trin mi

v bnh hon ca m.- neoplasm lnh tnh- neoplasm c tnh

Neoplasms c tnh

- Wilms tumor, Hodgkins disease, Kaposi sarcoma.- myeloma v lymphoma- carcinomas- sarcomas

Leukemia: sn xut gp i, gp ba lng bch cu bnh thng+ leukemia cp tnh: can thip vo s sn xut bnhthng nhng t bo mu trng trng thnh.

+ leukemia mn tnh: sn xut nhng t bo mu trng

trng thnh bt thng

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-Di cn (metastases): khi u c tnh cui cng s di cn nu khngiu tr.

t bo ca khi u c tnh

pht tn khi khi u ban u

h bch huyt v mch mu

khi u th cp.

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CC BNH UNG TH C TH CHA KHI

Ung th nhau, bch cu cp tr em dng lymphoBnh Hodgkin, mt s ung thlympho (Burkin)

Ung th tinh hon, K bung trng

Ung th t cung

Bu Wilm

Sarcom c vn bo thai

Sarcom Ewing

Tng bch cu ty ngi ln

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S hot ha khc thng ca yu t tng trng hays biu hin gim ca cht c ch tng trng s dn

n mt vic kim sot bnh thng s tng trng, an s sinh si ny n t bo gia tng bt thng.

Nguyn nhn cn c ca nhng s khc thng ny mc t bo cha c xc nh mt cch hon ton.

Tuy nhin, ngi ta tin l do proto-oncogen, gen kim sots tng trng v bit ha bnh thng, c chuyn thnh

oncogen.

Oncogen lm bin i c ch kim sot t bo, kch thchnhng tin trnh c v s pht trin t bo.

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* Chuk tbo (CKTB) vs iu ha

- G1/S v G2/M: 2 im kim sat ch yu trong CKTB

-Yu t tng trng v cht c ch tng trng (p53)

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nhng khi u, phn t bo pht trin gia tng so vi tbo ng v cht nn c s gia tng h thng v slng t bo.

nhng khi u, t bo mi c to ra trong nhngvng thiu oxy, gn trung tm khi u hn v poorlyperfused (c sinh ra trong tnh trng khng tng

trng). Nhng t bo ny khng nhy cm vi thuc.

Sau khi khi u tip xc vi ha tr liu, a s nhng tbo pha ngoi, ch yu trong tnh trng tng trngnhy cm v b tiu; nhng t bo tnh trng khng

tng trng c th chuyn thnh tnh trng tng trng.

dit tn gc khi u cn phi nhiu chu k ha trliu ung th.

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Cn bn sinh ha v ung th- Kt qu ca s a t bin- Qu trnh hnh thnh ung th v s di cn bao gm:

(1) S t bin khi u

(2) Giai on tin trin xy ra trong sut thi gian t bo tbin pht trin c tr gip bng cch tip xc vi nhng

hp cht non-genotoxic khc.

(3) Mt khi u nh lnh tnh c to thnh hay mt chnglon sn nh xy ra trong thi gian pht trin ca phenotype

c tnh

(4) Khi u c tnh s khi c hnh thnh

(5) T bo long ra, v nh v ti mt v tr xa v khi u th hai

hnh thnh (di cn).

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Initiators, t nht nhng liu thp, khng gy ung th,mc d chng thng xuyn gy t bin. Khng c skch thch th cp, s chuyn dng thnh t bo c tnhkhng xy ra. Tuy nhin, nu nhng t bo ny tip xc vimt promoter, s tri dy ca phenotype c tnh s xy ra.

Promoters trong s vng mt ca initiator ni chung s

khng gy c tnh trn gen (genotoxic) hay gy t bingen (mutagenic).

Vi promoter quan trng bao gm:

-12-O-tetradecanoyl phorbol-13-acetat (TPA)- thuc tr su clor hu c- hormone th d estrogen.

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- Ha cht

benzo[a]pyren benzo[a]pyren 7,8-oxid

O

7,8-dihydrobenzo[a]pyren 7,8-diol

epoxidhydroxylase

HO

OH

CYP450

CYP450

HO

OH

O

GuaninHN

NH

N

N

N

O

OH

HO

OH

S hat ha chuyn ha ca benzo[a]pyren

t bin im

trng hp tn ti dai dng

Ung th

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Cht sinh ung th Lai ung th Ngun t mi trng-Naphtylamin bng quang phm nhum

Amiang phi

Bc x ion ha phi, xng qung uranium

Hydrocarbon da,phi tip xc hc n, sn phm t

a nhn thm chy (combustion products)

nh sng UV da ngi tm nng, lm vic di nng

Aflatoxin gan thc phm b nhimKhi thuc l phi, ming ngi ht thuc

Tc nhn alkyl ha xng, bang quang tc nhn ha tr liu ung th

Ngun cc cht sinh ung th

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-Virus oncogenicC nhiu ung th ngi m nguyn nhn cthlin quan n virus.

- Biu hin gen b bin i

(1) biu hin oncogen bt thng hay gia tng hoc(2) hot tnh b gim ca nhng cht km hm khi u(anti-oncogen).

Thd: s t bin ca p53 c thcho php ssinh si ny n ca nhng tbo t bin.

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Phn chia th phn ca cc thuc iu tr ung th hng mc tiu nm2009 ti th trng Hoa k.

