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Chemotherapeutic Agents -Introduction

Chemotherapeutic Agents -Introduction. 化療藥物的種類. Alkylating agent Platium Antimetabolite Topoisomerase poison Antimicrotubule Others . Cell Cycle. DNA damage: Radiation, Platiums alkylating agent topoisomerase inhibitors Anti-metabolites. DNA duplication. S. G1. G2.

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Chemotherapeutic Agents -Introduction

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  1. Chemotherapeutic Agents-Introduction

  2. 化療藥物的種類 • Alkylating agent • Platium • Antimetabolite • Topoisomerase poison • Antimicrotubule • Others

  3. Cell Cycle DNA damage: Radiation, Platiums alkylating agent topoisomerase inhibitors Anti-metabolites DNA duplication S G1 G2 Protein synthesis Protein synthesis Mitosis G0 M Anti-microtubules

  4. Alkylating Agent • Nitrogen mustard • Cyclophosphamide • Ifosfamide • BCNU/CCNU • Busulfan • Temozolomide • Tiotepa • DTIC • ……

  5. PPO 7th edition Alkylation Site O6AT: O6-alkyltransferase

  6. Cytotoxicity: forming covalent interstrand cross-links in DNA PPO 7th edition

  7. PPO 7th edition Cyclophosphamide • Clinical: lymphoma, breast, lung.. • 口服和靜脈給藥的效果相當(口服吸收率100%) • Toxicity: hemorrhagic cystitis (出血性膀胱炎), bone marrow, heart, GI mucosa, gonad, lung, alopecia, carcinogenesis 不活性代謝物 hemorrhagic cystitis

  8. Micromedex PPO 7th edition Ifosfamide • Structural isomer of cyclophosphamide • 與Endoxan 有交互抗性(cross-resistance) • More potent than cyclophosphamide? • Hemorrhagic cystitis: • Mesna (Sodium 2-mercaptoethane sulfonate) • reacts with acrolein and other urotoxic metabolites to form non-urotoxic compounds • 不影響也不具抗癌效果

  9. BCNU: bischloroethylnitrosourea BCNU • Characteristic: BCNU與其代謝物具高度脂溶性, 可以輕易通過blood-brain barrier • Mechanism:將DNA氯乙醇化(chloroethylate) 之後形成交叉鏈結(cross-links) • Resistance:與其它alkylating agent之間有部分的交互抗藥性 • Clinical: hematologic malignancy (high dose C/T before BMT), brain tumor • Toxicity:延遲性累積性骨髓抑制,黏膜,皮膚,肺臟纖維化,掉髮,致癌性 PPO 7th edition

  10. Busulfan Mechanism • Alkyl Sulfonate • Toxicity: veno-occlusive disease of the liver,延遲性累積性骨髓抑制,黏膜,皮膚,肺臟纖維化,掉髮,致癌性 • Clinical: CML, high dose C/T before BMT PPO 7th edition

  11. Mitomycin (Mitomycin C) • 抗生素, 最初在1958年分離自Streptomyces caespitosus • Structure: aziridine ring • Mechanism: activated especially in hypoxic status; causing DNA cross-links • Indication: H/N (MEPFL), breast, GI, cervical cancers • Toxicity: GI, kidney, prolonged myelosupression, lung 絲裂黴素 PPO 7th edition

  12. CDDP: cis-diamminedichloroplatinum (II) PPO 7th edition Cisplatin (Platinex) • 1965年, Rosenberg發現大腸桿菌的複製可被通過鉑電極間的電子流所抑制 • Toxicity: neurotoxicity (cumulative, usually reversible), nephrotoxicity, emesis, ototoxicity (cumulative and irreversible), myelosuppression Mechanism like alkylating agent Must dilute in normal saline

  13. cis-diamminecyclobutanedicarboxylato platinum (II) Carboplatin (Paraplatin) • Less renotoxicity • Similar anti-cancer spectrum to cisplatin PPO 7th edition

  14. 1,2-diaminocyclohexaneoxalato platinum (II) Oxaliplatin • 泡製於chloride-free solutions • 勿和鹼性藥品或溶液(特別是5-FU鹼性溶液)混合使用 • Indication: colorectal cancer(unlike cisplatin) • Toxicity: myelosuppression, peripheral neuropathy (pharyngolaryngeal dysesthesia, sensory neuropathy), N/V 臨床腫瘤學 PPO 7th edition Semin Oncol 30 (suppl 6):78-87; 2003

  15. Antimetabolite • Folate analog • Methotrexate • Pemetrexed • 5-FU(IV and oral) • Purine/Purimidine analog • C: Cytarabine(ara-C), Gemcitabine • A: Fludarabine • U: 5-FU

  16. Methotrexate • Polyglutamation: inhibitors of DHFR, TS, aminoimidazole carboxamide ribonucleotide and glycinamide ribonucleotide transformylases • Toxicity: myelosuppression,kidney, liver, lung High dose MTX: monitor drug level & leucovorin rescue PPO 7th edition

  17. Pemetrexed (Alimta) • Polyglutamation • Toxicity: mucositis, BM, skin rash, liver =>reversed by folic acid 350ug po qd, and vit B12 1000ug im 1-3wks before Tx=> not reduce its activity • Clinical: mesothelioma, NSCLC-2nd line PPO 7th edition Cancer 2003;97(8 Suppl):2056–63.

