FARMAKOLOGI ANTIKANKERINDAH PRIHANDINI

OVERVIEW25% of the population of USA will face a

diagnosis of cancer during their lifetime1 million new cancer patients diagnosed each

yearLess than a quarter of these patients will be

cured solely by surgery and/or local radiationMost of the remainder wil receive systemic

chemotherapy at some time during their illness

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

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

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

PRINCIPLES OF CANCER CHEMOTHERAPYCancer chemotherapy strives to cause

a lethal cytotoxic event in the cancer cell that can arrest a tumor progression

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

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

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

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

Treatment Strategies

1. Goal of treatment• the ultimate goal of chemotherapy

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

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

Indication For TreatmentChemotherapy is indicated when

neoplasms are disseminated and are not amenable to surgery

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

Tumor Susceptibility And The Growth Cycle Cell that are in the replicative

cycle (growth fraction) influences their susceptibility to most cancer chemotheurapeutic agents

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

Cell cycle specificity of drugs◦Both normal cells and tumor cells go

through growth cycle◦However, normal and neoplastic tissues

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

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

Tumor growth rate◦Solid tumor, initially rapid but

decreases as the tumor size increases

◦Because of unavailability of nutrients and oxygens caused by inadequate vascularization

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

Treatment regimens and schedulingDrugs are usually administered on

the basis of BSA1. log kill

dectruction of cancer cells by chemotherapeutic agents follows first order kinetics; that is a given dose of drug destroys a constant fraction of cells

2. Pharmacologic sanctuaries3. Treatment protocolsa. Combination drugs chemotherapy

is more successful than single drug treatment in most cancers for which chemotherapy is effective- different toxixities- different molecular sites and MOA

Adventages of drugs combinations◦provide maximal cell killing which

the range of tolerated toxixity◦are effective against a broader range

of cell lines in the hetergeneous tumor population

◦may delay or prevent the development of resistant cell lines

Problem Associated With ChemotherapyResistance

◦Minimized by short term, intensive, intermitten therapy with combinations of drugs

Multidrugs resistance

Treatment induced tumors◦Antineoplastic agents are mutagens,

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

Toxicity◦Common adverse effects

Narrow therapeutic index Severe vomiting Stomatitis Alopecia myelosupression

◦Minimizing adverse effects Perfusing the tumor locally Removing some of patient’s marrow prior to

intensive treatment and reimplant it Promoting intensive diuresis to prevent

bladder toxicities

antikankerInhibitor mitosisAlkylating agentsAntimetabolitAntibiotikHormon

ANTIKANKER

1. Inhibitor mitosisa. kolkhisin

MK: menghambat terbentuknya kumparan pembelahan sehingga terjadi inti poliploida

Luas terapeutiknya kecil → tidak digunakan lagi sebagai sitostatika

b. Turunan podofilinEtoposid dan teniposidInhibitor mitosisIndikasi: limfoma ganas,

karsinoma bronkhus, tumor otak ganas, karsinoma kandung kemih

c. Alkaloid vinca Vinblastin dan Vinkristin MK: menghambat pembelahan sel dalam metafase

dengan berikatan pada tubulin Waktu paruh vinblastin 24 jam, vinkristin 85 jam Eliminasi melalui empedu Indikasi utama vinblastin: linfoma Hodgkin,

limfosarkoma, tumor testis, serta khorionepitelioma ganas

Vinkristin digunakan untuk LLA, limfoma Hodgkin dan non Hodgkin, neuroblastoma dan tumor Wilms

Berbeda dengan vinblastin, vinkristin tidak merusak sumsum tulang, tetapi kerja neurotoksiknya (neuropati perifer) membatasi penggunaan dosis tinggi

