PRINSIP TERAPI PRINSIP TERAPI ANTIKANKERANTIKANKER

EVI SOVIAEVI SOVIA

LAB. FARMAKOLOGILAB. FARMAKOLOGI

FK UNJANIFK UNJANI

OVERVIEWOVERVIEW

• 25% of the population of USA will face a 25% of the population of USA will face a diagnosis of cancer during their lifetimediagnosis of cancer during their lifetime

• 1 million new cancer patients diagnosed each 1 million new cancer patients diagnosed each yearyear

• Less than a quarter of these patients will be Less than a quarter of these patients will be cured solely by surgery and/or local radiationcured solely by surgery and/or local radiation

• Most of the remainder wil receive systemic Most of the remainder wil receive systemic chemotherapy at some time during their illnesschemotherapy at some time during their illness

• in a small fraction (10%) of patients with cancer in a small fraction (10%) of patients with cancer representing selected neoplasma, the representing selected neoplasma, the chemotherapy will result in a cure or a chemotherapy will result in a cure or a prolonged remission. prolonged remission.

• in most cases the drugs will produce in most cases the drugs will produce only a regresion of the disease, and only a regresion of the disease, and the complication and/or relaps may the complication and/or relaps may eventually lead to deatheventually lead to death

• the overall 5 years survival rate for the overall 5 years survival rate for patients is about 40%patients is about 40%

PRINCIPLES OF CANCER PRINCIPLES OF CANCER CHEMOTHERAPYCHEMOTHERAPY

• Cancer chemotherapy strives to cause a Cancer chemotherapy strives to cause a lethal cytotoxic event in the cancer cell that lethal cytotoxic event in the cancer cell that can arrest a tumor progressioncan arrest a tumor progression

• The attack is generally directed against The attack is generally directed against metabolic sites essential to cell replication, metabolic sites essential to cell replication, for example, the availability the purine and for example, the availability the purine and pyrimidines that are the buildings blocks for pyrimidines that are the buildings blocks for DNA or RNADNA or RNA

• Ideally, these anticancer drugs should Ideally, these anticancer drugs should interfere only with cwllular processes that interfere only with cwllular processes that are unique to malignant cellare unique to malignant cell

• Unfortunately, most currently Unfortunately, most currently available anticancer drugs do not available anticancer drugs do not specifically recognize neoplastic cell specifically recognize neoplastic cell but rather affects all proliferating but rather affects all proliferating cells both normal and abnormal cells both normal and abnormal

• Therefore, almost antitumor agents Therefore, almost antitumor agents have a step dose response curve for have a step dose response curve for both toxic and therapeutic effectsboth toxic and therapeutic effects

Treatment StrategiesTreatment Strategies

1.1. Goal of treatmentGoal of treatment• the ultimate goal of chemotherapy is a the ultimate goal of chemotherapy is a

curecure• if a cure is not attainable, then the if a cure is not attainable, then the

goal becomes palliation (alleviation of goal becomes palliation (alleviation of symptoms and avoidance of life-symptoms and avoidance of life-threiting toxocity)threiting toxocity)

Indication For TreatmentIndication For Treatment

• Chemotherapy is indicated when Chemotherapy is indicated when neoplasms are disseminated and are neoplasms are disseminated and are not amenable to surgerynot amenable to surgery

• Chemotherapy is also used as a Chemotherapy is also used as a suplemental treatment to attack suplemental treatment to attack micrometastases following surgery micrometastases following surgery and radiation treatment and radiation treatment

Tumor Susceptibility And Tumor Susceptibility And The Growth Cycle The Growth Cycle

• Cell that are in the replicative cycle Cell that are in the replicative cycle (growth fraction) influences their (growth fraction) influences their susceptibility to most cancer susceptibility to most cancer chemotheurapeutic agentschemotheurapeutic agents

• rapidly dividing cells are generally rapidly dividing cells are generally more sensitive to anticancer drugs, more sensitive to anticancer drugs, whereas nonproliferating cells whereas nonproliferating cells

• Cell cycle specificity of drugsCell cycle specificity of drugs– Both normal cells and tumor cells go Both normal cells and tumor cells go

through growth cyclethrough growth cycle– However, normal and neoplastic tissues However, normal and neoplastic tissues

may differ in the number of cells that are may differ in the number of cells that are in the various stages of the cyclein the various stages of the cycle

