KARSINOGEN DAN KARSINOGENESIS Dr Aswiyanti Asri,M.Si.Med,SpPA

Karsinogen vs Karsinogenesis Kanker

Karakteristik sel kanker Diferensiasi <<, tidak relevan dengan fungsi tubuh (normal). Inti abnormal (membesar), dan mungkin jumlah kromosom. Kemampuan membelah tidak terbatas : telomerase. Membentuk massa tumor. Dapat membelah diri tanpa growth factors. Abnormalitas terbentuk melalaui proses multistage. Mengalami angiogenesis dan metastasis.

Six hallmarks of cancer

Environmental vs. Hereditary Cancer

Karsinogen lingkungan Agen (lingkungan) penyebab kanker 3 kelompok utama : Kimiawi Fisika (radiasi) Biologi (terutama virus)

Human carcinogens - environmental Aflatoxins Asbestos Benzene Cadmium Coal tar Creosote DDT Polycyclic aromatic hydrocarbons Radon Solar radiation

Human carcinogens - drugs/therapeutic agents Adriamycin (doxorubicin) Androgenic steroids Chlorambucil Cisplatin Cyclophosphamide Cyclosporin A Diethylstilbestrol Ethylene oxide Melphalan Tamoxifen

Karsinogen kimiawi Direct-acting : electrophilic Nitrogen mustard Nitrosomethylurea Benzyl chloride Indirect-acting (dimetabolisme menjadi bentuk aktif : Polycyclic aromatic hydrocarbons (PAH) Terbentuk dari pembakaran tidak sempurna material organik Cerobong asap, makanan yang dibakar, rokok.

Electrophilic Theory of Chemical Carcinogenesis Electrophilic (electron-seeking) molecules will bind to nucleophilic (electron-rich) macromolecules in the cell DNA RNA Proteins

Ionizing radiation (X-rays) Asbestos Physical Carcinogens Ultraviolet light Ionizing radiation (X-rays) Asbestos

Karsinogenesis radiasi Direct effect on DNA Activation of cellular oncogenes UV light is believed to induce cross-linkages between DNA molecules and Cancer occurs when repair mechanisms are not efficient

Viral carcinogenesis 1 dari 7 kanker disebabkan virus, t.u virus DNA Human papillomaviruses - HPV Epstein-Barr Virus (EBV) Human herpes virus 8 (HHV8) Hepatitis B virus - HBV Hepatitis C virus - HCV HTLV-I, HTLV-II

How Do Viruses like HPV and HBV Cause Cancer? Very small viruses Can integrate their viral DNA into host genome They code for viral proteins which block tumor suppressor proteins in cells

Helicobacter pylori Gastric infection linked to gastric lymphomas and adenocarcinomas Detection of H pylori in majority of cases of gastric lymphomas Antibiotic treatment results in gastric lymphoma regression in most cases

Multistage theory of carcinogenesis Inisiasi Promosi Progresi

What is epigenetic ? Epigenetic refers to all heritable changes in gene expression and chromatin organization that occur without alteration in DNA sequence. Epigenetic changes do not depend on DNA sequence changes. They do depend on modification of the DNA, but on modifications that leave the basic sequences of A, G, C and T nucleotides unchanged.. Level transkripsi, translasi dan posttranslasi

Epigenetics Mechanisms RNA Interference Gene Expression DNA Methylation Histone Modifications

Epigenetics stands at the center of modern medicine because epigenetic changes, unlike DNA sequence which is the same in every cell, can occur as a result of dietary and other environmental exposure

DNA Methylation and Cancer Robertson, Nature Reviews Genetics, Vol6, 597

Histone Modifications http://porpax.bio.miami.edu/~cmallery/150/gene/c7.19.4.histone.mod.jpg

Epigenetic changes

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