2. Sitostatika pengalkilasi (alkylating agent)kerja sitostatiknya terutama didasarkan pada alkilasi asam nukleat → perubahan DNA di beberapa tempat → reduplikasi asam nukleat dan pembelahan sel terganggu

a. Turunan diklordietilsulfida Gas mustar (diklordietilsulfida) digunakan

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

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

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

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

karsinoma bronkhus, Ca payudara, Ca ovarium

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

diklordietilsulfida, tetapi hasilnya tidak sebaik senyawa tsb

Dosis: 15mg iv 1-2 kali /minggu

c. Busulfan Kerja hambatan yang spesifik pada sistem

mieloid Indikasi: leukemia mieloid kronisDosis: 4mg/hari p.o selama beberapa bulan

d. Turunan N-NitrosureaKarmustin, lomustin, dan nimustinDapat menembus BBB → tumor otak Indikasi lain: limfoma Hodgkine. SisplatinMK: membuat jaringan antar untai-untai DNA

→ menghambat pembelahan sel Indikasi: Ca ovarium, Ca serviks, Ca

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

ES: gagal ginjal ireversibel

3. AntimetabolitMK: mengusir secara kompetitif

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

Sangat tidak spesifik → toksik → pemakaian dibatasi

a. Antagonis asam folat Dengan mengubah secara kimiawi

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

Metotreksat Indikasi: leukemia akut,

khorionepitelioma dan berbagai karsinoma, dan dipakai juga pada penyakit autoimun

b. Antagonis basa purin dan pirimidinAnalog purin: merkaptopurin, tioguaninAnalog pirimidin: fluorourasil, sitarabin Merkaptopurin

Bekerja secara kompetitif menghambat biosintesis purin

Menghambat berbagai enzim a.l adenilosuksinat sintetase dan fosforibosil-pirofosfatamido-transferase → sintesis DNA dan RNA ditekan

Tioguanin ≈ merkaptopurin

FluorourasilMK: memblok timidilat sintetase →menghambat metilasi asam disoksiuridilat menjadi asam timidilat → hambatan sintesis DNA

SitarabinMK: menghambat ribonukleotidareduktase

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

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

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

a. Daktinomisin Diisolasi dari Actinomycetes Digunakan untuk terapi tumor Wilms,

Rhabdomiosarkoma, dan Ca testisb. Antrasiklin Diisolasi dari jenis Streptomyces MK: mempengaruhi sintesis DNA maupun

RNA a.l terjadi pemutusan untai tunggal dan ganda DNA yg diakibatkan oleh adanya pembentukan radikal bebas

Kardiotoksik

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

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

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

ovarium, gaster, dan rektumc. Bleomisin Didpt dari Streptomyces verticillus Karsinoma epitel pipih Toksisitas pd sumsum tulang dan kerja imunosupresifnya relatif

kecil ES: skleroderma dan fibrosis paru

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

a. Hormon hipotalamus Analog GnRH : buserelin dan

leuprorelinasetat Digunakan untuk Ca prostat Keuntungan dibanding estrogen: feminisasi

<<<, komplikasi CV ↓ Dosis buserelin 0,5mg sc sehari 3X selama

7 hari Dosis leuprorelinasetat 0,2mg setiap hari ES: libido ↓, impotensi, perubahan kulit

dan mukosa

b. EstrogenDulu digunakan untuk Ca prostatES: komplikasi CV (retensi air,

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

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

c. Antiestrogen Indikasi: Ca payudara dg reseptor hormon (+), Ca

korpus yg resisten progerteron Remisi 55-60% Tamoksifen dan aminoglutetimida

Tamoksifen MK: memblok kerja perifer estrogen dg cara berikatan

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

perdarahan pd vagina, trombositopenia

AminoglutetimidaMK: menghambat biosintesis

hormon steroidAbsorpsi p.o cepatEksresi di ginjalDosis 4 X 250mg (ditambah

2X20mg kortisol)ES: lesu, pusing, ataksia, nausea,

eksantema

d. Senyawa androgenIndikasi: Ca payudaraTurunan androgen yg mempunyai

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

Keuntungan: maskulinisasi <<<

e. AntiandrogenCa prostatSiproteronasetat dan flutamidaDosis 750mgES: ginekomastia, ggn CV,

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

f. Hormon korteks adrenalKerja antiproliperatifLeukemia akut dan sub aku pd

anak-anak dan leukemia kronis pd dewasa

Kombinasi dg sitostatika lain