CANCER - KOCW
Transcript of CANCER - KOCW
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CANCER
NEOPLASIA-V
Nam Deuk Kim, Ph.D. 1
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Discovery
Pre-clinical Development
Phase 1
Phase 2
Phase 3
NDA
• Laboratory and animal test • IND Application
• 20-80 healthy volunteers • determine safety & dose
• 100-300 patient volunteers • POC (Proof of Concept)
• >3000 patient volunteers • Long-term use
• FDA Review • Approval
Phase 4 • Post marketing studies 1 Drug
>200,000 screened
200 preclinical studies
10 clinical studies
Success rate
Process for New Drug Development 신약개발과정
Time (year)
※IND, investigational new drug; NDA, new drug application 5
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Discovery Research Process Overview
Early Exploratory
Discovery Pre-clinical
Development Late
Exploratory
Advanced Hits Leading Series Lead Compound Confirmed
Hits
Development
Lead
Discovery Lead
Optimization
Pre-clinical
Evaluation Assay
Development
Exploratory Team
Formation
Phase 1
•Target identification
•Validation & characterization
•Chemical libraries
•High throughput screening
•Hit selection
•Assay development
(in vitro enzyme & receptor)
•In vivo assay SAR
•Selectivity test
•Computational modeling
•In vivo PK & metabolism
•Analog synthesis
•Synthesis scale up
•Toxicology
•Formulation development
•Property characterization
•Clinical candidate selection
•IND application
Discovery Research Process Overview
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Medicinal chemistry and pharmacology
Preformulation research
Formulation development
Process R&D Analytical R&D
Toxicology & drug
metabolism
Drug Discovery
Literature search Preliminary data - Stability assay - Key stability data - Key solubility data
Molecular optimization - salt and solvates - prodrugs
Evaluation and selection of drug
Formulation request
Physical characterization - bulk properties - solubility profile - stability profile
Formulation development - compatibility & stability - dissolution - bioavailability
Phase 1 formulation - IND stability - bioavailability - scale-up
Process research - improve yield - alternate route - produce bulk
Process development - bulk scale-up
Analytical research - assay development
Analytical development - bulk clearance - toxicology potency
- formulation assay - IND stability
Bioavailability - in vivo models
Toxicology - acute - chronic
IND (investigational new drug) Application
Tim
e incr
easi
ng
Multidisciplinary Development of a Drug Candidate
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Purine Pyrimidine
Ribonucleotides
Deoxyribonucleotides
DNA
RNA
Proteins
Enzymes Microtubules
6-Mercaptopurine
6-Thioguanine
Methotrexate
Bleomycins
Hydroxyurea
Cytarabine
5-Fluorouracil
5-Azacytidine
Alkylating agents
Cis-Platinum
Procarbazine
Vinca Alkaloids
Taxol
L-Asparaginase
Actinomycin
Daunorubicin
Doxorubicin
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Antimetabolites
Methotrexate, Fluorouracil, Gemcitabine 9
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Topoisomerase inhibitors
Doxorubicin, CPT-11 10
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Alkylating Agents
Cyclophosphamide, Chlorambucil
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Vinblastine, Vinorelbine,
Paclitaxel, Docetaxel
Plant Alkaloids
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G0
G1
S
G2
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Reliance on Cell Cycle Kinetics
Cell cycle-nonspecific agents: nitrosourea, radiation
Phase-nonspecific agents: alkylating agents,
antitumor antibiotics, cisplatin, asparaginase
Phase-specific agents
a. M phase: vinca alkaloids, taxanes
b. G1 phase: asparaginase, prednisone
c. S phase: antimetabolites
d. G2 phase: bleomycin, etoposide
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Nitrosoureas (Phase) Nonspecific Agents
Alkylating Agents Chlorambucil, Mechlorethamine, Melphalan,Altretamine Busulfan Carmustine, Lomustine, Streptozocin Cisplatin, Carboplatin, Oxaliplatin Dacarbazine Procarbazine Cyclophosphamide, lfosfamide Antitumor Antibiotics Dactinomycin, Daunorubicin, Doxorubicin,Ldarubicin, Mitomycin, Mitoxantrone, Bleomycin, Dactinomycin,Epirubicin, Valrubicin
Taxanes
Docetaxel
Paclitaxel
Vinca Alkaloids
Vinblastine
Vincristine
Vinorelbine
Bleomycin
Epipodophyllotoxins
Etoposide
Teniposide
Camptothecins
lrinotecan
Topotecan
Steroids
Asparaginase
1. Cell death
2. Differentiation
Cell Cycle
Model
3. “G0” state
G2
S Phase
Antimetabolites Folic Acid Analogs: Methotrexate
Pyrimidine Analogs: Cytarabine, Floxuridine, Gemcitabine, Capecitabine, Fluorouracil
Purine Analogs: Mercaptopurine, Thioguanine, Fludarabine, Cladribine, Pentostatin
Miscellaneous: Hydroxyurea
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Ras Protein begins as an inactive precursor
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WHO's pain ladder
WHO has developed a three-step "ladder" for cancer pain relief.