  18. 5-FU (Fluorouracil) • Developed by Heidelberger and patented in 1957 • remains at the very core of most chemotherapeutic approaches to colorectal cancer • effectively metabolized by the same enzymatic pathways as uracil • Leucovorin 可增加其療效 PPO 7th edition

  19. bolus CIF 5-formyl-tetrahydrofolate DPD: dihydropyrimidine dehydrogenase TS: thymidylate synthase MTX Clinical Colorectal Cancer 2002;1(4):220-9

  20. HDFL-Encephalopathy • High ammonia and lactic acidosis in HDFL therapy • Mechanism: disturbance in urea cycle ? • Risk factor: poor nutritional status • Symptoms: delirium, coma, seizure… • Treatment: withhold chemotherapy and do best supportive care

  21. Oral 5-FU UFUR Capecitabine The Oncologist 2002;7:288-323

  22. Capecitabine (Xeloda) Clinical Colorectal Cancer 2002;2(1):16-23

  23. Cytarabine (Ara-C) • Ara-C→ DCK→ Ara-CMP • →dCMP-K→ Ara-CDP → NDP-K→ Ara-CTP • →dCMP deaminase → Ara-UMP → Cytidine deaminase→ Ara-U Mechanism: inhibition of DNA synthesis Most sensitive in S phase Cross BBB in high dose (7-14% of serum level) Clinical: solid & hematological malignancy Toxicity: myelosuppression, cerebellar, N/V Prophylactic steroid for rash and conjunctivitis PPO 7th edition

  24. Gemcitabine (Gemzar) • dFdCdCKdFdCMPdFdCTP=>DNA termination • Toxicity: BM, transient flu-like in 45% patients, asthenia, liver, lung, HUS • Clinical: NSCLC, pancreatic, bladder cancer Gemzar (dFdC) PPO 7th edition

  25. PPO 7th edition Fludarabine (Fludara) • Mechanism: metabolized to F-ara-ATP as DNA chain terminator, inhibitor of RNA function, processing, mRNA translation and an inhibitor of DNA polymerases, DNA primase, DNA ligase I, and ribonucleotide reductase • Clinical: CLL, NHL, PLL, CTCL, WM • Toxicity: myelosuppression, immunosuppression, lymphopenia, opportunistic infection, lung, skin

  26. Topoisomerase Inhibitors • Topoisomerase I inhibitor • Topotecan • Irinotecan • Topoisopmerase II inhibitor • Etoposide • Anthracyclins: • Doxorubicin • Idarubicin • Epirubicin • Daunorubicin

  27. Camptothecin-Mechanism PPO 7th edition

  28. Topo-II Function PPO 7th edition

  29. Topotecan (Hycamtin) • Derivatives of natural camptothecin • Indication: SCLC, ovarian cancer • Metabolism: renal (major) • Toxicity: myelosuppression (neutropenia), N/V, diarrhea, fatigue; alopecia; skin rash PPO 7th edition

  30. derivatives of natural camptothecin As a prodrugSN-38 Metabolism: liver (major) Toxicity: early-onset diarrhea: cholinergic symptoms (flushing, diaphoresis, cramping, and vomiting) late-onset diarrhea myelosuppression, alopecia; N/V; mucositis; fatigue UGT1A1 polymorphism: SN-38 glucuronidation Irinotecan (喜樹鹼) Camptotheca acuminate 喜樹 PPO 7th edition

  31. Topo-II poison Etoposide (Vepesid) • derivative of the natural podophyllotoxin (鬼臼毒素) • Target: topoisomerase II→cause ds and ss DNA breaks • 口服吸收率: 50% (variable) • Toxicity: myelosuppression, alopecia, hypersensitivity (Cremophor EL); mucositis; secondary AML • Clinical: GCT, ovarian, lung cancer, NHL, acute leukemia, Ewing's sarcoma, Kaposi's sarcoma, and neuroblastoma, BMT Podophyllum peltatum 八角蓮 PPO 7th edition Current Medicinal Chemistry, 2004, 11, 2443-2466

