KULIAH KANKER
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Transcript of KULIAH KANKER
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KankerKuliah Umum
Aru W. Sudoyo
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Besarnya Masalah
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Penyebab Kematian Utama di Dunia
Percent of Total Deaths
US data/Adapted from Cancer Journal for Clinicians , 1994.
33.5%
23.5%
6.7%4.3% 4.0% 3.7%
2.2%1.4% 1.2% 1.2%1.2%
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0 1 2 3 4 5 6 7 8
Tuberculosis
HIV/AIDS
Malaria
Total TB+HIV+Mal
Cancer
Global mortality 2002
WHO, 2003
Millions of deaths
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5
Angka Kematian akibat Kanker : Distribusi Negara Maju danSedang Berkembang
http://www.who.int/healthinfo/statistics/
7.59.1
11.4
Proyeksi WHO di Seluruh Dunia
2.1 2.3 2.5
5.5 6.7 8.9
0 2 4 6 8
10 12
2005 2015 2030 T o
t a l K e m a t
i a n
( d a l a m
j u t a )
Negara-Negara Maju Negara-Negara Sedang Berkembang
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WHO, 2003
Proyeksi Kasus-kasus Kanker Baru per Tahun: Antara Negara Maju dan Berkembang
3
4
5
6
7
8
9
10
1990 1995 2000 2005 2010 2015 2020
n e
w c a n c e r c a s e s ( m
i l l i o n s
)
year
developing
countries
industrializedcountries
NegaraBerkembang
Negara Maju
Tahun
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Kanker Paling Sering( Pathology Based Cancer Registry )
242923%
218121%
99310%
9239%
9159%
7737%
6106%
5595%
5075%
4775%
Cases
Cervix
Breast
Nasopharynx
Rectum
Skin
Ovarium
Thyroid
Colon
Lymphnode
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687
19%
47713%
47613%464
13%
3259%
323
9%
2908%
2457%
1895%
1634%
Cases
Nasopharynx
Prostate
RectumSkin
Lymphnode
Bladder
Colon
Soft Tissue
Nasal Cavity
Thyroid
Kanker Paling Sering Pada Laki-lakiPathology Based Cancer Registry
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MUTASI BERULANG SEBAGAI PENYEBAB KANKER
Sel normal
Mutasipertama
Mutasikedua
Mutasikeempat
Mutasiketiga
Sel-sel
ganas
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MUTASI BERULANG SEBAGAI PENYEBAB KANKER
Sel normal
Mutasipertama
Mutasikedua
Mutasikeempat
Mutasiketiga
Sel-sel
ganas
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MUTASI BERULANG SEBAGAI PENYEBAB KANKER
Sel normal
Mutasipertama
Mutasikedua
Mutasikeempat
Mutasiketiga
Sel-sel
ganas
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MUTASI BERULANG SEBAGAI PENYEBAB KANKER
Sel normal
Mutasipertama
Mutasikedua
Mutasikeempat
Mutasiketiga
Sel-sel
ganas
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MUTASI BERULANG SEBAGAI PENYEBAB KANKER
Sel normal
Mutasipertama
Mutasikedua
Mutasikeempat
Mutasiketiga
Sel-sel
ganas
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Karsinoma (sel2 yangmelapisi permukaan tubuhdalam dan luar)
Jenis Kanker
paru
Payudara
Ususbesar
Kdg kemihProstat(laki2)
Leukemia(sel-sel darah)Limfoma
(kelenjar dan jaringan limfe)
Sarkoma
Sel-s el otot dan
jairngan penunjang
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Faktor-Faktor Risiko
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ROKOK
- Kanker paru-paru
- Kanker mulut (tembakaukunyah)
- Kanker larynx, pharynx,esophagus (pipa) dan kolon
- Fakta: 514000 kematian karenakanker 164000 disebabkan olehrokok.