If pain occurs, there should be prompt oral administration of drugs in the following order: nonopioids (aspirin and paracetamol); then, as necessary, mild opioids (codeine); then strong opioids such as morphine, until the patient is free of pain.
To calm fears and anxiety, additional drugs – “adjuvants” – should be used.
To maintain freedom from pain, drugs should be given “by the clock”, that is every 3-6 hours, rather than “on demand”.
This three-step approach of administering the right drug in the right dose at the right time is inexpensive and 80-90% effective.
Surgical intervention on appropriate nerves may provide further pain relief if drugs are not wholly effective.
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WHO 3-step Pain Ladder
mild
(1-4)
moderate
(5-6)
severe
(7-10)
Morphine
Hydromorphone
Methadone
Levorphanol
Fentanyl
Oxycodone
± Adjuvants
A/Codeine
A/Hydrocodone
A/Oxycodone
A/Dihydrocodeine
Tramadol
± Adjuvants
ASA
Acetaminophen
NSAIDs
± Adjuvants
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Drugs Benefits Side Effects
Nonopioids
Acetaminophen
Aspirin
Ibuprofen
Can control mild
to moderate
pain;
Some versions
can be bought
without
prescription
Can cause slow
blood clotting
and upset
stomach,
bleeding in the
stomach and
kidney problems
Painkillers for Cancer (1)
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Drugs Benefits Side Effects
Opioids
Morphine
Hydromorphone
Oxycodone
Codeine
Fentanyl
Methadone
Can
control
moderate
to severe
without
bleeding
Can cause
constipation,
sleepiness, nausea
and vomiting,
itchiness, and
urinary problems;
may also slow
breathing when first
taken
Painkillers for Cancer (2)
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Drugs Benefits Side Effects
Antidepressants
Amitriptyline
Imipramine
Can help
control tingling
or burning pain
from nerve
injury; may
improve sleep
Can cause dry
mouth,
sleepiness,
constipation and
dizziness on
standing up
suddenly
Painkillers for Cancer (3)
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Drugs Benefits Side Effects
Anticonvulsants
Carbamazepine
Phenytoin
Can help
control tingling
or burning from
nerve injury
Can affect liver
and blood cell
function
Painkillers for Cancer (4)
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Drugs Benefits Side Effects
Steroids
Prednisone
Dexamethansone
Can help
relieve bone
pain and pain
caused by
spinal cord and
brain tumors
May cause
confusion, fluid
buildup,
bleeding and
irritation in
stomach
Painkillers for Cancer (5)
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조선일보 김철중 기자 2011년 11월 15일
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Chemoprevention refers to the use of defined chemical
regimens to inhibit, retard, or reverse the process multi-
stage carcinogenesis.
화학적암예방이란 규명된 화학물질을 이용하여 다단계 암발생 과정을 억제, 저지, 혹은 암세포를 정상세포로 돌리는 것을 말한다.
CHEMOPREVENTION
화학적암예방
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Healthy Cell Damaged Cell (precancerous)
• Cell Death
• Differentiation
Cancer Cell
Repeated damage
Chemotherapy
C h e m o p r e v e n t i o n
Activated Carcinogens
Procarcinogens Detoxification & Secretion
Initiation Promotion Progression
(1-2 days) ( >10 years) ( >1 years )
Metabolic activation
Chemoprevention 화학적 암예방의 기전
Initiated Cell
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Factor Estimated % of all cancer deaths
Doll & Peto’s Estimates of What Causes Cancer
Diet(식이) 35
Tobacco(흡연) 30
Infection 10 ?
Reproductive & sexual behavior 7
Occupation 4
Alcohol 3
Geophysical factors 3
Pollution 2
Industrial products 1
Medicines & medical procedures 1
Food additives < 1
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Factors Believed to
Contribute to Global
Causes of Cancer
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Cancer & Diet
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Preventing Cancer through Diet and Lifestyle
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(오렌지껍질)
Curry(카레)
녹차 Red raspberry(복분자)
Resveratrol, 포도
마늘 Broccoli sprouts (브로콜리)
대표적 화학적암예방제
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복분자 녹차
포도
카레 브로콜리
마늘
오 렌 지
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암 예방 14개 권장사항(92년 대한암협회 제정) 1. 편식하지 말고 영양분을 골고루 균형 있게 섭취한다.
