PRINSIP TERAPI ANTIKANKER

EVI SOVIA LAB. FARMAKOLOGI FK UNJANI

OVERVIEW
25% of the population of USA will face a diagnosis of cancer during their lifetime 1 million new cancer patients diagnosed each year Less than a quarter of these patients will be cured solely by surgery and/or local radiation Most 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 CHEMOTHERAPY

Cancer 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 Treatment

Chemotherapy 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 scheduling

Drugs are usually administered on the basis of BSA 1. 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 sanctuaries 3. Treatment protocols a. 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 Chemotherapy

Resistance
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 patients marrow prior to intensive treatment and reimplant it Promoting intensive diuresis to prevent bladder toxicities

antikanker
Inhibitor mitosis Alkylating agents Antimetabolit Antibiotik Hormon

ANTIKANKER
1. Inhibitor mitosis a. kolkhisin MK: menghambat terbentuknya kumparan pembelahan sehingga terjadi inti poliploida Luas terapeutiknya kecil tidak digunakan lagi sebagai sitostatika

b. Turunan podofilin Etoposid dan teniposid Inhibitor mitosis Indikasi: 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 kronis Dosis: 4mg/hari p.o selama beberapa bulan

d. Turunan N-Nitrosurea Karmustin, lomustin, dan nimustin Dapat menembus BBB tumor otak Indikasi lain: limfoma Hodgkin e. Sisplatin MK: 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. Antimetabolit MK: 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 pirimidin Analog purin: merkaptopurin, tioguanin Analog 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
Fluorourasil MK: memblok timidilat sintetase menghambat metilasi asam disoksiuridilat menjadi asam timidilat hambatan sintesis DNA Sitarabin MK: menghambat ribonukleotidareduktase Merkaptopurin, tioguanin dan sitarabin digunakan pada leukemia akut dan eksaserbasi akut leukemia kronis Fluorourasil 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 sitostatik Aktinomisin (daktinomisin), antrasiklin (aklarubisin, daunorubisin, doxorubisin, epirubisin), dan bleomisin a. Daktinomisin Diisolasi dari Actinomycetes Digunakan untuk terapi tumor Wilms, Rhabdomiosarkoma, dan Ca testis b. 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 akut b.2. Daunorubisin Diisolasi dari Streptomyces coeruleorubidus dan peucetius Indikasi: leukemia mielositik akut dan leukemia limfositik akut b.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 rektum c. 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 hormon Digunakan 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. Estrogen Dulu digunakan untuk Ca prostat ES: 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

Aminoglutetimida MK: menghambat biosintesis hormon steroid Absorpsi p.o cepat Eksresi di ginjal Dosis 4 X 250mg (ditambah 2X20mg kortisol) ES: lesu, pusing, ataksia, nausea, eksantema

d. Senyawa androgen Indikasi: Ca payudara Turunan androgen yg mempunyai kerja menghambat tumor yg sama kuat dg testosteron tetapi kerja androgen jauh lebih kecil : drostanolopropionat dan testolakton Keuntungan: maskulinisasi <<<

e. Antiandrogen Ca prostat Siproteronasetat dan flutamida Dosis 750mg ES: ginekomastia, ggn CV, nausea, nafsu makan , libido <<, produksi sperma <<, kerusakan hati

f. Hormon korteks adrenal Kerja antiproliperatif Leukemia akut dan sub aku pd anak-anak dan leukemia kronis pd dewasa Kombinasi dg sitostatika lain