– Chemotherapeutic agents that are Chemotherapeutic agents that are effective only against replicating cells are effective only against replicating cells are said to be cell cycle said to be cell cycle specific(antimetabolites, bleomycin, specific(antimetabolites, bleomycin, antibiotics, etoposide) whereas other antibiotics, etoposide) whereas other agents are said to be cell cycle non agents are said to be cell cycle non specific (alkylating agents, antibiotics, specific (alkylating agents, antibiotics, cisplatin, nitrosurea)cisplatin, nitrosurea)

• Tumor growth rateTumor growth rate– Solid tumor, initially rapid but decreases as Solid tumor, initially rapid but decreases as

the tumor size increasesthe tumor size increases– Because of unavailability of nutrients and Because of unavailability of nutrients and

oxygens caused by inadequate oxygens caused by inadequate vascularizationvascularization

– Reducing the tumor burden through surgery Reducing the tumor burden through surgery or radistion promotes the recruitment of the or radistion promotes the recruitment of the remaining cells into active proliferation and remaining cells into active proliferation and increases their susceptability to increases their susceptability to chemotherapeutic agents chemotherapeutic agents

Treatment regimens and Treatment regimens and schedulingscheduling

Drugs are usually administered on the Drugs are usually administered on the basis of BSAbasis of BSA

1.1. log killlog killdectruction of cancer cells by dectruction of cancer cells by

chemotherapeutic agents follows first chemotherapeutic agents follows first order kinetics; that is a given dose of order kinetics; that is a given dose of drug destroys a constant fraction of drug destroys a constant fraction of cellscells

2. Pharmacologic sanctuaries2. Pharmacologic sanctuaries

3. Treatment protocols3. Treatment protocols

a.a. Combination drugs chemotherapy is Combination drugs chemotherapy is more successful than single drug more successful than single drug treatment in most cancers for which treatment in most cancers for which chemotherapy is effectivechemotherapy is effective

- different toxixities- different toxixities

- different molecular sites and MOA- different molecular sites and MOA

• Adventages of drugs combinationsAdventages of drugs combinations– provide maximal cell killing which the provide maximal cell killing which the

range of tolerated toxixityrange of tolerated toxixity– are effective against a broader range of are effective against a broader range of

cell lines in the hetergeneous tumor cell lines in the hetergeneous tumor populationpopulation

– may delay or prevent the development may delay or prevent the development of resistant cell linesof resistant cell lines

Problem Associated With Problem Associated With ChemotherapyChemotherapy

• ResistanceResistance– Minimized by short term, intensive, Minimized by short term, intensive,

intermitten therapy with combinations intermitten therapy with combinations of drugsof drugs

• Multidrugs resistanceMultidrugs resistance

• Treatment induced tumorsTreatment induced tumors– Antineoplastic agents are mutagens, Antineoplastic agents are mutagens,

neoplasms may arise ten or more years neoplasms may arise ten or more years after the original cancer was curedafter the original cancer was cured

• ToxicityToxicity– Common adverse effectsCommon adverse effects

• Narrow therapeutic indexNarrow therapeutic index• Severe vomitingSevere vomiting• StomatitisStomatitis• AlopeciaAlopecia• myelosupressionmyelosupression

– Minimizing adverse effectsMinimizing adverse effects• Perfusing the tumor locallyPerfusing the tumor locally• Removing some of patient’s marrow prior to Removing some of patient’s marrow prior to

intensive treatment and reimplant itintensive treatment and reimplant it• Promoting intensive diuresis to prevent Promoting intensive diuresis to prevent

bladder toxicitiesbladder toxicities

antikankerantikanker

• Inhibitor mitosisInhibitor mitosis• Alkylating agentsAlkylating agents• AntimetabolitAntimetabolit• AntibiotikAntibiotik• Hormon Hormon

ANTIKANKERANTIKANKER

1.1. Inhibitor mitosisInhibitor mitosis

a. kolkhisina. kolkhisin• MK: menghambat terbentuknya MK: menghambat terbentuknya

kumparan pembelahan sehingga kumparan pembelahan sehingga terjadi inti poliploidaterjadi inti poliploida

