[혈종] 20151013 화12 임동석 항암제

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[혈종] 20151013 화12 임동석 항암제 by Mind Map: [혈종] 20151013 화12 임동석 항암제

1. Biochemistry of Genome Synthesis, Stability, and Maintenance

1.1. Nucleotide synthesis

1.2. Purine Ribonucleotide synthesis

1.3. Ribonucleotide Reduction and Thymidylate Synthesis

1.4. Nucleic acid synthesis

1.4.1. RNA and DNA are formed by polymerization of nucleotides.

1.4.2. DNA or RNA polymerase needed

1.5. DNA Repair and Chromosome Maintenance

1.5.1. Mismatch Repair

1.5.2. Base Excision Repair

1.5.3. Nucleotide Excision Repair

1.5.3.1. bulky adducts

1.5.3.2. xeroderma pigmentosa

1.5.3.3. Cockyane syndrome

1.5.4. Double-Strand Break Repair

1.5.4.1. BRCA1

1.5.4.2. BRACA2

1.5.5. Telomere Biology

1.6. Microtubules and Mitosis

2. Pharmacologic Classes and Agents

2.1. #1. Old classification of Antineoplastic drugs

2.1.1. I. Antimetabolites

2.1.1.1. 일반적으로 S-phase에 특이적으로 작용

2.1.1.2. ★Inhibitors of thymidylate synthase

2.1.1.2.1. antimetabolite중 가장 많이 쓰임

2.2. 1. ★Inhibitors of thymidylate synthase (antimetabolite 중 가장 많이 쓰임)

2.2.1. 5-FU

2.2.1.1. 항암요법에서 basic하게 쓰이는 항암제

2.2.1.2. 경구투여가 불가능

2.2.1.3. DPD: 동양인의 0.1%에서는 이 효소의 활성 결핍되어 5-FU의 독성이 심함

2.2.1.4. 5-FU + Leucovorin (folinic acid)

2.2.1.4.1. folic acid 유사체로 reduced folic acid derivatives로 바뀐 후 암세포내에서 polyglutamate가 부은 대사물로 바뀜

2.2.1.5. 5-FU + MTX (Methotrexate)

2.2.1.5.1. MTX에 의해 PRPP가 축적되어 5-FU가 활성을 가진 물질로 전환되는 과정이 촉진된다.

2.2.2. S-1

2.2.2.1. 매우 polar

2.2.2.2. 5-FU의 단점 보완한 항암제 (경구투여 불가능하고 정맥주사 해야하는 5-FU)

2.2.2.3. 5-FU의 전구물질인 FT와 CDHP, Oxo 를 함꼐 투여한다

2.2.2.3.1. FT는 간에서 대사되어 5-FU로 전환되어 기능

2.2.2.3.2. CDHP와 Oxo는 5-FU가 활성이 없는 물질로 대사되는 과정을 억제하여 기능을 도움

2.2.3. Capecitabine

2.2.3.1. 경구투여 가능하도록 만들어진 5-FU의 prodrug

2.2.3.2. thymidine phosphrylase의 활성이 정상세포보다 암세포에서 더 높기 때문에 선택적 독성을 가진다

2.3. 2. Purine metabolism Inhibitor: Purine과 유사한 구조

2.4. Inhibitors of RIBONUCLEOTIDE REDUCTASE

2.4.1. hydroxyurea

2.4.1.1. analog of urea

2.4.1.2. inhibit ribonucleotide reductase

2.4.1.3. 이름만 기억

2.5. PURINE AND PYRIMIDINE ANALOGUES THAT ARE INCORPORATED INTO DNA

2.5.1. cytarabine

2.5.2. gemcitabine

2.5.3. fludarabine phosphate

2.5.4. cladarabine

2.5.5. 5-azacytidine

2.6. Agnts that Directly modify DNA structure

2.6.1. 1. Alkylating Agents

2.6.1.1. 1) 개요

2.6.1.1.1. nitrogen mustard

2.6.1.1.2. Alkylation mechanism

2.6.1.2. 2) pharmacologic effects of each drug

2.6.1.2.1. 말초혈관으로 주기어렵다 썩어버릴수 있어서

2.6.1.3. 3) Toxicity & Resistance

2.6.1.3.1. emesis & BM depression

2.6.1.3.2. acrolein & Mesna

2.6.1.3.3. cyclophosmammide에 대한 해독제는 MESNA

2.6.2. 2. Platinum Compounds

2.6.2.1. cisplatin

2.6.2.2. carboplatin

2.6.3. 3. mitomycin (alkylating agent)