2. 황록색 채소를 주로 한 과일 및 곡물 등 섬유질을 많이 섭취한다.
3. 우유와 된장의 섭취를 권장한다.
4. 비타민 A, C, E를 적당량 섭취한다.
5. 이상 체중을 유지하기 위하여 과식하지 말고 지방분을 적게 먹는다.
6. 너무 짜고 매운 음식과 너무 뜨거운 음식은 피한다.
7.불에 직접 태우거나 훈제한 생선이나 고기는 피한다.
8. 곰팡이가 생기거나 부패한 음식은 피한다.
9. 술은 과음하거나 자주 마시지 않는다.
10. 담배는 금한다.
11. 태양 광선, 특히 자외선에 과다하게 노출하지 않는다.
12. 땀이 날 정도의 적당한 운동을 하되 과로는 피한다.
13. 스트레스를 피하고 기쁜 마음으로 생활한다.
14. 목욕이나 샤워를 자주 하여 몸을 청결하게 한다.
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`암을 예방하는 10가지 생활습관` (2006. 10. 3. 보건복지부)
1. 담배를 피우지 말고, 남이 피우는 담배 연기도 피하기
2. 채소와 과일을 충분하게 먹고, 다채로운 식단으로 균형 잡힌 식사하기
3. 음식을 짜지 않게 먹고, 탄 음식을 먹지 않기
4. 술은 하루 두 잔 이내로만 마시기
5. 주 5회 이상, 하루 30분 이상, 땀이 날 정도로 걷거나 운동하기
6. 자신의 체격에 맞는 건강 체중 유지하기
7. 예방접종 지침에 따라 B형 간염 예방접종 받기
8. 성 매개 감염병에 걸리지 않도록 안전한 성생활 하기
9. 발암성 물질에 노출되지 않도록 작업장에서 안전 보건 수칙 지키기
10. 암 조기 검진 지침에 따라 검진을 빠짐없이 받기
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암 한번 걸렸는데 또? 기존 암 추적해도 다른 암 못 막아(2012. 8. 31. 조선일보)
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2차암 조기발견 요령
위암=대장암 발병 위험이 일반인에 비해 1.5배, 유방암 위험이 2배 높다. 대장내시경 3년마다 받아야 한다.
대장암=위암이 될 가능성이 약 1.5배 높고, 대장암 진단 후 1년 내에는 2배가 넘어간다. 여성은 유방암과 부인과암(자궁내막암·자궁경부암·난소암) 위험도 1.5~3배로 뛰고, 갑상선암 위험도 약 3배 높다.
간암=식도암 위험이 2배 정도, 위암과 대장암 가능성도 1.2~1.4배 높다. 난소암 위험이 3~4배 뛴다.
폐암=위암과 대장암 가능성이 각각 1.4배, 1.3배 높다. 유방암 위험도 올라가고, 갑상선암 위험도 2~4배 뛴다. 20년간 흡연한 경우, 두경부암·신장암·방광암 위험이 4배 높다.
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2차암 조기발견 요령
유방암=위암·대장암을 비롯해 자궁내막암·난소암 위험이 1.2~2.5배 올라간다. 갑상선암 위험도 3배 정도 높다.
자궁경부암=위암·대장암 위험이 일반인보다 20~70% 높다.
전립선암=광범위하게 방사선치료를 한 환자는 방광과 직장에 암이 생길 위험이 각각 2.3배, 1.3배 높다.
갑상선암=위암·대장암 위험이 1.1~1.3배, 유방암 위험이 1.2~2배, 신장암 위험이 2~4배 올라간다.
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2차암 조기발견 요령
2차암인 위암을 조기에 발견하려면 1~2년 간격으로 위내시경을 해보는 게 좋다.
대장·직장암은 45세 이후 3년마다 대장내시경을 받자.
유방암은 유방촬영·유방초음파, 갑상샘암은 갑상샘초음파, 자궁내막암 등 부인과암은 부인과초음파를 1~2년마다 해본다.
콩팥암·방광암은 미세혈뇨검사, 두경부암은 이비인후과 의사의 진찰을 1~2년마다 받으면 2차암을 조기에 발견할 수 있다.
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