• Luas terapeutiknya kecil Luas terapeutiknya kecil → tidak → tidak digunakan lagi sebagai sitostatikadigunakan lagi sebagai sitostatika

b. b. Turunan podofilinTurunan podofilin• Etoposid dan teniposidEtoposid dan teniposid• Inhibitor mitosisInhibitor mitosis• Indikasi: limfoma ganas, karsinoma Indikasi: limfoma ganas, karsinoma

bronkhus, tumor otak ganas, bronkhus, tumor otak ganas, karsinoma kandung kemihkarsinoma kandung kemih

c. c. Alkaloid vincaAlkaloid vinca• Vinblastin dan VinkristinVinblastin dan Vinkristin• MK: menghambat pembelahan sel dalam metafase dengan MK: menghambat pembelahan sel dalam metafase dengan

berikatan pada tubulinberikatan pada tubulin• Waktu paruh vinblastin 24 jam, vinkristin 85 jamWaktu paruh vinblastin 24 jam, vinkristin 85 jam• Eliminasi melalui empeduEliminasi melalui empedu• Indikasi utama vinblastin: linfoma Hodgkin, limfosarkoma, Indikasi utama vinblastin: linfoma Hodgkin, limfosarkoma,

tumor testis, serta khorionepitelioma ganastumor testis, serta khorionepitelioma ganas• Vinkristin digunakan untuk LLA, limfoma Hodgkin dan non Vinkristin digunakan untuk LLA, limfoma Hodgkin dan non

Hodgkin, neuroblastoma dan tumor WilmsHodgkin, neuroblastoma dan tumor Wilms• Berbeda dengan vinblastin, vinkristin tidak merusak Berbeda dengan vinblastin, vinkristin tidak merusak

sumsum tulang, tetapi kerja neurotoksiknya (neuropati sumsum tulang, tetapi kerja neurotoksiknya (neuropati perifer) membatasi penggunaan dosis tinggi perifer) membatasi penggunaan dosis tinggi

2. 2. Sitostatika pengalkilasi Sitostatika pengalkilasi ((alkylating agent)alkylating agent)

kerja sitostatiknya terutama kerja sitostatiknya terutama didasarkan pada alkilasi asam didasarkan pada alkilasi asam nukleat nukleat → perubahan DNA di → perubahan DNA di beberapa tempat → reduplikasi asam beberapa tempat → reduplikasi asam nukleat dan pembelahan sel nukleat dan pembelahan sel tergangguterganggu

a.a. Turunan diklordietilsulfidaTurunan diklordietilsulfida• Gas mustar (Gas mustar (diklordietilsulfidadiklordietilsulfida) digunakan dalam ) digunakan dalam

perang dunia I, pada otopsi ditemukan perang dunia I, pada otopsi ditemukan kerusakan semua jaringan yg berproliferasi dgn kerusakan semua jaringan yg berproliferasi dgn cepat terutama sumsum tulang cepat terutama sumsum tulang → kemoterapi→ kemoterapi

• Karena terlalu toksik diganti dg senyawa Karena terlalu toksik diganti dg senyawa analognya: mustar nitrogen analognya: mustar nitrogen ((diklordietilmetilaminadiklordietilmetilamina))

• Zat yang paling terkenal dan juga paling banyak Zat yang paling terkenal dan juga paling banyak digunakan dari kelompok ini: digunakan dari kelompok ini: siklofosfamidsiklofosfamid

• Dosis: 200-300mg iv atau oral setiap hariDosis: 200-300mg iv atau oral setiap hari• Indikasi: limfoma Hodgkin, non Hodgkin, Indikasi: limfoma Hodgkin, non Hodgkin,

karsinoma bronkhus, Ca payudara, Ca ovariumkarsinoma bronkhus, Ca payudara, Ca ovarium

b. b. Turunan etilenemin (AziridinTurunan etilenemin (Aziridin))• Mekanisme kerja dan indikasi sama dg Mekanisme kerja dan indikasi sama dg

diklordietilsulfida, tetapi hasilnya tidak sebaik diklordietilsulfida, tetapi hasilnya tidak sebaik senyawa tsbsenyawa tsb