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Penyebab Punahnya Dinosaurus
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Kurang berolah raga
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Kegemukan (obesitas)
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Makanan
Rokok : palingpreventable
Makanan : TOTAL >merokok
Makanan : lebih sulitdicegah
Amat terkait dengankebiasaan dan PILIHANbahan-bahan
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9/25/01 Nutrition 28
Peran Faktor Makanan pada
Karsinogenesis
Manifestasi kanker
Struktur DNA
Reaksi dgn sasaran2 dlm selKerusakan DNA, Mutagenesis
Penghambat aktivasi
Blocking Agents
zat penekan
Pajanan thdpKarsinogen
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HETEROCYCLIC AMINES-Memasak daging temperatur/suhutinggi zat kimia (heterocyclicamines/HCAs)
-Perhatikan:- Cara memasak- Temperatur/suhu- Waktu
-HCAs masakan rumah dan nonfast food rest
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Makanan Tinggi Lemak
Asam empedu tinggi + kurang serat
Kotoran lambat Asam empedu
merusak
Jaringan tumbuh takterkontrol Kanker usus besar
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AKRILAMID- Bahan kimia dalam bentuk
butiran kristal atau cairan yangbanyak digunakan padapembuatan kertas, dyes danplastik atau sebagai pada
proses pengolahan air minumdan sampah.
- Efek: kerusakan pada inti sel
- Pembentukan:menggoreng/membakar/merebus pada temperatur tinggi FRENCH FRIES
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Formalin danKankerFormaldehyde has beenclassified as a humancarcinogen (cancer-causingsubstance) by theInternationa l Agenc y forResearch on Cancer and asa probable humancarcinogen by the U.S.Environmental ProtectionAgency Association betweenformaldehyde expo sure
and can cers of the na sal sinuses, nasopharynx , andbrain, an d possiblyleukemia
http://www.cancer.gov/Common/PopUps/popDefinition.aspx?term=cancer&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?term=cancer&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?term=carcinogen&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?term=carcinogen&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?term=nasal&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?term=nasopharynx&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?term=nasopharynx&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?term=nasal&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?term=nasopharynx&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?term=leukemia&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?term=leukemia&version=Patient&language=Englishhttp://sexychef.blogsome.com/images/baso.jpghttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?term=leukemia&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?term=nasopharynx&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?term=nasal&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?term=carcinogen&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?term=cancer&version=Patient&language=English -
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Nutrition 33
Proportion of Cancer DeathsAttributable to Various Factors
(Doll and Peto, 1981)Factor Best Estimate Range of Acceptable Estimates
Tobacco 30 25-40
Alcohol 3 2-4
Diet 35 10-70Food Additives 1 (-5**)-2
Reproductive/Sexual Behavior 7 1-13
Occupation 4 2-8
Pollution 2 1-5
Industrial Products 1 1-2
Medicines/Medical Products 1 0.5-3
Geophysical Factors 3 2-4
Infection 10 1-?
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Faktor-Faktor Makanan yang berhubungan
dengan Pengurangan Risiko Kanker Dietary fiber
colorectal, pancreas, breast
Folic acid cervix, colorectal
Vitamin D and calcium colorectal, breast
Antioxidants (nutrient and non-
nutrient) from foods colorectal, lung, breast, cervix,
prostate, esophagus, stomach
Vitamin C from foods oral cavity, esophagus, lung,
stomach, pancreas, cervix
Tea (flavonoids) lung, colorectal
Alpha-tocopherol lung
Soy isoflavones? breast
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Nutrition
Faktor makanan yang memicu /meningkatkan risiko Kanker
Alcohol mouth, pharnyx, larnyx,
esophagus, liver-convincing
breast, colon, rectum-probable
Salt stomach- probable
Sucrose colon, rectum
Meat (especially charbroiled) colon and rectum- probable
Total and Saturated Fat lung, colon, rectum, breast,
prostate- possible
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9/25/01 Nutrition 36
Chemopreventive Non-nutritive
Dietary FactorsCompound Food Source
Cinnamic acid Fruit, vegetables, coffee beans
Flavonoids (catechins,quercitin, isoflavones,anthocyanins)
vegetables, fruit, citrus fruit, celery,parsley,onions, grains, tea, soybean
Indoles Cruciferous vegetables
Isothiocyanates Cruciferous vegetables
Lignans Whole grains, flax
Organosulfur Garlic, Onion
Terpenes Citrus, spices
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Metastasis
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Metastasis Terjadi pada setiap jenis kanker Penyebaran Jauh ke organ tubuh lainnya
Paru Hati
Buli-buli Rongga abdomen Dapat terjadi setelah ada kesembuhan (remisi)
Paling tinggi dalam dua tahun pertama
Semakin kecil di tahun-tahun selanjutnya
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Modalitas (cara) pengobatan lain:pada kanker dengan penyebaran
(metastasis)
Paling banyak: terapi regional / lokal TACE Radiofrequency ablation (untuk metastasis
hati) Bedah dingin / cryosurgery
Belum baku / standar Biasanya PALIATIF bukan KURATIF
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Pengobatan
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Apakah bisa disembuhkan ?