Tng doanh s t 10,4 t USD v doanh s ca 5 thuc hng u

chim 86% doanh s.

(n v t USD)

50% doanh sphn tnho

5 thuc hng uchim 86% doanh s

C th i t th h ti h th d

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Cc thuc iu tr ung th hng mc tiu c chp thun s dng

Th i h h i

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M rng cc ch nh ca imatinib da trn s chp thun caCc qun l thc phm v thuc Hoa K (US FDA) t nm 2001-2009

Imatinib

2009: doanh s imatinib ti M t 1,1 t USD v doanh s trn ton cu t3,95 t USD.D kin nm 2014, doanh s trn ton cu ca imatinib c th c nhiu hn 5t USD

Thuc iu tr ung th hng mc tiu

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Mc ch ca ha tr liu: l iu tr mt ung th c hiu- lm gim kch thc ca khi u trc khi gii phu,

- lm khi u nhy cm hn i vi x tr,- hoc chn ng di cn sau khi khi u c ly i.

Hu ch trong loi tr khi u kch thc nh; km hiu qu khi u ln v khi u ln th s ti mu b km v cc tc nhn ha tr liu ung th kh von bn trong.

Thiu tnh chn lc ca nhng tc nhn ha tr liu i vi t bo bnh thngso vi t bo c tnh.

T bo c tnh, sinh si ny n nhanh, bt gi nhng cht ngoi bo (thunhn thuc) mt tc ln hn t bo bnh thng.

Mt vi loi t bo bnh thng sinh si ny n nhanh nh t bo tc, t boty xng, t bo vin ca d dy-rut

rng tc, c ch h min dch, bun nn v tiu chy. Nhng tcdng ny s bin mt khi ngng ha tr liu.

Ha tr liu ung th

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Thnh cng ca ha tr liu ung th

Spht hin sm l ng vai tr quan trng c c t l

sng sau 5 nm v nhng khi u nh th thng nh v

nhng khi u thhai thng khng xut hin.

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iu tr ung th HA TR LIU

1. TC NHN ALKYL HA

2. CHT CHNG CHUYN HA V CHT TNG NGNUCLEOSID

3. KHNG SINH KHNG UNG TH

4. TC NHN CHNG PHN BO

5. HORMON LIU PHP

6. THUC IU TR UNG TH KHC

i t th HA TR LIU

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1. TC NHN ALKYL HA

Nit mustard: Meclorethamin, Clorambucil, Melphalan,Estramustin, Cyclophosphamid, Ifosphamid

MESNA: giaic

Aziridin (Ethyleneimin): Thiotepa

Methan sulfonat:Busulfan

Nitrosourea: Carmustin (BCNU), Lomustin (CCNU),Streptozocin

Triazen: Dacarbazin (DTIC), Temozolomid

Hp cht platinum: Cisplatin, Carboplatin

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i t th HA TR LIU

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3. KHNG SINH KHNG UNG TH

-Bleomycin: glycopeptid - a c ch, to phc chelat lchnh

-Dactinomycin hay actinomycin D: ln vo DNA, c chtopoisomerase

-Mitomycin C: alkyl ha

-Anthracyclin: Doxorubicin, Daunorubicin, idarubicin,epirubicin, valrubicin: ln vo DNA, c chtopoisomerase

-Mitoxantron: ln vo DNA, c chtopoisomerase


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i t ng th HA TR LIU

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5. HORMON LIU PHP

Estrogen- Cht khng estrogen: Tamoxifen, Toremifen- Cht c charomatase: Anastrozol, Letrozol

Androgen- Cht khng androgen: flutamid, bicalutamid, nilutamid- Cht ch vn GnRH: Leuprolid (leuprorelin), goserelin- Cht i vn GnRH: abarelix


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CC TC NHN IU TR UNG THTC NHN ALKYL HAC ch tc ng

HN

N

N

O

H2NADN

7

Guanin

+Cl

NCl

R

nitrogen mustard

HN

N

N

O

H2NADN

NCl

R

+ HN

N

N

O

H2NADN

NN

R

N N

NH

O

ADN

NH2

S alkyl ha guanin trong ADN bng tc nhn alkyl ha

Cc tc nhn alkyl ha tc ng bng cch alkyl ha ADN. V tr alkyl ha thng thng nhtl v tr N-7 ca guanin. Nhng v tr khc trn nhng base ADN (guanin, adenin, thymin hoccytosin) hay nhng oxygen phosphat ca xng sng ADN cng c th b alkyl ha.

Mt khi s alkyl ha ADN xy ra, nhng v tr alkyl ha b tch a n s v chui n ADN.

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Nhng tc nhn alkyl ha c bit l phn ng vi ADN, ARN v protein.Mc d phn ng vi ADN c cho l quan trng nht.

Nhng tc nhn alkyl ha 2 chc c th gy ra inter v intra strand cross-links. Inter-strand links to thnh t nhng ion meclorethamin aziridium,ngn cn s tch ADN v gy c tnh t bo

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CC TC NHN IU TR UNG TH

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CC TC NHN IU TR UNG THTC NHN ALKYL HA

* Nitrogen mustard

Melphalan (L-phenylalanin mustard)

N CH2

Cl

Cl

CH COOH

NH2

melphalan

(Site-directed nitrogen mustards)

Carcinoma bung trng,

multiple myeloma

Hi nhp vo trong nhng phn c hy vng l tch t u i tbo khi u.

ng phn L ca phenylalanin c vn chuyn vo trong t bo uth hn, c gi nh vi s tr gip ca mt transporter L-aminoacid hot ng.

