ANTI KANKER

KANKER ??
Proliferasi abnormal dari sel jaringan tubuh manusia yang tidak terkendali dengan kecenderungan menyebar ke tempat di luar tempat asal sel-sel jaringan tubuh tadi (metastasis).
Uncontrolled growth and The ability to metastasize

Penyebab
Virus : Epstein-barr African burkitts Lymph, Bahan Kimia co aflatoksin (Ca liver), ikatan nitroso, benzene, anilin Radiasi, cahaya ultraviolet Hormon dan obat-obatan

Eksogen (Carcinogenic Agent)

Endogen (Genetik)

2 gen terlibat dalam cacinogenesis Oncogen Tumor-suppressor gens Oncogen gen normal (protooncogen) Carcinogen terjadi pertumbuhan yg berlebihan Tumor supresor gen mengatur dan mencegah pertumbuhan sel

CARCINOGENESIS

Proses Karsinogenesis

Exposure sel normal oleh senyawa karsinogenik Carcinogen kerusakan genetik jika tdk direparasi menyebabkan mutasi sel yg irreversible Sel yg bermutasi akan mempengaruhi respon thd lingkungan

Promotion

Initiation

Carcinogen mempengaruhi lingkungan sehingga menyebabkan pertumbuhan abnormal dari populasi sel Pada saat ini sel yg bermutasi mjd cancereous

Tergantung dari type cancer 5-20 th setelah proses carcinogenic dan berkembang menjadi kanker yg dapat terdeteksi

Progression

Transformation

Perubahan genetik yg lebih lanjut peningkatan proliferasi sel Invasi tumor ke dalam jaringan lokal dan perkambangan kearah metastase

KINETIKA SEL KANKER

Pola pertumbuhan sel kanker scr matematik

tergambar dalam Gompertzian growth curve Pertumbuhan sel kanker : logaritmik Sel kanker proliferasi 1 sel mjd 2, 4, dst mll proses mitosis Doubling time berbeda-beda tiap jenis kanker (hitungan jam hingga hari) Mulai teraba ukuran 1 mm3 hingga 1 cm3 (106 109) Pertumbuhan sel tidak akan berhenti hingga mencapai a lethal tumor burden kematian

Ukuran 1012 - 1013 (1 L-10 L) pada organ penting

Tabel kinetika sel kanker

Jml doubling 1x 2x 3 4 5 6 7 8 9 10 Sel awal 1 2 4 8 16 32 64 128 256 512 Sel akhir 2 4 8 16 32 64 128 256 512 1024 = 10

GOMPERTZIAN KINETICS

KOMPARTEMEN SEL KANKER dan SIKLUS SEL

G2

Proliferasi
S M

Non Proliferasi

G1
G1 G1 G1 G0 G ~ G1= persiapan sintesa DNA S = syntesis DNA M = mitosis G2= gap fase/tetrafloid G1= resting, phase for long period G1 = makin jauh, makin lama mendapatkan makanan

Sel mati

Tujuan pengobatan kanker

1. Terapi Kuratif : menyembuhkan kanker. Kanker menghilang seluruhnya dan tidak timbul lagi meskipun tanpa pengobatan 2. Paliatif : terapi tidak bertujuan menyembuhkan tapi memperbaiki kualitas hidup dan atau memperpanjang kemampuan hidup (survival)

CCS
Ditinjau dari siklus

CCNS

sel, obat anti kanker dibagi 2 golongan : 1. CCS (Cell Cycle Specific) Obat yang memperlihatkan toksisitas selektif terhadap fase-fase tertentu sel 2. CCNS (Cell Cycle Non Specific) tidak selektif terhadap fase tertentu sel

CELL CYCLE ACTIVITY FOR ANTICANCER DRUGS

MEKANISME KERJA ANTI KANKER

ALKYLATING AGENT
Bekerja dengan pembentukan ion karbonium atau

kompleks lain yang sangat reaktif Ikatan kovalen (alkilasi)akan terjadi dengan berbagai nukleofilik penting dalam tubuh, seperti fosfat, amino, sulfhidril, hidroksil, karboksil, atau gugus imidazol. Efek sitistatik atau efek sampingnya berhubungan langsung dengan terjadinya alkilasi DNA Contoh : alkilator mustar nitrogen dapat berikatan kovalen dengan 2 gugus asam nukleat pada rantai yang berbeda membentuk cross linking sehingga terjadi kerusakan pada fungsi DNA.

Major Clinically Useful Alkylating Agents

Bis(mechloroethyl)amines Nitrosoureas

Cancer Chemotherapy Chapter 55. B.G. Katzung

Aziridines

An Example of DNA Crosslinking

O HN H2 N HO O N N N

R
N N N

O NH N NH2 OH

O P

O O P O

Crosslinking: Joining two or more molecules by a covalent bond. This can either occur in the same strand (intrastrand crosslink) or in the opposite strands of the DNA (interstrand crosslink). Crosslinks also occur between DNA and protein. DNA replication is blocked by crosslinks, which causes replication arrest and cell death if the crosslink is not repaired.