  32. Doxorubicin (Adriblastina) • Target: topo-IIα, helicase • Metabolism: liver • Toxicity: myelosuppression; cardiotoxicity, potent vesicant (ice and DMSO), N/V, radiation recall • CHF : rare if doxorubicin < 450 mg/m2 550 ,600 ,700 mg/m2  7% ,15% ,30% • Clinical: breast, lymphoma, ALL, AML, sarcoma… Source: Streptomyces peucetius var. caesius 放線菌目鏈黴菌科 PPO 7th edition

  33. Epirubicin Idarubicin • Toxicity: same as doxorubicin; less cardiotoxic; cumulative dose limit of 900 mg/m2 (epirubicin) • Indication: as doxorubicin • 3 + 7 regimen for AML (I3A7, H3A7…) PPO 7th edition

  34. Antimicrotubule Agent • Vinka alkaloid: prevent microtubule formation • Vincristine • Vindesine • Vinblastine • Vinorelbine • Taxane: stablize microtubule formation • Paclitaxel • Docetaxel

  35. Cancer Chemotherapy & Biotherapy 4th edition Structure of Microtubule PPO 7th edition Lancet Oncol 2005; 6: 229–39

  36. (－) • Treadmilling: • net growth at one end and net shortening at the other end • Dynamic instability: • the plus end switch spontaneously between slow growth and rapid shortening (＋)

  37. Vincristine (Oncovin) • potent vesicant (heat) • Mechanism: inhibit microtubule assembly & block mitosis • Metabolism: liver • Toxicity: neurotoxicity by a peripheral, symmetric sensorymotor, and autonomic polyneuropathy, phlebitis, alopecia Catharanthus roseus G. Don 日日春,長春花 Dose capping: 1.4mg/m2 Up to 2mg (due to toxicity) PPO 7th edition

  38. Paclitaxel • Mechanism: enhance microtubule polymerization, cause delay or blockage of mitosis • Toxicity: myelosuppression (non-cumulative), hypersensitivity (Cremophor EL), symmetric neuropathy, alopecia, myalgia, arthralgia • CDDP->Phy(24hr) => neutropenia↑ Phy(24hr)->Adria => cardiotoxicity/neutropenia/mucositis↑ • Premedication: corticosteroids / H1+H2-receptor antagonists for prevention of hypersensitivity • 不應接觸polyvinyl chloride(PVC)裝置!! Taxus brevifolia 太平洋紫衫 PPO 7th edition

  39. Docetaxel • Clinical: NSCLC, breast, prostate, gastric cancer • Toxicity: neutropenia, hypersensitivity (not due to Cremophor EL), fluid retention (increased capillary permeability), skin (rash, desquamation of the hands and feet, palmar-plantar erythrodysesthesia that may respond to pyridoxine or cooling and onychodystrophy), neuropathy, asthenia • Post-medication: corticosteroids for fluid retention Taxus baccata 歐洲紫杉 臨床腫瘤學 PPO 7th edition

  40. Other

  41. Bleomycin (Bleocin) Source: Streptomyces verticillus放線菌目 • 抗生素複合物, 1962年從日本煤礦土壤中的Streptomyces verticillus菌株分離出來 • Mechanism: redox with Fe(II) & break DNA ss/ds (1/10) • Excretion: 45-70% by renal in first 24hrs • Indication: GCT, HL, NHL, SCC; intracavity C/T (45% systemic absorption) • Route: iv, im, cavity (pleural, peritoneal, bladder), topical • Toxicity: pulmonary fibrosis, mucosal & skin rash/ulceration, thrombophlebitis, N/V, anaphylaxis; caution in Ccr<35ml/min (reduce dose 50% in Ccr<80ml/min) Cancer Chemotherapy & Biotherapy 4th edition PPO 7th edition

  42. Bleomycin-Lung Toxicity • 肺纖維化的高危險群: • 曾經接受或同時接受放射療法。 • 先已存在的肺部疾病。 • 在麻醉的整個期間使用高劑量氧氣。 • 年齡大於 > 70歲。 • 使用單一劑量 > 26 units/m2或 累積總劑量 > 400 units。 • 合併其它化療藥物使用。 • Incidence 3-5% in total dose <450U • Diagnosis: biopsy • 肺臟毒性約10%病人發生; 致命的肺纖維化發生在1-2%病人。偶而, 肺功能異常是由於過敏性反應的結果, 它會對corticosteroid有反應。在這些案例病人通常會有發燒、廣泛肺臟浸潤、和 嗜伊紅血球增多(eosinophilia)。 Cancer Chemotherapy & Biotherapy 4th edition 臨床腫瘤學

  43. Combination chemotherapy • Alkylating agent: Cyclophosphamide: • Topoisomerase II inhibitor: Doxorubicin • Anti-microtubule: Vincristine • Prednisolone  CHOP

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