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* Nitrogen mustard

Estramust in

OCN

O

Cl

Cl

O P

OO

O

Na

Na

estramustin phosphat

(Site-directed nitrogen mustards)

Estramustine was designed as a prodrug, since the electron density of its nitrogen atom is not sufficient to

trigger aziridinium formation because of the electron-withdrawing effect of the carbonyl group.

Estramustinewas thus expected to target estrogenic hormone receptors before release of the active nitrogen

mustard group following cleavage of the carbamate ester link. However, this function was stable to

enzymatic cleavage, and therefore estramustine did not possess alkylating activity.

On the other hand, estramustine is also active in tissues and cell lines which lack estrogen receptors, and

therefore its antitumor activity is not hormone related. On exposure to estramustine, cells were arrested in

the metaphase and the mitotic spindle was absent, which suggested that estramustine acts by interaction

with microtubules to promote microtubule disassembly.

Estramustine has moderateactivity against prostate cancers because of the existence in the prostate of the

so-called estramustine binding protein (EMBP), which facilitates its uptake.

Lin kt carbamat ester bn Thc t estramustin khng c hat tnh alkyl ha


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Nitrogen mustard

Cyclophosphamid

P N

OO

NH

Cl

Cl

cyclophosphamid

Site-directed nitrogen mustards

Another strategy for the development of site-directed nitrogen mustards can be selectivebioactivation of prodrug forms if biochemical differences can be found between a tumor and normal

tissue. Thus, a report stating that some tumors contain high levels of phosphoramidases led to the

design of prodrug nitrogen mustards, which were expected to be activated by phosphoramide

enzymatic hydrolysis.

The electron-withdrawing effect of the P=O bond prevents their activation to aziridinium cations.

Carcinoma v hay bung trng, ALL,

acute monocytic leukemia, AML,CLL, chronic myelocytic leukemia,

Hodgkins & non-Hodgkinslymphoma, multiple myeloma,

neuroblastoma, retinoblastoma.

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S hat ha chuyn ha cacyclophosphamid


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Nitrogen mustard

Ifosphamid

P NH

OO

N

Cl

Cl

Ifosfamid

Carcinoma tinh han

P N

OO

NH

Cl

Cl

cyclophosphamid

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Detoxification of acrolein by mesna

(MESNA = 2-mercaptoethanesulfonat natri)

MESNA c cho km vicyclophosphamid hay ifosphamid

gim c tnh ca acrolein,cht chuyn ha t nhng chtny. Acrolein gy ra vim bng

i chy mu trm trng dn nc tnh thn (nephrotoxicity) vc tnh ng tit niu(urotoxicity). MESNA lin hp vinhng cht chuyn ha gy ctnh ny.

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Alkyl ha DNA bng cc aziridin

CC TC NHN IU TR UNG THTC NHN ALKYL HAAziridin (Ethyleneimin)

Since the active species involved in DNA alkylation by nitrogen mustards is an aziridinium cation, several

aziridine derivatives were also tested as antitumor agents.

Electron-releasing substituents raise the aziridine nitrogen pKa and lead to a high concentration of aziridinium

cations 5.20, which renders these compounds too reactive to be of therapeutic value. For this reason, the aziridine

units are attached to electron-withdrawing groups, which reduce their reactivity as bases but still allow formation ofDNA-alkylation products such as 5.22, which then are protonated to 5.21.

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C C C U U G TC NHN ALKYL HA

Methan sulfonat

Busul fan

H3CO2SOOSO2CH3

busulfan

Guanin

S

OH

O O

3-hydroxytetrahydrothiophen-1,1-dioxid

HN

N N

N

O

ADNH2N

OSO2CH3

+

HN

N N

N

O

ADNH2N

N

N N

NH

ADN

O

NH2

S alkyl ha ADN ca busulfan

Chronic myelocytic leukemia

Methanesulfonate is a good leaving group because of the efficient delocalization of negative

charge between three oxygen atoms. For this reason, several compounds containing two

methanesulfonate groups separated by a polymethylene chain were tested as antitumor

agents, finding that the optimal activity corresponded to the compound with four carbon

atoms (busulfan)


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TC NHN ALKYL HA

Nitrosourea

In a random screen carried out by the NCI in 1959, 1-methyl-3-nitro-1-nitrosoguanidineshowed very weak

antileukemic activity. Assay of analogs of this compound led to the discovery of the antitumor activity of 1-methyl-

1-nitrosourea, the lead compound of the nitrosourea group. It was soon discovered that introduction

of a 2-chloroethyl chain on the nitrogen atom bearing the nitroso group (CNUs) led to much increased activity.