Alkylating Agents (Covalent DNA binding drugs)

G C G T

1. The first class of chemotherapy agents used. 2. They stop tumour growth by crosslinking guanine nucleobases in DNA double-helix strands - directly attacking DNA. 3. This makes the strands unable to uncoil and separate. 4. As this is necessary in DNA replication, the cells can no longer divide. 5. Cell-cycle nonspecific effect 6. Alkylating agents are also mutagenic and carcinogenic

Cancer Chemotherapy Chapter 55. B.G. Katzung

A. Alkylating agents
1. Mechanism of Action a. Nitrogen Mustards 2. Clinical application 3. Route 4. Side effects

A. Mechlorethamine

DNA cross-links, resulting in inhibition of DNA synthesis and function

Same as above

Hodgkins and nonHodgkins lymphoma

Must be given Orally

Nausea and vomiting, decrease in PBL count, BM depression, bleeding, alopecia, skin pigmentation, pulmonary fibrosis
Same as above

B. Cyclophosphamide

Breast, ovarian, CLL, soft tissue sarcoma, WT, neuroblastoma Chronic lymphocytic leukemia Multiple myeloma, breast, ovarian Germ cell cancer, cervical carcinoma, lung, Hodgkins and non-Hodgkins lymphoma, sarcomas

Orally and I.V.

C. Chlorambucil D. Melphalan E. Ifosfamide

Same as above Same as above Same as above

Orally effective Orally effective Orally effective

Same as above Same as above Same as above

Cancer Chemotherapy Chapter 55. B.G. Katzung

A. Alkylating agents
1. Mechanism of Action b. Alkyl Sulfonates 2. Clinical application 3. Route 4. Side effects

A. Busulfan

Atypical alkylating agent.

Chronic granulocytic leukemia

Orally effective

Bone marrow depression, pulmonary fibrosis, and hyperuricemia

4. Side effects Bone marrow depression, CNS depression, renal toxicity Nausea and vomiting, Nephrotoxicity, nerve dysfunction

c. Nitrosoureas A. Carmustine

1. Mechanism of Action DNA damage, it can cross blood-brain barrier Lomustine alkylates and crosslinks DNA, thereby inhibiting DNA and RNA synthesis. Also carbamoylates DNA and proteins, resulting in inhibition of DNA and RNA synthesis and disruption of RNA processing. Lomustine is lipophilic and crosses the blood-brain barrier DNA damage

2. Clinical application Hodgkins and nonHodgkins lymphoma, brain tumors, G.I. carcinoma Hodgkins and nonHodgkins lymphoma, malignant melanoma and epidermoid carcinoma of lung

3. Route Given I.V. must be given slowly. Orally effective

B. Lomustine

C. Streptozotocin

pancreatic cancer

Given I.V.

Nausea and vomiting, nephrotoxicity, liver toxicity

A. Alkylating agents
d. Ethylenimines A. Triethylene thiophosphoramide (Thio-TEPA) B. Hexamethylmelamine (HMM) 1. Mechanism of Action DNA damage, Cytochrome P450 DNA damage 2. Clinical application Bladder cancer 3. Route Given I.V. 4. Side effects Nausea and vomiting, fatigue Nausea and vomiting, low blood counts, diarrhea

Advanced ovarian tumor

Given orally after food

d. Triazenes A. Dacarbazine (DTIC)

1. Mechanism of Action Blocks, DNA, RNA and protein synthesis

2. Clinical application Malignant Melanoma, Hodgkins and nonHodgkins lymphoma

3. Route Given I.V.

4. Side effects Bone marrow depression, hepatotoxicity, neurotoxicity, bleeding, bruising, blood clots, sore mouths.

Cancer Chemotherapy Chapter 55. B.G. Katzung

TUBULIN BINDING AGENT

Zat ini berikatan secara spesifik dengan tubulin, komponen protein mikrotubulin, spindle mitotik, dan memblok

polimerisasinya. Akibatnya terjadi disolusi mikrotubulus, sehingga sel terhenti dalam metafase (spindle poison)

Tubulin Binding Agents

Polymerization
Vincristine
e.g., Vincristine, Vinblastine, Vindesine Vinorelbine: Inhibition of mitotic spindle formation by binding to tubulin. M-phase of the cell cycle.

tubulin

Depolymerization
Paclitexal (taxol)

e.g., Paclitexal: binds to tubulin, promotes microtubule formation and retards disassembly; results in mitotic arrest.