• Dosis: 15mg iv 1-2 kali /mingguDosis: 15mg iv 1-2 kali /minggu

c. c. BusulfanBusulfan • Kerja hambatan yang Kerja hambatan yang spesifik pada sistem spesifik pada sistem

mieloidmieloid• Indikasi: leukemia mieloid kronisIndikasi: leukemia mieloid kronis• Dosis: 4mg/hari p.o selama beberapa bulanDosis: 4mg/hari p.o selama beberapa bulan

d. d. Turunan N-NitrosureaTurunan N-Nitrosurea• Karmustin, lomustin, dan nimustinKarmustin, lomustin, dan nimustin• Dapat menembus BBBDapat menembus BBB → tumor otak→ tumor otak• Indikasi lain: limfoma HodgkinIndikasi lain: limfoma Hodgkine. e. SisplatinSisplatin• MK: membuat jaringan antar untai-untai DNA → MK: membuat jaringan antar untai-untai DNA →

menghambat pembelahan selmenghambat pembelahan sel• Indikasi: Ca ovarium, Ca serviks, Ca Indikasi: Ca ovarium, Ca serviks, Ca

endometrium, Ca testis, Ca prostat, Ca kandung endometrium, Ca testis, Ca prostat, Ca kandung kemih, Ca bronkhus, karsinoma epitel pipih, kemih, Ca bronkhus, karsinoma epitel pipih, karsinoma di daerah kepala dan leher, melanoma karsinoma di daerah kepala dan leher, melanoma dan sarkomadan sarkoma

• ES: ES: gagal ginjal ireversibelgagal ginjal ireversibel

3. 3. AntimetabolitAntimetabolit• MK: mengusir secara kompetitif MK: mengusir secara kompetitif

senyawa dasar metabolisme alami senyawa dasar metabolisme alami (metabolit) atau memblok enzim (metabolit) atau memblok enzim → → menghambat metabolisme dan menghambat metabolisme dan pertumbuhan selpertumbuhan sel

• Sangat tidak spesifik → toksik → Sangat tidak spesifik → toksik → pemakaian dibatasipemakaian dibatasi

a.a. Antagonis asam folatAntagonis asam folat• Dengan mengubah secara kimiawi asam Dengan mengubah secara kimiawi asam

folat, akan didapat antagonis asam folat folat, akan didapat antagonis asam folat yg mempunyai afinitas yang jauh lebih yg mempunyai afinitas yang jauh lebih tinggi tehadap dihidrofolatreduktase tinggi tehadap dihidrofolatreduktase dibandingkan dengan asam folat sendiri dibandingkan dengan asam folat sendiri → sintesis asam nukleat terganggu→ sintesis asam nukleat terganggu

• MetotreksatMetotreksat• Indikasi: leukemia akut, Indikasi: leukemia akut,

khorionepitelioma dan berbagai khorionepitelioma dan berbagai karsinoma, dan dipakai juga pada karsinoma, dan dipakai juga pada penyakit autoimunpenyakit autoimun

b. Antagonis basa purin dan pirimidinb. Antagonis basa purin dan pirimidin

Analog purin: Analog purin: merkaptopurin, tioguaninmerkaptopurin, tioguanin

Analog pirimidin: Analog pirimidin: fluorourasil, sitarabin fluorourasil, sitarabin

MerkaptopurinMerkaptopurin• Bekerja secara kompetitif menghambat Bekerja secara kompetitif menghambat

biosintesis purin biosintesis purin • Menghambat berbagai enzim a.l Menghambat berbagai enzim a.l

adenilosuksinat sintetase dan fosforibosil-adenilosuksinat sintetase dan fosforibosil-pirofosfatamido-transferase pirofosfatamido-transferase → sintesis DNA → sintesis DNA dan RNA ditekandan RNA ditekan

TioguaninTioguanin ≈ merkaptopurin≈ merkaptopurin

FluorourasilFluorourasilMK: memblok timidilat sintetase →menghambat metilasi MK: memblok timidilat sintetase →menghambat metilasi asam disoksiuridilat menjadi asam timidilat → hambatan asam disoksiuridilat menjadi asam timidilat → hambatan sintesis DNAsintesis DNA

SitarabinSitarabinMK: menghambat ribonukleotidareduktaseMK: menghambat ribonukleotidareduktase