These chloroethyl derivatives were lipophilic enough to cross the bloodbrain barrier and therefore wereuseful in the treatment of brain tumors

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S to thnh cu ni trn DNA bng nitrosourea

Hu ht cc nitrosoureac mt nhm cloroethyltrn N c nitro ha, To thnh nhm ckh nng to cu nitrn DNA

1-(2-chloroethyl)-

2-hydroxydiazene(S hin din canhm nitroso lm

linh ng lin ktnitrogen-carbon)

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TC NHN ALKYL HA

Nitrosourea

- Lomustin (CCNU)

NH

N

O NO

Cl

lomustin

ClN N

H

Cl

NO

O

carmustin

Hodgkinslymphoma, khi uchnh hay di cn no

CC TC NHN IU TR UNG TH O O NO

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TC NHN ALKYL HA

Nitrosourea

- Streptozocin

O

OH

OH

HOH2CHO

HN C

O

N

NO

CH3

streptozocin

ClN N

H

Cl

NO

O

carmustin

NH

N

O NO

Cl

lomustin

Carcinoma ty

Streptozocin c tnh cht khc vi cc nitrosourea khc:- Tan trong nc do khngqua hng ro mu no vgim kh nng thm qua ty sng- c tnh: gy hi chng ging tiu ng do cc cht vnchuyn glucose tp trung vn chuyn thuc vo trong ty/

2-Deoxy-2-(3-methyl-3-nitrosoureido)-D-glucopyranose


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TC NHN ALKYL HA

* Triazen

Dacarbazin (DTIC) Hodgkins lymphoma, melanoma c tnh di cn

Temozolomid Khi u no

N

NH

C

N

ONH2

N N

CH3

CH3

dacarbazin

N

N

C

O

NH2

temozolomid

NN

N

O

CH3

N

NH

C

N

ONH2

N N

CH3

H

MTIC

Dimethyl triazenyl imidazol

carboxamid (DTIC)


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TC NHN ALKYL HA* Triazen

Dacarbazin (DTIC) v Temozo lom id

N

NH

C

N

ONH2

N N

CH3

CH3

dacarbazin

N

NH

C

N

ONH2

N N

CH3

H

MTIC

CYP450+ CH2O

N N CH3 +N

NH

C

NH2

ONH2

HN

N N

N

ADNH2N

OH3C

N N

HN

N N

N

ADNH2N

O CH3

S chuyn ha v c ch tc ng ca DTIC

diazomethan

(tc nhn methyl ha mnh)

5 amino-imidazol-4-

carboxamid (cht chuynha chnh pht hintrong nc tiu)


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TC NHN ALKYL HA

* Methylhydrazin

Procarbazin Hodgkins lymphoma

S hat ha - chuyn ha ca procarbazin

H3CHNHNH2C

O

NH

procarbazin

O2

H3CN=NH2C

O

NH+ H2O2

O

NHNNH

H3CCH3-NH-NH2 +

O

NHO

Hmethylhydrazin

CH3-N=NH

methyldiazen

CH3. + H. + N2

S oxid ha methylhydrazin xy ra c in vitroln in vivo, to ra methyldiazen v sau l gc t do. Methyl hydrazin methyl ha ADN v ARN. Trn ADN, s methyl haxy ra v tr C8 ca guanin.

Procarbazin c ch nhng enzym lin quan n s chuyn ha alcol v s chuyn hacatecholamin. Bnh nhn s dng procarbazin c th b hin tng antabuse khidng ethyl alcol. Monoamin oxidase b c ch bi procarbazin.


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TC NHN ALKYL HA

* Hp cht platinumCisplat in Carcinoma bng quang, bung trng

PtH3N

H3N

Cl

Cl

cis-diclorodiamineplatinum (II)

Intracellular bioactivation of cisplatin

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Coordination complex generated from

the cisplatin active species and DNA

The active complexes enter the nucleus and become attracted by the negatively charged DNA. This

electrostatic interaction is followed by complexation with nitrogen atoms of purine bases, normally the

N-7 atoms of two vicinal guanine units that displace the two water molecules leading to intrastrand

cross-linking.


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TC NHN ALKYL HA

Hp cht platinum

Carboplat inCarcinoma bung trng

PtNH3

NH3

O

O

O

O

carboplatin

-Carboplatin tng t cu trc vicisplatin trong c cha nhm cis-diamin v platin (II). v tr 2 nhm cloca cisplatin, carboplatin c 2 nhmcyclobutanplatin c kim.

cis-Diammine(cyclobutane-1,1-

dicarboxylato)platinum

Carboplatin has a mechanism of action identical to that of cisplatin, forming cross-links with

guanine in DNA. At effective doses, carboplatin produces substantially reduced nephrotoxicity

because of the dicarboxylate ligands which facilitate its excretion.

Tn Ch nh

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Tn Ch nh

Carmustin

LomustinStreptozocin

Busulfan

Dacarbazin

TemozolomidProcarbazin

Thiotepa

Cisplatin

Carboplatin

Hodgkins & non-Hodgkins lymphoma, multiple myeloma, khi uchnh no.

Hodgkins lymphoma, khi u chnh hay di cn noCarcinoma ty

Chronic myelocytic leukemiaHodgkins lymphoma, melanoma c tnh di cn

Khi u noHodgkins lymphomaCarcinoma v, bng quang, bung trng, Hodgkins & non-Hodgkins lymphoma, malignant sffusions, lymphosarcoma.Carcinoma bng quang, bung trng.

Carcinoma bung trng

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CC TC NHN IU TR UNG THCHT CHNG CHUYN HA V CHT TNG NG NUCLEOSID

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CHT CHNG CHUYN HA V CHT TNG NG NUCLEOSIDCht chng chuyn ha pyrimidin5-Fluorouraci l Carcinoma v, rut, trc trng, d dy, ty, carcinoma da.