2.6.3.1. mechanism: enzyme mediated reduction

2.6.3.1.1. → acts as an alkylating agent

2.6.3.2. used as adjuvant of radiotherapy for hypoxic tumor cells

2.6.3.3. topical use: intravesical treatment for bladder papilloma

2.6.3.4. bone marrow depression 은 수회 치료한 후 늦게 나타남

2.6.3.4.1. progenitor cell 보다 더 이 전의 stem cell 에 작용하는 독성으로 추정됨

2.6.4. 4. bleomycin

2.6.4.1. metal chelating glycopeptide → degrade preformed DNA

2.6.4.2. mechanism: chelation of ferrous iron & interaction with oxygen

2.6.4.3. acts mostly on G2 & M phase, but also active on G0 phase

2.6.4.4. ADR: BM toxicity ↓, pulmonary fibrosis, anaphylaxis:

2.6.4.4.1. therefore, its use is restricted to potentially curative combination chemothetrapy for testicular ca. or Hodgkins’s lymphoma

2.6.4.4.2. 폐에 대한 독성은 누적용량과 관련되어있는것이 아님; fibrosis에 의한것

2.7. TOPOISOMERASE INHIBITORS

2.7.1. 1. epipodophyllotoxins (etoposide & teniposide):

2.7.1.1. DNA topoisomerase II blocker, act on late S-G2 phase

2.7.1.1.1. resistance by P-glycoprotein

2.7.1.2. synergy of combination chemo: drugs damaging DNA directly (e.g., cisplatin or bleomycin) + topoisomerase II inhibitor

2.7.1.3. bone marrow toxicity

2.7.2. 2. anthracycline (doxorubicin, daunorubicin)

2.7.2.1. mechanism: intercalation into DNA strands→ topoisomerase II mediated DNA scission, influence membrane fluidity & ion transport, radical generation

2.7.2.2. PK: i.v. administration, blood conc. decrease by 50% in 30 min, but significant levels persists for 20 hrs, 간에서 대사, bile 로 배설: serum bilirubin 높으면 감량해야 함.

2.7.2.3. ADR: irreversible, cumulative, dose related cardiotoxicity (from excessive production of free radicals in the myocardium)

2.7.2.3.1. Dexrazoxane: free radical inhibitor, used as a cardiac protectant

2.7.3. 3. camptothecins (topotecan & irinotecan):

2.7.3.1. DNA topoisomerase I (transcription, replication, recombination and DNA repair 등에 관여함) blocking

2.7.3.2. A. initially for colon cancer

2.7.3.3. B. severe GI toxicity (life threatening diarrhea)

2.7.3.4. C. SN-38: toxic, active metabolite. UGT1A1 에 의해 제거. *28 mutation 시 활성감소

2.8. MICROTUBULE INHIBITORS

2.8.1. Inhibitors of Microtubule Polymerization

2.8.1.1. Vinca Alkaloids

2.8.1.1.1. toxic to M phase

2.8.2. Inhibitors of Microtubule Depolymerization

2.8.2.1. Taxane

2.8.2.2. Acute hypersensitivity reaction:

2.8.2.3. Toxicity

2.8.3. microtubule inhibitors: vinca alkaloids, taxane, colchicine (for gout), griseofulvin (antifungal)

2.8.4. 아시아 인종에서 백인종보다 taxol 계 약물에 대한 부작용의 빈도가 훨씬 높다.

2.9. METHOTREXATE

2.9.1. Mechanism: inhibit dihydrofolate reductase

2.9.1.1. → inhibit purine & pyrimidine synthesis

2.9.2. intracellular enzymatic polyglutamate addition: make MTX accumulated in cell, the enzyme activity higher in tumor cell !

2.9.2.1. polyglutamate에 붙어서 빠져나가지 않으므로 정상세포내에 축적된다.

2.9.3. intracellular transport of MTX:

2.9.3.1. carrier mediated (saturable delivery, related to cancer cell resistance)

2.9.4. 세포 내부에 더 많은 약물을 넣기 위해 high dose MTX i.v. infusion 함

2.9.5. indications other than cancer: psoriasis, extremely toxic to fetus (folic acid essential for fetal cell differentiation and neural tube closure), rheumatoid arthritis...

2.9.6. GI mucosa and BM toxicity

2.10. HORMONAL AGENTS

2.10.1. 1) estrogen & androgen inhibitors

2.10.1.1. tamoxifen:

2.10.1.2. flutamide

2.10.1.3. finasteride

2.10.2. 2) GnRH agonists

2.10.3. 3) aromatase inhibitors: aminoglutethimide

2.10.3.1. anastrozole

2.11. MISCELLANEOUS

2.11.1. 1) asparaginase

2.11.1.1. cause catabolic depletion of asparagine (→aspartic acid), leukemic cell lack asparagine synthase.