Merkaptopurin, tioguanin dan sitarabin digunakan pada Merkaptopurin, tioguanin dan sitarabin digunakan pada leukemia akut dan eksaserbasi akut leukemia kronisleukemia akut dan eksaserbasi akut leukemia kronisFluorourasil digunakan sebagai terapi paliatif Fluorourasil digunakan sebagai terapi paliatif

Dosis: merkaptopurin 2,5mg/kgBB/hari, tioguanin 1-2 Dosis: merkaptopurin 2,5mg/kgBB/hari, tioguanin 1-2 mg/kgBB/hari, fluorourasil 12 mg/kgBB/hari selama 5 hari, mg/kgBB/hari, fluorourasil 12 mg/kgBB/hari selama 5 hari, dan sitarabin 2-3 mg/kgBB/hari selama 5-6 haridan sitarabin 2-3 mg/kgBB/hari selama 5-6 hari

4. 4. Antibiotika yg bekerja sitostatikAntibiotika yg bekerja sitostatikAktinomisin (daktinomisin), antrasiklin (aklarubisin, Aktinomisin (daktinomisin), antrasiklin (aklarubisin, daunorubisin, doxorubisin, epirubisin), dan bleomisindaunorubisin, doxorubisin, epirubisin), dan bleomisin

a.a. Daktinomisin Daktinomisin • Diisolasi dari Diisolasi dari ActinomycetesActinomycetes• Digunakan untuk terapi tumor Wilms, Digunakan untuk terapi tumor Wilms,

Rhabdomiosarkoma, dan Ca testisRhabdomiosarkoma, dan Ca testisb.b. AntrasiklinAntrasiklin• Diisolasi dari jenis Diisolasi dari jenis StreptomycesStreptomyces• MK: mempengaruhi sintesis DNA maupun RNA a.l MK: mempengaruhi sintesis DNA maupun RNA a.l

terjadi pemutusan untai tunggal dan ganda DNA yg terjadi pemutusan untai tunggal dan ganda DNA yg diakibatkan oleh adanya pembentukan radikal bebasdiakibatkan oleh adanya pembentukan radikal bebas

• KardiotoksikKardiotoksik

b.1. Aklarubisinb.1. Aklarubisin• Diisolasi dari Diisolasi dari Streptomyces galilaeusStreptomyces galilaeus• Indikasi: leukemia mielositik akutIndikasi: leukemia mielositik akutb.2. Daunorubisinb.2. Daunorubisin• Diisolasi dari Diisolasi dari Streptomyces coeruleorubidus dan peucetiusStreptomyces coeruleorubidus dan peucetius• Indikasi: leukemia mielositik akut dan leukemia limfositik akutIndikasi: leukemia mielositik akut dan leukemia limfositik akutb.3. Doksorubisin b.3. Doksorubisin ≈ daunorubisin≈ daunorubisin

Indikasi: leukemia akut, limfogranolumatosis, serta berbagai Indikasi: leukemia akut, limfogranolumatosis, serta berbagai karsinoma dan sarkomakarsinoma dan sarkoma

b.4. Epirubisinb.4. Epirubisin• Kardiotoksik lebih kecil dari doksorubisinKardiotoksik lebih kecil dari doksorubisin• Indikasi: limfoma non Hodgkin, sarkoma, melanoma, Ca Indikasi: limfoma non Hodgkin, sarkoma, melanoma, Ca

payudara ovarium, gaster, dan rektumpayudara ovarium, gaster, dan rektumc. c. BleomisinBleomisin• Didpt dari Didpt dari Streptomyces verticillusStreptomyces verticillus• Karsinoma epitel pipihKarsinoma epitel pipih• Toksisitas pd sumsum tulang dan kerja imunosupresifnya relatif Toksisitas pd sumsum tulang dan kerja imunosupresifnya relatif

kecilkecil• ES: skleroderma dan fibrosis paruES: skleroderma dan fibrosis paru

5. 5. Hormon dan antagonis hormonHormon dan antagonis hormonDigunakan pd tumor yg pertumbuhannya tgt pd Digunakan pd tumor yg pertumbuhannya tgt pd hormon (Ca prostat, Ca payudara, Ca uterus)hormon (Ca prostat, Ca payudara, Ca uterus)

a.a. Hormon hipotalamusHormon hipotalamus• Analog GnRH : Analog GnRH : buserelinbuserelin dan dan leuprorelinasetatleuprorelinasetat• Digunakan untuk Ca prostatDigunakan untuk Ca prostat• Keuntungan dibanding estrogen: feminisasi <<<, Keuntungan dibanding estrogen: feminisasi <<<,