HN

NH

O

O

F

5-FU

HN

NH

O

O

F

H

5-fluoro-5,6-dihydrouracil

dihydropyrimidinedehydrogenase

OHOH2C N

HN

O

O

F

HO OH

5-FUR

OOH2C N

HN

O

O

F

HO

PHO

OH

O

5-FdUMP

inhibitor ofthymidilatesynthetase

5-fluorodeoxyuracil

triphosphat

ADN

5-fluorouraciltriphosphat

ARN

S chuyn ha ca 5-fluorouracil


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CHT CHNG CHUYN HA V CHT TNG NG NUCLEOSIDCht chng chuyn ha pyrimidin

HN

N

H

O

O

CCH

5-ethynyluracil

HN

N

O

O

F

OHOH2C

HO

5-fluorodeoxyuridine(floxuridin)

* 5-Ethynyluracil c ch dihydropyrimidin dehydrogenase - cht ny ci thin chs tr liu ca 5-FU t 2-4 ln.

* Floxuridin (5-fluorodeoxyuridin) : tin dc ca 5-fluorouracil. V mt chuyn haphn ng desoxy ca floxuridin c tch mt cch nhanh chng cung cp 5-fluorouracil. Ngc li vi 5-fluorouracil, floxuridin d tan trong nc


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CHT CHNG CHUYN HA V CHT TNG NG NUCLEOSIDCht chng chuyn ha pyrimidinCytarab in (ARA-C)

OHO

HOH2C

HO

N

N

O

NH2

ARA-C

OHO

OH2C

HO

N

N

O

NH2

P

O

HO

OH

ARA-CMP

OHO

H2C

HO

N

N

O

NH2

OP

O

OH

OH

3

ARA-CTP

metabolicinactivation

OHOHOH2C

HO

N

HN

O

O

arabinofuranosyluracil

S hat ha chuyn ha v s bt hat ca1--D-arabinofuranosylcytosine (ARA-C)

ALL, AML,

chronic

myelocytic

leukemia,

meningealleukemia

ARA-C : phnng c bini: mt arabinosetrong nhm 2-

OH c cu dngbeta (khc vi cudng alpha-bnhthng).

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CHT CHNG CHUYN HA V CHT TNG NG NUCLEOSIDCht chng chuyn ha purin6- Mercaptopur in (6-MP) ALL, AML, myelomonocytic leukemia cp

S hat ha chuyn ha ca 6-mercaptopurin (6-MP) thnhribose monophosphat tng ng (6-MPMP) v 6-methylthioinosinat

hypoxantin-guanin

phosphoribosyltransferasese

HN

N NH

N

6-MP

HPGRT O

OH OH

H

H2CH2O3PO N

N

HN

N

S

6-thioinosinate (6-MPMP)

O

OH OH

H

H2CH2O3PO N

N

HN

N

S CH3

6-methylthioinosinate

SH


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CHT CHNG CHUYN HA V CHT TNG NG NUCLEOSIDCht chng chuyn ha purin6-Thioguanin

S hat ha sinh hc ca 6-thioguanin (6-TG) thnh monophosphat

tng ng (6-TGMP) v sau thnh triphosphat (TGTP)

HN

N NH

N

S

HPGRT O

OH OH

H

H2CH2O3PO N

N

HN

N

S

O

OH OH

H

H2CH2O3 PO N

N

HN

N

S

H2N

6-TG

H2N H2N

6-TGMP 6-TGTP

3

HN

N NH

N

6-MP

SH


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CHT CHNG CHUYN HA V CHT TNG NG NUCLEOSIDCht chng chuyn ha purinFludarab in phosphat vCladr ib in

O

OH

H

H2CO N

N

HN

NF

HO

NH2

P

O

HO

OH

f ludarabin phosphat

O

OH

H2CHO N

N

HN

N

Cl

NH2

cladribin

(cu trc lin quan n adenosin) (2-chloro fludarabin)


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CHT CHNG CHUYN HA V CHT TNG NG NUCLEOSIDCc cht chng chuyn ha khcMethotrexat (MTX)

N

NN

N

NH3C

H2N

NH2 C

OHN

COOH

COOHmethotrexat

Leukemia cp, meningealleukemia, carcinoma v, u,c, phi. Burkitts lymphoma,

lymphosarcoma,osteosarcoma khng di cn.

MTX v nhng cht tng ng l nhng

pteridin, tng tranh vi cc cht nnbnh thng acid folic v dihydrofolat vtr tc ng trn enzym dihydrofolatreductase (DHFR).


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CHT CHNG CHUYN HA V CHT TNG NG NUCLEOSIDCc cht chng chuyn ha khcMetho trexat (MTX)

N

NN

N

NH3C

H2N

NH2 C

OHN

COOH

COOHmethotrexatN

NN

N

HN

H2N

OH C

OHN

COOH

COOH

R

acid folic

N

N

NH2N R

NHNH2N

dihydrofolatreductase

(DHFR) NHNH2N

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NN

HNOH C

OHN

COOH

COOH

HNN

HN RO

( )