2.11.1.2. Used for childhood ALL

2.11.2. 2) mitoxantrone

2.11.2.1. structure similar to anthracycline, for resistant leukemia

2.11.3. 3) mitotane

2.11.3.1. used for adrenal carcinoma only

2.11.4. 4) retinoic acid derivatives

2.11.4.1. all-trans-retinoic acid

2.11.4.2. used for APL (acute promyelocytic leukemia)

2.11.4.3. APL: t(15:17) chromosomal translocation→ 서로 다른 염색체 상의 두 유전자가 융합되어 비정상적으로 많은 양의 retinoic receptor-α를 생산 The mechanism of action for PO use in acute promyelocytic leukemia (APL) is not known.

2.11.4.4. 13-cis-retinoic acid

2.11.4.4.1. chemoprevention of head & neck squamous carcinoma

2.11.5. 5) bone marrow growth factors

3. Pharmacology of Cancer: Signal Transduction

3.1. BIOCHEMISTRY OF INTERCELLULAR AND INTRACELLULAR SIGNAL TRANSDUCTION 

3.1.1. GROWTH FACTOR AND GROWTH FACTOR RECEPTORS

3.1.1.1. Cell growth: interaction of growth factors with specific cell surface receptors (extracellular ligand-binding domain)

3.1.1.2. EGFR family (HER 또는 ErbB family 라고도 불림): EGFR (HER1/ErbB1), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4)로 구성됨

3.1.2. INTRACELLULAR SIGNAL TRANSDUCTION PATHWAYS

3.1.3. PROTEASOME STRUCTURE AND FUNCTION

3.1.4. ANGIOGENESIS

3.2. PHARMACOLOGIC CLASSES AND AGENTS

3.2.1. GROWTH FACTOR RECEPTOR AND SIGNAL TRANSDUCTION ANTAGONISTS

3.2.1.1. 1. EGF receptor tyrosine kinase inhibitors (EGFR TKI)

3.2.1.1.1. 1) Gefitinib and Erlotinib

3.2.1.1.2. 2) Cetuximab and Trastustumab

3.2.1.2. 2. BCR-ABL/C-KIT/PDGFR Inhibition

3.2.1.2.1. 1) Imatinib mesylate

3.2.1.2.2. 2) Dasatinib and Nilotinib

3.2.1.3. 3. FLT3 Inhibitors: AML

3.2.1.4. 4. JAK2 Inhibitors:

3.2.1.5. 5. RAS/MAP Kinase pathway inhibition

3.2.2. mTOR (mammalian target of rapamycin) Inhibitors

3.2.2.1. hamartoma syndromes such as tuberous sclerosis: mTOR activation

3.2.2.2. TOR was originally in yeast

3.2.2.3. Rapamycin (sirolimus) and its analogues are studied for malignanacies.

3.2.3. PROTEASOME INHIBITORS

3.2.3.1. Bortezomib

3.2.4. ANGIOGENESIS INHIBITORS

3.2.4.1. 1. Anti-VEGF Antibodies

3.2.4.1.1. 2

3.2.4.2. 2. VEGFR Inhibitors

3.2.4.2.1. Thalidomide and Lenalidomide

3.2.5. TUMOR SPECIFIC MONOCLONAL ANTIBODIES

3.2.5.1. Most hematologic malignancies express specific cell-surface markers that have been used to subclassify the malignancies by immunohistochemistry and flow cytometry.

3.2.5.2. B-cell lymphomas

3.2.5.2.1. The anti-CD20 IgG1 monoclonal antibody rituximab for B-cell non-Hodgkin's lymphoma (NHL)

3.2.5.2.2. Radioimmunotherapy

3.2.5.3. Alemtuzumab

3.2.5.3.1. against the pan-leukocyte antigen CD52.

3.2.5.4. crossfire effect

3.2.5.5. Denileukin diftitox (Ontak®):

3.2.5.5.1. combination of interleukin + Diphtheria toxin for cutaneous T-cell lymphoma:

3.2.5.6. Gemtuzumab ozogamicin

3.2.6. Immune Checkpoint Inhibitors (ICIs)

3.2.6.1. Immune checkpoint:

3.2.6.1.1. costimulatory signals, inhibitory signals

3.2.6.2. Checkpoint receptors:

3.2.6.2.1. Cytotoxic T-lymphocyte antigen-4 receptor (CTLA-4) and programmed death-1 receptor (PD-1), etc...

3.2.6.3. *biological response modifiers (BRMs):

3.2.6.3.1. include monoclonal antibodies, autologous cellular immunotherapy, interferons, interleukins, colony stimulating factors, vaccines, and ICIs.

3.2.6.4. Ipilimumab (Yervoy):

3.2.6.5. Pembrolizumab (Keytruda, formerly lambrolizumab), Nivolumab (Opdivo)

3.2.6.6. upregulating the immune system

3.2.6.7. Pseudoprogression:

3.2.6.8. mmune related adverse effects: