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).

Penyebab

CARCINOGENESIS

Proses Karsinogenesis

KINETIKA SEL KANKER

Pola pertumbuhan sel kanker scr matematik tergambar dalam Gompertzian growth curvePertumbuhan sel kanker : logaritmikSel kanker proliferasi 1 sel mjd 2, 4, dst mll proses mitosisDoubling 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

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

Tabel kinetika sel kanker

Jml doubling Sel awalSel akhir

1x2 x345678910 1248163264128256512 2481632641282565121024 = 10 3

GOMPERTZIAN KINETICS

KOMPARTEMEN SEL KANKER dan SIKLUS SEL

ProliferasiNon ProliferasiSel mati G1= persiapan sintesa DNAS = syntesis DNAM = mitosisG2= gap fase/tetrafloid

G1= resting, phase for long period G1= makin jauh, makin lama mendapatkan makanan SG2MG1G1G1G1 G 0G ~

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)

Ditinjau dari siklus sel, obat anti kanker dibagi 2 golongan :CCS (Cell Cycle Specific) Obat yang memperlihatkan toksisitas selektif terhadap fase-fase tertentu selCCNS (Cell Cycle Non Specific) tidak selektif terhadap fase tertentu sel

CELL CYCLE ACTIVITY FOR ANTICANCER DRUGS

MEKANISME KERJA ANTI KANKER

ALKYLATING AGENTBekerja dengan pembentukan ion karbonium atau kompleks lain yang sangat reaktifIkatan 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 DNAContoh : 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 AgentsBis(mechloroethyl)aminesNitrosoureasAziridinesCancer ChemotherapyChapter 55. B.G. Katzung

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.An Example of DNA Crosslinking

Cancer ChemotherapyChapter 55. B.G. KatzungAlkylating Agents (Covalent DNA binding drugs)The first class of chemotherapy agents used.They stop tumour growth by cross-linking guanine nucleobases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. Cell-cycle nonspecific effectAlkylating agents are also mutagenic and carcinogenic

A. Alkylating agentsCancer ChemotherapyChapter 55. B.G. Katzung

1. Mechanism of Action2. Clinical application3. Route4. Side effectsa. Nitrogen MustardsA. MechlorethamineDNA cross-links, resulting in inhibition of DNA synthesis and functionHodgkins and non-Hodgkins lymphomaMust be given OrallyNausea and vomiting, decrease inPBL count, BM depression, bleeding, alopecia, skin pigmentation, pulmonary fibrosisB. CyclophosphamideSame as aboveBreast, ovarian, CLL, soft tissue sarcoma, WT, neuroblastomaOrally and I.V.Same as above

C. ChlorambucilSame as aboveChronic lymphocytic leukemiaOrally effectiveSame as above

D. MelphalanSame as aboveMultiple myeloma, breast, ovarianOrally effectiveSame as above

E. Ifosfamide Same as aboveGerm cell cancer, cervical carcinoma, lung, Hodgkins and non-Hodgkins lymphoma, sarcomasOrally effectiveSame as above

A. Alkylating agents

1. Mechanism of Action2. Clinical application3. Route4. Side effectsb. Alkyl SulfonatesA. BusulfanAtypical alkylating agent. Chronic granulocytic leukemiaOrally effectiveBone marrow depression, pulmonary fibrosis, and hyperuricemia

c. Nitrosoureas1. Mechanism of Action2. Clinical application3. Route4. Side effectsA. CarmustineDNA damage, it cancross blood-brain barrierHodgkins and non-Hodgkins lymphoma, brain tumors, G.I. carcinomaGiven I.V. must be given slowly.Bone marrow depression,CNS depression, renal toxicityB. LomustineLomustine 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 barrierHodgkins and non-Hodgkins lymphoma, malignant melanoma and epidermoid carcinoma of lungOrally effectiveNausea and vomiting, Nephrotoxicity, nerve dysfunctionC. StreptozotocinDNA damagepancreatic cancerGiven I.V.Nausea and vomiting, nephrotoxicity, liver toxicity

A. Alkylating agentsCancer ChemotherapyChapter 55. B.G. Katzung

d. Ethylenimines 1. Mechanism of Action2. Clinical application3. Route4. Side effectsA. Triethylene thiophosphoramide (Thio-TEPA)DNA damage, CytochromeP450Bladder cancerGiven I.V.Nausea and vomiting, fatigueB. Hexamethylmelamine(HMM)DNA damageAdvanced ovarian tumorGiven orally after foodNausea and vomiting, low blood counts, diarrhea

d. Triazenes1. Mechanism of Action2. Clinical application3. Route4. Side effectsA. Dacarbazine (DTIC)Blocks, DNA, RNA and protein synthesisMalignant Melanoma, Hodgkins and non-Hodgkins lymphomaGiven I.V.Bone marrow depression, hepatotoxicity, neurotoxicity, bleeding, bruising, blood clots, sore mouths.