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KematianAlami
Lahir
kerentananPre-initiation
Perubahanmenjadi ganas
Evolusi ?progresi
Fenotipmematikan
Rentang Usia
Kematiankrn Kanker
Beban Kanker
Proses Kanker
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KematianAlami
Lahir Rentang Usia
KematianakibatKanker
Cegah atau
Perlambat
Deteks i d anEradikasi
Ku asai Kanker
2010 2020
Kesempatan untuk Intervensi
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KematianAlami
Lahir
kerentananPre-initiation
Perubahanmenjadi ganas
Evolusi ?progresi
Fenotipmematikan
Rentang Usia
Kematiankrn Kanker
Beban Kanker
Proses Kanker
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KematianAlami
Lahir Rentang Usia
KematianakibatKanker
Cegah atau
Perlambat
Deteks i d anEradikasi
Ku asai Kanker
2012 2022
Kesempatan untuk Intervensi
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KematianAlami
Lahir Rentang Usia
KematianakibatKanker
Cegah atau
Perlambat
Deteks i d anEradikasi
Ku asai Kanker
2012 2022
Kesempatan untuk Intervensi
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Kemoterapi
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Cytotoxic Chemotherapy
Cytotoxic literally translated means toxic tocells. Hence these drugs are those which killcells.
Chemotherapy - the treatment of disease by theuse of chemical substances
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History of Cancer Chemotherapy
1940-1950 Beginnings of the modern era of chemotherapy
traced directly to discovery of nitrogen
mustard (chemical warfare agent) as aneffective treatment for cancer.
Autopsy observations of people exposed tomustard gas revealed lymphoid and myeloidsuppression
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Cl
S
Cl
R
NCl Cl
Chemical Warfare circa 1914
Two most common agents: Chlorine gas Mustard gas
Mustard Gas!
Nitrogen Mustard
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History of Cancer Chemotherapy
1940-1950 Goodman and Gilman reasoned that this agent
could be used to treat lymphoma, since
lymphoma is a tumour of lymphoid cells. Set up an animal model, establishing
lymphoma in mice and treated them withmustard gas.
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History of Cancer Chemotherapy
1940-1950 In collaboration with a thoracic surgeon, they injected
a related agent (mustine) into a patient with non-
hodgkins lymphoma and observed a dramaticreduction in the patients tumour mass.
Although this effect only lasted a few weeks, this wasthe first step to the realisation that cancer could betreated with pharmacological agents
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History of Cancer Chemotherapy
Combination chemotherapy 1965 Cancer cells could conceivably mutate to
become resistant to a single agent, but using
different drugs concurrently would make itextremely difficult for the tumour to developresistance to the combination.
Induced long term remission in children withALL.
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BASIC PRINCIPLES
Prevents cancer cells from multiplying,invading, metastasising and killing patient.
Affects cell multiplication and tumour growth. Especially affects cells with a rapid rate of
turnover. Effectively given - marked effect and minimal
toxicity.
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CELL CYCLE
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ROUTES OF ADMINISTRATION
Orally e.g. methotrexate
IV
SC
Intrathecal e.g. methotrexate, cytarabine
CELL CYCLE SPECIFIC VERSUS NON
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CELL CYCLE SPECIFIC VERSUS NON-SPECIFIC
Certain chemotherapy drugs require cells to bein cycle for activity (i.e. not resting).
Cell Cycle specific - most active against cellsin a specific phase therefore need prolongedexposure or repeated doses.
Cell Cycle Non-specific - most effectiveagainst actively dividing cells but alsoeffective in G0.
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BASIC PRINCIPLES
Prevents cancer cells from multiplying,invading, metastasising and killing patient.
Affects cell multiplication and tumour growth. Especially affects cells with a rapid rate of
turnover. Effectively given - marked effect and minimal
toxicity.
Significant Progress has Already
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64
Significant Progress has Alreadybeen Achieved in Extending Life
64
12 mo
15-17 mo
23+ mo
2000s
1980s
Anthracyclines
BSC
Taxanes (Docetaxel, Paclitaxel)
1990s
Metastatic Breast Cancer(Median Overall Survival - months)
6 mo
10-12 mo
18-22+ mo
2000s
1980s
5-FU/LV
+Oxaliplatin/ Irinotecan/bevacizumab
1990s
BSC
Metastatic Colorectal Cancer(Median Overall Survival - months)
BSC Best Supportive Care
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Sasaran KemoterapiSembuh : tumor atau kanker hilang dan tidakkembali lagi
Kontrol : bila sembuh tidak mungkin, tujuannyaadalah untuk menghentikan penyakit (kanker tidaktumbuh dan menyebar lagi), perpanjang hidupdengan kualitas hidup terbaik
Paliasi : bila kontrol tidak mungkin atau kankersudah stadium lanjut. Kemoterapi bertujuanmengurangi gejala dan mempertahankan kualitashidup yang baik
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Bagaimana kerja kemoterapi?