HNNH

HN RO

acid folic dihydrofolat tetrahydrofolat

N

HN N

HN

N R

H2N

O

serin/pyridoxal

N5, N 10-methylen

-tetrahydrofolic acid

thymidylatesynthetase

N

HN N

HN

N R

H2N

O

N5, N 10-methenyl

-tetrahydrofolic acid

N

HNNH

HN

N R

H2N

O

N10-formyltetrahydrofolic acid

HC

O

isomerase

N

HNN

HN

HN R

H2N

O CHO

N5-formyltetrahydrofolic acid

S han chuyn ca cc dn cht quan trngca acid folic trong s sinh tng hp

thymidin v purin

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Main targets for antifolate drugs

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Biosynthesis of purine nucleotides


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CHT CHNG CHUYN HA V CHT TNG NG NUCLEOSIDCht b tr khng ung th

HN

N

N

HN

HNHN

CO2

H2N

O CO H

CO2

Ca 2+

calcium 5-formyltetrahydrofolat(calcium leucovorin)

S

O

O

O CH2 CH2 SHNa

2-mercaptoethanesulfonat

Khi s dng liu ln MTX v sau cht gii

cu leucovorin c cho bng ng IV cung cp cho nhng t bo khng ung thtetrahydrofolat nhm gim c tnh. Calciumleucovorin cng c kt hp vi 5-FU cithin s iu tr

MESNA c cho km vicyclophosphamid hay ifosphamid

gim c tnh ca acrolein,cht chuyn ha t nhng chtny. Acrolein gy ra vim bng

i chy mu trm trng dn nc tnh thn (nephrotoxicity) vc tnh ng tit niu(urotoxicity). MESNA lin hp vinhng cht chuyn ha gy ctnh ny.

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Trong thin nhin, bleomycin

dng chelat vi ng vinhng ligand cung cp binhng nhm chc pyrazin,

imidazol, amid v amin. Mcd ng c loi i trongtin trnh tinh ch, nhngkhuynh hng to thnhchelat kim loi cableomycin l cha kha cahot tnh chng khi u.

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Roles of several blemoycin structural fragments

Ngi ta cho rng trong t bobleomycin to chelat vi Fe2+.Nm trong 6 v tr phi hp cphi tr mnh vi bleomycin. V trth 6 sn sng cho s phi hpvi oxygen.

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Bleomycin transport

and bioactivation

Trong t bo bleomycinto chelat vi Fe2.

Chelat ny cng thayi kh nng oxy hakh ca st oxygenkt hp b kh, bin ioxygen thnh mt loigc t do phn ng, gc

t do hydroxyl (.OH).Gc t do hydroxyl sau phn ng ADN nhn,thoi ha n v kt qul gy c tnh t bo.

CC TC NHN IU TR UNG THKHNG SINH KHNG UNG TH

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KHNG SINH KHNG UNG THDac tinomyc in hay ac tinomyc in D

(Khung cn bn: 3-phenoxazone-1,9-dicarboxylic acid= actinocin)

Carcinoma tinh han, ewingssarcoma, Welms tumor

H vng thm v phng, c th lngvo (intercalate) hay chn vo (insert)vo ADN gia 2 bc ca cp base.Trong tin trnh chn vo ADN, chuixon c phi m ra mc no c c khng gian cho phnactinocin. Mt khi c chn vo hvng actinocin c gi trong chui

xon kp ADN bi tng tc stacking- gia h vng actinocin v nhngcp base ca ADN. S vn vo(distortion) ti ch gy bi s hindin ca tc nhn chn vo nhhng n tc ng catopoisomerase II, tc nhn iu ha

bnh thng s m ca chui xonkp ADN can thip vo s saochp ADN v s phin m dn ncht t bo.

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Deformation of DNA by an intercalating agent

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DNA intercalation by actinomycin D

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Inter- and intrastrand DNA cross-linking by mitomycin


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KHNG SINH KHNG UNG THAnthracyc l in

O

OR1

OH

OH O

O

NH2

CH3

C

OH

O

CH2 R2

1

5 8

12

R3

R4

O

O

OH

OH O

O

NH

CH3

C

OH

O

CH2 O

1

5 8

12

OH

H3CO

C

O

C4H9

C CF3

O

valrubicin

doxorubicin R1=CH3O, R2 =OH, R3=H, R4=OH

daunorubicin R1=CH3O, R2 =H, R3=H, R4=OH

idarubicin R1=R2=R3=H, R4=OH

epirubicin R1=CH3O, R2=OH, R3=OH, R4=H

Acute lymphoblastic & myeloblastic leukemia, Welmstumor, bnh Hodgkins, malignant lymphoma.Doxorubicin


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KHNG SINH KHNG UNG THMitoxantron

. 2HCl

mitoxantrone HCl

- antracenedion chng ung th- anthracenedion l nhng quinon lin hp cao , nn

dung dch nc c mu xanh en. Mt tc ng cp tnhca vic iu tr vi mitoxantron l nc tiu nhum muxanh v mng cng mt nhum mu xanh.

Acute monocyticleukemia, AML,

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Mode daction de doxorubicine (inhibiteur Topo II)

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Catalytic cyclic of topoisomerase II and its main inhibitors

Tn Ch nh Dng liu lng(mg/n v)

l i C i h h i h (1 30

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Bleomycin

Dactinomycin

DaunorubicinDoxorubicin

Idarubicin

Epirubicin

Mitomycin CMitoxantron

Pentostatin

Vincristin

Vinblastin

Vinorelbin

Paclitaxel

Docetaxel

Carcinoma c t cung, u v c, thanh qun, tinhhan, da, lymphoma Hodgkins v non-HodgkinsCarcinoma tinh han, ewings sarcoma, Welms tumor

ALL, AML, acute monocytic leukemiaAcute lymphoblastic & myeloblastic leukemia, Welmstumor, bnh Hodgkins, malignant lymphoma.ALL, AML

iu tr b sung u hch trong ung th v

Carcinoma d dy, tyAcute monocytic leukemia, AML,Leukemia t bo tc ngi lnALL, lymphoma Hodgkins v non-Hodgkins,neuroblastoma.