TUBULIN BINDING AGENTZat 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 aPolymerizationtubulinDepolymerizatione.g., Vincristine, Vinblastine, Vindesine Vinorelbine: Inhibition of mitotic spindle formation by binding to tubulin.M-phase of the cell cycle.

e.g., Paclitexal: binds to tubulin, promotes microtubule formationand retards disassembly; results in mitotic arrest.Paclitexal (taxol)Vincristine

ANTI METABOLITAntipurin dan antipirimidin mengambil tempa purin dan pirimidin dalam pembentukan nukleosida, sehingga mengganggu berbagai reaksi penting dalam tubuhPenggunaannya 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 normalTerdiri dari antagonis purin, antagonis pirimidin, dan antagonis folat

Antagonis Folat

Natural Products1. Antimitotic Drugs2. Antimitotic Drugs

1. Mechanism of Action2. Clinical application3. Route4. Side effectsA. VincristineCytotoxic: Inhibition of mitotic spindle formation by binding to tubulin.M-phase of the cell cycle.Metastatic testicular cancer, Hodgkins and non-Hodgkins lymphoma, Kaposis sarcoma, breast carcinoma, chriocarcinoma, neuroblastomaI.V.Bone marrow depression, epithelial ulceration, GI disturbances, neurotoxicityB. VinblastineMethylates DNA and inhibits DNA synthesis and functionHodgkins and non-Hodgkins lymphoma, brain tumors, breast carcinoma, chriocarcinoma, neuroblastomaI.V.Nausea and vomiting, neurotoxicity, thrombocytosis, hyperuricemia.

1. Mechanism of Action2. Clinical application3. Route4. Side effectsPaclitaxel (Taxol)Cytotoxic: binds to tubulin, promotes microtubule formation and retards disassembly; mitotic arrest resultsMelanoma and carcinoma of ovary and breastI.V.Myelodepression and neuropathy

ANTIBIOTIK

1. Mechanism of Action2. Clinical application3. Route4. Side effectsa. Dactinomycin (ACTINOMYCIN D)It binds to DNA and inhibits RNA synthesis, impaired mRNA production, and protein synthesisRhabdomyosarcoma and Wilm's tumor in children;choriocarcinoma (used with methotrexateI.V.Bone marrow depression, nausea and vomiting, alopecia,GI disturbances, and ulcerations of oral mucosab. Daunorubicin(CERUBIDIN)

Doxorubicin (ADRIAMYCIN)inhibit DNA and RNA synthesisAcute lymphocytic/granulocytic leukemias; treatment ofchoice in nonlymphoblastic leukemia in adults whengiven with cytarabineI.V.Side effects: bone marrow depression, GI disturbances and cardiac toxicity (can be prevented by dexrazoxane)inhibit DNA and RNA synthesisAcute leukemia, Hodgkin's disease, non Hodgkin'slymphomas (BACOP regimen), CA of breast & ovary,small cell CA of lung, sarcomas, best available agentfor metastatic thyroid CAI.V.Cardiac toxicity, Doxorubicin mainly affects the heart muscles, leading to tiredness or breathing trouble when climbing stairs or walking, swelling of the feet . c. Bleomycin (BLENOXANE)fragment DNA chains and inhibit repairGerm cell tumors of testes and ovary, e.g., testicularcarcinoma (can be curative when used with vinblastine & cisplatin), squamous cell carcinomaGiven I.V. or I.M.Mucosocutaneous reactions and pulmonary fibrosis; bonemarrow depression much less than other antineoplastics

ENZIM

1. Mechanism of Action2. Clinical application3. Route4. Side effectsL-asparaginaseHydrolyzes L-asparagine (to L-aspartic acid) an essential amino acid to many leukemic cellsAcute lymphocytic leukemia, induction of remission in acute lymphoblastic leukemia whencombined with vincristine, prednisone, and anthracyclinesI.V. or I.M.Nausea and vomiting, Poor appetite, Stomach cramping, Mouth sores, Pancreatitis. Less common: blood clotting

HAMBATAN TOPOISOMERASE

1. Mechanism of Action2. Clinical application3. Route4. Side effectsA. EtoposideBinds to and inhibits Topoisomerase II and its function. Fragmentation of DNA leading to cell death, apoptosis.Testicular cancer, small-cell lung carcinoma, Hodgkin lymphoma, carcinoma of breast, Kaposis sarcoma associated with AIDSI.V.Myelosuppression, alopeciaB. TeniposideSame as aboveRefractory acute lymphocytic leukemiaI.V.Myelosuppression,

EFEK SAMPING OBAT ANTI KANKERKarena anti kanker umumnya bekerja pada sel yang sedang aktif, maka efek sampingnya akan mengenai jaringan dengan proliferasi tinggi yaitu sistem hemopoeitik dan gastrointestinalSupresi hemopoeisis leukopenia, trombositopenia, anemiaGangguan saluran cerna anoreksia, mual, muntah, diare, dan stomatitisReaksi kulit eritema, urtikaria, sampai sindrom SJSNefropati hiperurisemikTeratogenesis

***In next slide we will compare how Vincristine and Paclitexal act on one of the major components of mitotic apparatus.*