komplikasi CV komplikasi CV ↓↓• Dosis buserelin 0,5mg sc sehari 3X selama 7 hariDosis buserelin 0,5mg sc sehari 3X selama 7 hari• Dosis Dosis leuprorelinasetat 0,2mg setiap hari leuprorelinasetat 0,2mg setiap hari • ES: libido ES: libido ↓, impotensi, perubahan kulit dan ↓, impotensi, perubahan kulit dan

mukosamukosa

b. b. EstrogenEstrogen• Dulu digunakan untuk Ca prostatDulu digunakan untuk Ca prostat• ES: komplikasi CV (retensi air, ES: komplikasi CV (retensi air,

tromboemboli, insufisiensi jantung, tromboemboli, insufisiensi jantung, infark jantung), ginekomastia, infark jantung), ginekomastia, keluhan lambung, dan kholestasiskeluhan lambung, dan kholestasis

• Indikasi lain: Ca payudara pd pasien Indikasi lain: Ca payudara pd pasien usia lanjut yg mengalami menopause usia lanjut yg mengalami menopause 5 th atau lebih5 th atau lebih

c. c. AntiestrogenAntiestrogen• Indikasi: Ca payudara dg reseptor hormon (+), Ca korpus Indikasi: Ca payudara dg reseptor hormon (+), Ca korpus

yg resisten progerteronyg resisten progerteron• Remisi 55-60%Remisi 55-60%• Tamoksifen dan aminoglutetimidaTamoksifen dan aminoglutetimida

TamoksifenTamoksifen• MK: memblok kerja perifer estrogen dg cara berikatan dg MK: memblok kerja perifer estrogen dg cara berikatan dg

reseptor estrogenreseptor estrogen• Pd pemberian p.o: absorpsi lambatPd pemberian p.o: absorpsi lambat• Eksresi melalui empeduEksresi melalui empedu• Dosis 20-40mg /hariDosis 20-40mg /hari• ES: ggn GIT, sakit kepala, pruritus, retensi air, perdarahan ES: ggn GIT, sakit kepala, pruritus, retensi air, perdarahan

pd vagina, trombositopeniapd vagina, trombositopenia

AminoglutetimidaAminoglutetimida• MK: menghambat biosintesis MK: menghambat biosintesis

hormon steroidhormon steroid• Absorpsi p.o cepatAbsorpsi p.o cepat• Eksresi di ginjalEksresi di ginjal• Dosis 4 X 250mg (ditambah 2X20mg Dosis 4 X 250mg (ditambah 2X20mg

kortisol)kortisol)• ES: lesu, pusing, ataksia, nausea, ES: lesu, pusing, ataksia, nausea,

eksantemaeksantema

d. d. Senyawa androgenSenyawa androgen• Indikasi: Ca payudaraIndikasi: Ca payudara• Turunan androgen yg mempunyai Turunan androgen yg mempunyai

kerja menghambat tumor yg sama kerja menghambat tumor yg sama kuat dg testosteron tetapi kerja kuat dg testosteron tetapi kerja androgen jauh lebih kecil : androgen jauh lebih kecil : drostanolo-propionatdrostanolo-propionat dan dan testolaktontestolakton

• Keuntungan: maskulinisasi <<<Keuntungan: maskulinisasi <<<

e. e. AntiandrogenAntiandrogen• Ca prostatCa prostat• Siproteronasetat Siproteronasetat dan dan flutamidaflutamida• Dosis 750mgDosis 750mg• ES: ginekomastia, ggn CV, nausea, ES: ginekomastia, ggn CV, nausea,

nafsu makan nafsu makan ↓, libido <<, produksi ↓, libido <<, produksi sperma <<, kerusakan hatisperma <<, kerusakan hati

f. f. Hormon korteks adrenalHormon korteks adrenal• Kerja antiproliperatifKerja antiproliperatif• Leukemia akut dan sub aku pd anak-Leukemia akut dan sub aku pd anak-

anak dan leukemia kronis pd dewasaanak dan leukemia kronis pd dewasa• Kombinasi dg sitostatika lainKombinasi dg sitostatika lain