Carcinoma v v tinh han, lymphoma Hodgkins vnon-Hodgkins, Kaposi sarcomaUng th phi t bo nonsmallCarcinoma bung trng di cn, ung th v di cnUng th v tin trin ti ch hay di cn, ung th phi t

bo nonsmall

IM, IV(15, 30 nv/l)IV (0,5/l)

IV (20/l)IV (10, 20, 50, 100,

200/l).IV (5, 20/l)IV (2/ml)

IV (5, 20, 40/l)IV (20, 25/l)IV (10/l)IV (1, 2, 5/l)

IV (10/l)

IV (10, 50/l)IV(30/5ml,100/16,6ml

IV (20, 80/l)

CC TC NHN IU TR UNG THTC NHN CHNG PHN BO

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Tc nhn chng phn bo

Ngn cn s phn chia tbo, v c bit can thipvo thoi gin phn (mitotic spindle)

Protein cu trc

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Paclitaxel(Taxol )

O

O

OH

NHO

HO

O O

OO

OH

OO O

O

N

NNH

H

HO

N

H

OH

R

Vinblastin (R = CH3)Vincristin (R = CHO)

O

O

O

O

OO

O

Thuc iu tr ung th theo c ch c ch s thnh lp (alkaloid vinca)

v phn hy (taxan) vi ng

Colchicin c ch qu trnh hnh thnh ving bng cch gn kt vi tubulin

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Vinca alkalo ids Vinc ris tin , Vinb lastin , vVino relbin

vinorelbin vinscristin

vinblastin

catharanthin

ALL, lymphomaHodgkins v non-Hodgkins,neuroblastoma.

Carcinoma v v

tinh han,

lymphomaHodgkins v non-Hodgkins, Kaposisarcoma

vindoline

- nhm amino bc 3 c thto thnh nhng mui d tantrong nc.- c vinblastin ln vincristingn mt cch c hiu vitubuline v gy ra sdeplolymer ha.


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Taxan Pacl i taxel vDocetaxel

paclitaxel docetaxel

Paclitaxel (taxol) lm cho nhngmicrotubule t sp xp thnh nhng

hng song song hn l s sp xp cnthit ca thoi gin phn. Tuy nhin tcng cui cng th ging nh cc vincaalkaloid l gy ra s dng phn bo.

Docetaxel l mt taxoid khccu trc vi paclitaxel c t hnmt nhm acetat v mt chcbutyl carbamat bc 3 v tr canhm benzamido

Carcinoma bung trng di cn,

ung th v di cn

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Bn tng hp taxan

The Pacific Yew is a limited resource

that grows very slowly. About 4,000

trees were required to provide 360 gof taxol for the early clinical trials,

and 38,000 trees were necessary to

isolate 25 kg of taxol to treat 12,000

cancer patients after approval of the

use of taxol for treating advanced

ovarian cancer in 1992.

Paclitaxel lm cho nhngmicrotubule t sp xp thnhnhng hng song song hn l s

sp xp cn thit ca thoi ginphn

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paclitaxel docetaxel

Paclitaxel c kh nng thn du cao,khng to mui bn vi acid hay base,

v khng tan trong nc.

Docetaxel l mt taxoid khc cu trc vipaclitaxel c t hn mt nhm acetat vmt chc butyl carbamat bc 3 v tr

ca nhm benzamido.

Tc dng mnh hn v d tan hnpaclitaxel.

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Th th nm bn trong t bo

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C ch tc ng ca estrogen (A) v tamoxifen (B) ln th th estrogen (ER).Tamoxifen l khng ch vn trn ER v c dng trong iu tr ung th v.

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Sequence of events

related to steroid

hormone activity

the transcription process

initiated by the binding of

estrogens to their receptors

ultimately induces cell

proliferation in some targettissues. Examples are breast

tissue, where estrogens

trigger the proliferation of

cells lining the milk glands.

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Metabolism of estradiol

This proliferative action is one of the physiological roles of estrogens,

but it can also lead to the development of breast or uterine cancer

because if cells from these tissues already possess a DNA mutation

that increases the risk of developing cancer, they will proliferate (along

with normal cells) in response to estrogen stimulation.

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DNA depurinization by estradiol-3,4-quinone

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Pathways involved in tumorogenesis by estrogens

HORMON LIU PHPAnt iestrogens

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Nonsteroidal antiestrogens [selective estrogen receptor modulators (SERMs)]

which interfere with the transcription process by binding to the hormone recognition

site in the ER and preventing the induction of the conformational change necessary

for recognition of the coactivators.