Menyerang sel-selyang sedangmembelah cepatMenghambat sel yangsedang membelah
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Bagaimana kerja kemoterapi?
Karena itu :digunakan
KOMBINASI OBAT-OBATAN (multipledrugs)
DiberikanBEBERAPA KALI
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Tumor growth kinetics
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CLASSIFICATION OF CYTOTOXIC AGENTS
BUSULFAN CYTOSINE ETOPOSIDE BLEOMYCIN L-ASPARAGINASE
CARMUSTINE ARABINOSIDE TENIPOSIDE DACTINOMYCIN HYDROXYUREA
CHLORAMBUCIL FLOXURIDINE VINBLASTINE DAUNORUBICIN PROCARBAZINE
CISPLATIN FLUOROURACIL VINCRISTINE DOXORUBICIN
CYCLOPHOSPHAMIDE MERCAPTOPURINE VINDESINE MITOMYCIN-C
IFOSFAMIDE METHOTREXATE TAXOIDS MITOXANTRONE
MELPHALAN PLICAMYCIN
ALKYLATINGAGENTS
ANTI-METABOLITES
MITOTICINHIBITORS
ANTIBIOTICS OTHERS
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Rand 50.3
Drug Targets in Cancer Chemotherapy
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Drug Targets in Cancer Chemotherapy1. DNA
a) bondage --alkylating agents (mechlorethamine, cyclophosphamide), cisplatin
b) vaporization --bleomycin
c) confusion --actinomycin D, doxorubicin, etoposide,irinotecan
d) starvation --methotrexate, 6-thioguanine,5-fluorouracil, cytosine arabinoside,hydroxyurea
e) regulation --tamoxifen, aromatase inhibitors
2. Protein synthesis: L-asparaginase
3. Mitotic Apparatus: vincristine, vinblastine, paclitaxel
4. Specific antigens: therapeutic antibodies (e.g. Herceptin, Avastin)
5. Protein kinase inhibitors: Gleevec (imatinib) inhibits BCR-ABL which causes
CML(chronic myeloid leukemia)
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How to Target Cancer Cells?
Exploit properties unique to Cancer cellsThe Grow th Facto r (Fract io n)
Major determinant of chemotherapy effectivenessDefined: Proliferating:Resting cell ratioRelated to the Cell Cycle
Enzyme productionVascularization
h C ll C l ( fl hb k )
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The Cell Cycle ( flashback )
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Drug Targets
Chemotherapy drugs are more toxic to tissue withhigh grow th f rac t ionHigh fraction = rapidly growing
Disseminated cancersLow fraction = slow growing
Solid tumors
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Obstacles to Chemotherapy
Healthy High Growth Fraction AreasBone marrowSkinHair follicles
SpermGastrointestinal tract
Toxicity is Dose LimitingPoor selectivity of drugsHealthy and cancerous cells affected
Toxicity Roadmap handout
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Toxicity Roadmap - handout
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Major Toxicities
Bone Marrow SuppressionNeutropenia Low WBCG-CSF ( filgrastim ) & GM-CSF ( sargramostim )
Thrombocytopenia Low platelete countOprelvekin ( Neumega )
Anemia Low RBChttp://www.medscape.com/mp/rc/anemiaErythropoetin
Digestive Tract ProblemsStomatitis inflammation of oral mucosaDiarrhea impaired nutrient absorption
Nausea & Vomiting (N/V)Occurs 17 98% (Psych factors)Ondansetron ( Zofran ) and others (handout)
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Major Toxicities cont
Other Alopecia hair lossReproductive sterility in malesHyperuricemia increased urination (DNA)Extravasation of vesicantsDrug-specific (hepatic, coronary, etc)Carcinogenesis some patients sensitive
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Obstacles cont
Cure requires 100% cancer cell deathNearly impossible!