ANTI METABOLIT
Antipurin dan antipirimidin mengambil tempa purin dan pirimidin dalam pembentukan nukleosida, sehingga mengganggu berbagai reaksi penting dalam tubuh Penggunaannya sebagai obat kanker karena metabolisme purin dan pirimidin lebih tinggi pada sel kanker dari sel normal. Dengan demikian, penghambatan sintesis DNA sel kanker lebih tinggi dari sel normal Terdiri dari antagonis purin, antagonis pirimidin, dan antagonis folat

Antagonis Folat

Natural Products
1. Antimitotic Drugs
1. Mechanism of Action A. Vincristine Cytotoxic: Inhibition of mitotic spindle formation by binding to tubulin. M-phase of the cell cycle. Methylates DNA and inhibits DNA synthesis and function 2. Clinical application Metastatic testicular cancer, Hodgkins and non-Hodgkins lymphoma, Kaposis sarcoma, breast carcinoma, chriocarcinoma, neuroblastoma Hodgkins and non-Hodgkins lymphoma, brain tumors, breast carcinoma, chriocarcinoma, neuroblastoma 3. Route I.V. 4. Side effects Bone marrow depression, epithelial ulceration, GI disturbances, neurotoxicity

B. Vinblastine

I.V.

Nausea and vomiting, neurotoxicity, thrombocytosis, hyperuricemia.

2. Antimitotic Drugs
1. Mechanism of Action Paclitaxel (Taxol) Cytotoxic: binds to tubulin, promotes microtubule formation and retards disassembly; mitotic arrest results 2. Clinical application Melanoma and carcinoma of ovary and breast 3. Route I.V. 4. Side effects Myelodepression and neuropathy

ANTIBIOTIK
1. Mechanism of Action a. Dactinomycin (ACTINOMYCIN D) It binds to DNA and inhibits RNA synthesis, impaired mRNA production, and protein synthesis inhibit DNA and RNA synthesis 2. Clinical application Rhabdomyosarcoma and Wilm's tumor in children; choriocarcinoma (used with methotrexate Acute lymphocytic/granulocytic leukemias; treatment of choice in nonlymphoblastic leukemia in adults when given with cytarabine Acute leukemia, Hodgkin's disease, non Hodgkin's lymphomas (BACOP regimen), CA of breast & ovary, small cell CA of lung, sarcomas, best available agent for metastatic thyroid CA Germ cell tumors of testes and ovary, e.g., testicular carcinoma (can be curative when used with vinblastine & cisplatin), squamous cell carcinoma 3. Route I.V. 4. Side effects Bone marrow depression, nausea and vomiting, alopecia, GI disturbances, and ulcerations of oral mucosa Side effects: bone marrow depression, GI disturbances and cardiac toxicity (can be prevented by dexrazoxane) Cardiac toxicity, Doxorubicin mainly affects the heart muscles, leading to tiredness or breathing trouble when climbing stairs or walking, swelling of the feet .

b. Daunorubicin (CERUBIDIN)

I.V.

Doxorubicin (ADRIAMYCIN)

inhibit DNA and RNA synthesis

I.V.

c. Bleomycin (BLENOXANE)

fragment DNA chains and inhibit repair

Given I.V. or I.M.

Mucosocutaneous reactions and pulmonary fibrosis; bone marrow depression much less than other antineoplastics

Menghambat Sintesis DNA dan RNA

ENZIM
1. Mechanism of Action L-asparaginase Hydrolyzes L-asparagine (to L-aspartic acid) an essential amino acid to many leukemic cells 2. Clinical application Acute lymphocytic leukemia, induction of remission in acute lymphoblastic leukemia when combined with vincristine, prednisone, and anthracyclines 3. Route I.V. or I.M. 4. Side effects Nausea and vomiting, Poor appetite, Stomach cramping, Mouth sores, Pancreatitis. Less common: blood clotting

HAMBATAN TOPOISOMERASE
1. Mechanism of Action A. Etoposide Binds to and inhibits Topoisomerase II and its function. Fragmentation of DNA leading to cell death, apoptosis. Same as above 2. Clinical application Testicular cancer, small-cell lung carcinoma, Hodgkin lymphoma, carcinoma of breast, Kaposis sarcoma associated with AIDS Refractory acute lymphocytic leukemia 3. Route I.V. 4. Side effects Myelosuppression, alopecia

B. Teniposide

I.V.

Myelosuppression,

EFEK SAMPING OBAT ANTI KANKER

Karena anti kanker umumnya bekerja pada sel yang sedang aktif, maka efek sampingnya akan mengenai jaringan dengan proliferasi tinggi yaitu sistem hemopoeitik dan gastrointestinal 1. Supresi hemopoeisis leukopenia, trombositopenia, anemia 2. Gangguan saluran cerna anoreksia, mual, muntah, diare, dan stomatitis 3. Reaksi kulit eritema, urtikaria, sampai sindrom SJS 4. Nefropati hiperurisemik 5. Teratogenesis