( iu tr ung th v)

Tamoxifen citrat = (Z)-2-[4-(1,2-Diphenylbut-

1-enyl)phenoxy]ethyldimethylamine citrate

(dn cht triphenyl ethylen)

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Mechanism proposed to explain tamoxifen long-term toxicity

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Destabilization of the electrophilic species derived from toremifene

Cht c ch aromatase:Anastrozol, Letrozol

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anastrozol letrozol

(iu tr ung th v tin trin)

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Regulation of steroidal hormone biosynthesis and interfering drugs

Gonadotropin-releasing hormone (GnRH) =

Luteinizing-hormone-releasing hormone (LHRH)

v luliberin FSH: follicle-stimulating hormone

LH: luteinizing hormone

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Strategies used to reduce testosterone levels

Gonadotropin-releasing hormone (GnRH) =

Luteinizing-hormone-releasing hormone (LHRH)

v luliberin

CC THUC TR UNG TH KHCHORMON LIU PHPCht kh d O

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Cht khng androgen

CF3

NO2

H N C C

O H

CH3

CH3

flutamid

CF3

NO2

HN C C

O OH

CH3

CH3

(active)

CF3

CN

H N C C

O OH

CH2

CH3

SO2 F

bicalutamid

CF3

NO2

N

NH

OO

H3CCH3

nilutamid

iu tr carcinoma tin lit tuyn

-c ch s di chuyn th th

androgen n nhn m chtrong trng hp ny l di iv tin lit tuyn ngn chntc ng ca testosteron vdihydrotestosteron.

-flutamid v bicalutamid cdng kt hp vi nhng cht chvn GnRH ngn cn hintng flaretrong iu tr ung thtin lit tuyn di cn.

- nilutamid, c dng nh mt

iu tr n c trong kt hp viphu thut ngn chn tc ngca testosteron vdihydrotestosteron.

,,-Trifluoro-2-methyl-4-

nitro-m-propionotoluidide

CC THUC TR UNG TH KHCHORMON LIU PHP

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leuprolid = leuprorelin

goserelin

Cht ch vn GnRH: Leup rol id (leuprorel in), go serel in

iu tr: Carcinoma tin lit tuyn

CC THUC TR UNG TH KHCHORMON LIU PHP

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leuprolid = leuprorelin

goserelin

Cht ch vn GnRH

Nhng cht ch vn hormon gia tng khi u nng testosteron, sau gy ra ssuy gim nng testosteron thng qua s iu ha gim (desensitization).Tin trnh ny mt khong 4 tun v dn n ct mt nng testosteron.

iu tr kt hp s dng tc nhn khng androgen vi cht ch vn GnRH.

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CC THUC TR UNG TH KHCEpipodophyl lotoxin : etoposid . tenipo sid

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Podophyllotoxin c cdi dng dch chit cyMay Apple v c dng

lu i nh thuc ctruyn do tc ng d dy

rut (gy nn v tynh).

S khc nhau ng k giacu trc ca nhng cht lytrch c t thin nhin vcht tng ng bn tnghp lin quan n mi quan

h ha lp th gia 2 nhmth ti v tr 1,4.

Nhiu nhm chc hin dintrong cu trc ca etoposidbao gm lacton, phenol, etherthm, acetal v nhmglucopyranosid.

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Catalytic cyclic of topoisomerase II and its main inhibitors

CC THUC TR UNG TH KHCHydroxyurea

O

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Sinh tng hp 2-deoxyribonucleotid

RNR plays a central role in cell growth and proliferation by ensuring a balanced

supply of nucleotide precursors for DNA synthesis

H2N

O

N OH

H

hydroxyurea

iu tr: carcinoma u v c; carcinoma bung trng

CC THUC TR UNG TH KHCHydroxyurea

O

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H2N

O

N OH

Hhydroxyurea

iu tr: carcinoma u v c; carcinoma bung trng

- chelat ha cofactor Fe

2+

. Tc nhn nyc hiu vi chu k t bo phase S vlm t bo dng li ti G1-S interface.

- rt hu ch i vi x tr v t bo phase G1c bit nhy cm i vi x tr.

CC THUC TR UNG TH KHCMitotan

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C

Cl

Cl

H

CHCl2

mitotan

1,1-Dichloro-2-(2-chlorophenyl)-2-(4-chlorophenyl)ethan

Mitotan ngn hon ton s sn xut ti thng thn glucocorticoid,mineralocorticoid v hormon sinh dc.

iu tr: Carcinoma v thng thn

Highly electrophilic acyl chloride, which has been shown to react with

proteins, leading to direct necrosis and atrophy of the adrenal cortex and

hence inhibition of glucocorticoid synthesis.

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Retinoids and their receptors

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Mcanisme dactionde la Topo I

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Mode daction de camptothecin (inhibiteur Topo I)

IU TR PHI HP

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Kt hp thuc Kt hp thuc Kt hp thuc

AdenocarcinomaCisplatin

Etoposide

Ung thvCyclophosphamid

DoxorubicinFluorouracil

Ung th rutIrinotecan

Fluorouracil

LeucovorinUng th d dyLeucovorin

Genitourinary MalignancyBladder

Cyclophosphamid

Doxorubicin

Cisplatin

Genitourinary MalignancyProstate

Estramustin

Vinblastin

Gynecologic Malignancy-

CervicalCisplatin

Fluouracil

Lymphoma HodgkinsDoxorubicin

Bleomycin

Vinblastin

Dacarbazin

Lymphoma- Non-HodgkinsCyclophosphamid

Doxorubicin

Vincristin

Prednison

Ung th tyStreptozocin

Mitomycin-C

Documents

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