Kinetic problems (drugs are 1 st order)Nonparticipation of immune system
Treatment duration? Example
Patient has 10 12 cancer cells systemicallyTreatment kills 99.999%Patient still has 10 7 cancer cells
Ob l D i P i
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Obstacles:Detection vs. Prognosis
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Absence of Early Detection
Only cervical cancer is detectable earlyConsequences of late detection
MetastasesDecreased responsiveness to Chemo
Solid tumors respond poorlyDrug resistanceTumor Cell HeterogeneityLimited Access (diffusion, transport, etc.)
Patient debilitation
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Resistance Mechanisms
Often produced by the drug itself (mutagen)Cellular adaptation altered enzyme levelsExample: Methotrexate increased dihydrofolatereductase produced to overwhelm drug
Reduced drug transport into cells
Reduced molecular target affinityStimulation of alternative biosynthetic pathwaysImpaired activation or increased metabolismCellular repair mechanisms for DNA
Example: repair of crosslinks or scission caused by
alkylating agentsMultiple Drug Resistance P-glycoproteinDrug efflux pumps become overexpressed
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Resistance cont
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Multidrug Resistance
Due to Increased expression of pumps Affected Drugs
AntibioticsVinca alkaloids
Surprising cross-resistance!No common mechanism of action!
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Chemo Strategies
Intermittent chemotherapyCombination chemotherapyRegional drug delivery
Intra-arterial solid tumorsIntrathecal CNS delivery (non-BBB drugs)Intracavity pleural, peritoneal, bladderPortal Vein Liver
Brain Implants
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Chemo Strategies cont
Intermittent Chemotherapy
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Cytotoxic Drugs
Classes
Alkylating agents Antimetabolites Antitumor antibioticsMitotic inhibitorsTopoisomerase inhibitorsOther
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Cell Cycle Specific Drugs
Toxic to cells in a specific phaseVincristine - causes mitotic arrestOnly effective in M-Phase
Require long presenceProlonged infusionsMultiple doses
Known as Schedule Dependent DrugsClasses
Antimetabolites (S)
Mitotic Inhibitors (M) Asparaginase (G 1 & S)Bleomycin (G 2)Etoposide (G 2)
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The Cell Cycle ( flashback )
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Cell Cycle Nonspecific Drugs
Act during any phase (even G 0)Synergistic w/cell cycle specific drugsMore toxic to proliferating cells
Cells use G 0 for repairToxicity apparent during proliferation
Include Alkylating Agents
Most antitumor antibiotics
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Cara Pemberian Kemoterapi
Oral (tablet)Parenteral (infus)
Intravena (perifer)Kateter sentral
Regional
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Kemoterapi Oral
Obat minumTidak banyak jenisnyaEfek samping samaLebih praktis
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Vena perifer
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Kateter Sentral
Lengan bebas daritusukan
Aman dari infeksiPermanen
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Setelah 2004 ..
Pengetahuan mengenai perangai sel kanker >>Diketahui adanya reseptor -reseptor khususpada permukaan sel yang mempengaruhipertumbuhan
Mulai ditemukan berbagai obat yangmentargetkan reseptor2 tersebut targeted therapi atau obat target
Tempat Pemberian
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p
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Kemoterapi Intratekal
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Kemoterapi Regional
Obat Sitostatika Alkohol PekatRadioFrequency
AblationLokal
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Terapi Innovatif
f h h
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History of Cancer Chemotherapy
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Target Therapy: Obat Pintar?
Smart Bomb
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Ob T / T d Th
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Obat Target / Targeted Therapy
Memberi tambahan harapan hidup (survival)Ditambahkan pada obat utama Sitostatik ?Kemotrapi + Terapi Target
Tetap tidak bisa menggantikan kemoterapiEfek samping : lebih sedikitKesulitannya : TARGET YANG MANA
clinicaloptions.com/oncologyTruth and Consequences: Antiangiogenic Therapies in Cancer
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Peran Terapi Biologik
clinicaloptions.com/oncologyTruth and Consequences: Antiangiogenic Therapies in Cancer
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Proliferation MetastasisAngiogenesisApoptosis
Shc
PI3-K
RafMEKK-1
MEKMKK-7
JNKERK
Ras
mTOR
Grb2
AKT
Sos-1
Sasaran yg mana?
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Shc
PI3-K
RafMEKK-1
MEKMKK-7
JNK ERK
Ras
mTOR
Grb2
AKT
Sos-1
Sasaran yg mana ?
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Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer Center.
Sos-1
Ras
MEKK-1MEK
Shc
PI3-K
Raf
MKK-7
Grb2
AKT
JNK
ERK
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Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer Center.
Sos-1
Ras
MEKK-1MEK
Shc
PI3-K
Raf
MKK-7
Grb2
AKT
JNK
ERK
clinicaloptions.com/oncologyTruth and Consequences: Antiangiogenic Therapies in Cancer
The Family of VEGF and VEGFRs
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The Family of VEGF and VEGFRsEpigenetic Induction
Hypoxia, cytokines, sex hormones,growth factors, chemokines
Genetic Induction
Mutant p53 , VHL, PTEN-suppressor genes, and activatedoncogenes (eg, ras, src, EGFR, and erb B-2/HER2 )
VEGF-A 121 VEGF-A 165VEGF-B PIGF
VEGF-CVEGF-D
s s s s Plasma
membrane
Endothelial
cell
VEGFR-1(flt-1)
NRP-1 NRP-2 VEGFR-3
(flt-4)
VEGFR-2(flk-1/KDR)
HostVEGF
Vascularpermeability Proliferation
Survival Migration
Mobilization(eg, of VEGFR-2+ endothelialprogenitor cells)
PLC g
Raf
MEK
MAPK
PKC PI3K
AKT
Kerbel RS. N Engl J Med. 2008;358:2039-2049.Copyright 2008 Massachusetts Medical Society. All rights reserved.
clinicaloptions.com/oncologyTruth and Consequences: Antiangiogenic Therapies in Cancer
A i i i i l d th h t t f ti
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Angiogenesis is involved throughout tumour formation,growth and metastasis
Adapted from Poon RT, et al. J Clin Oncol 2001;19:1207 25
Stages at which angiogenesis plays a role in tumour progression
Premalignantstage
Malignanttumour
Tumourgrowth
Vascularinvasion
Dormantmicrometastasis
Overtmetastasis
(Avasculartumour)
(Angiogenicswitch)
(Vascularisedtumour)
(Tumour cellintravasation)
(Seeding indistant organs)
(Secondaryangiogenesis)
clinicaloptions.com/oncologyTruth and Consequences: Antiangiogenic Therapies in Cancer
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The VEGF Family and Its Receptors
Neufeld G, et al. FASEB J. 1999;13:9-22.
VEGFR-3(Flt-4)
VEGFR-2(Flk-1/KDR)
VEGFR-1(Flt-1)
Angiogenesis LymphangiogenesisAngiogenesis
Lymphangiogenesis
PIGF VEGF-A VEGF-B VEGF-C VEGF-D
VEGF regulates angiogenesis via interaction with receptor tyrosine kinases
VEGFR-2/KDR and VEGFR-1/Flt-1
clinicaloptions.com/oncologyTruth and Consequences: Antiangiogenic Therapies in Cancer
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ProliferationApoptosis Resistance Transcription
TGF Interleukin-8bFGF VEGF
MetastasisAngiogenesis
Shc
PI3K
RafMEKK-1
MEKMKK-7
JNK ERK
Ras
mTOR
Grb2
AKT
Sos-1
EGF Pathway
Jalur pensinyalan estrogen
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Jalur pensinyalan estrogen
Osborne CK, Schiff R. Annu. Rev. Med. 2011 62: 233-47.
The HER2 signaling pathway
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The HER2 signaling pathway
ER
Nucleus
c-myc
Raf
MEK 1/2
MAPK
Akt
GSK3 BAD
Cell-cycleprogression
PTEN
mTOR
p27
Cyclin D1, E
FKHR
Grb2 Sos
Cell survival
Ras
Shc SosGrb2
PI3K
Cell proliferation
HER ligandsNK cell
FcGR
ER
p95 HER2
HER1 HER2 HER3 IGF1RHER2
Courtesy of L Gianni
Jalur pensinyalan HER2:b
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sasaran obat
ER
Nucleus
c-myc
Raf
MEK 1/2
MAPK
Akt
GSK3 BAD
Cell-cycleprogression
PTEN
mTOR
p27
Cyclin D1, E
FKHR
Grb2 Sos
Cell survival
Ras
Shc SosGrb2
PI3K
Cell proliferation
HER ligandsNK cell
FcGR
ER
p95 HER2
HER1 HER2 HER3 IGF1RHER2
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Tantangan di Masa Depan:
perangai kankersebagai target
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Personalized Medicine :B i C t
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Basic Concept
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TERIMA KASIH ATASPERHATIANNYA
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