Chemotherapeutic Agents-Introduction

化療藥物的種類

• Alkylating agent

• Platium

• Antimetabolite

• Topoisomerase poison

• Antimicrotubule

• Others

Cell Cycle

S

G1 G2

M

Protein synthesis

Protein synthesis

DNA duplication

Mitosis

DNA damage:

Radiation, Platiums

alkylating agent

topoisomerase inhibitors

Anti-metabolites

Anti-microtubulesG0

Alkylating Agent

• Nitrogen mustard• Cyclophosphamide• Ifosfamide• BCNU/CCNU• Busulfan• Temozolomide• Tiotepa• DTIC• ……

Alkylation SitePPO 7th edition

O6AT: O6-alkyltransferase

• Cytotoxicity: forming covalent interstrand cross-links in DNA

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

PPO 7th edition

hemorrhagic cystitis不活性代謝物

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

PPO 7th editionMicromedex

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

BCNU: bischloroethylnitrosourea

PPO 7th edition

Busulfan

• 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

Mechanism

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

PPO 7th edition

絲裂黴素

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

PPO 7th editionCDDP: cis-diamminedichloroplatinum (II)

Mechanism like alkylating agent

Must dilute in normal saline

Carboplatin (Paraplatin)

• Less renotoxicity

• Similar anti-cancer spectrum to cisplatin

PPO 7th edition

cis-diamminecyclobutanedicarboxylato platinum (II)

Semin Oncol 30 (suppl 6):78-87; 2003

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

PPO 7th edition

1,2-diaminocyclohexaneoxalato platinum (II)

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Antimetabolite

• Folate analog– Methotrexate– Pemetrexed– 5-FU(IV and oral)

• Purine/Purimidine analog– C: Cytarabine(ara-C), Gemcitabine– A: Fludarabine– U: 5-FU

Methotrexate

• Polyglutamation: inhibitors of DHFR, TS, aminoimidazole carboxamide ribonucleotide and glycinamide ribonucleotide transformylases

• Toxicity: myelosuppression,kidney, liver, lung

PPO 7th edition

High dose MTX: monitor drug level & leucovorin rescue

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

Cancer 2003;97(8 Suppl):2056–63.PPO 7th edition

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

Clinical Colorectal Cancer 2002;1(4):220-9

CIF

bolus

DPD: dihydropyrimidine dehydrogenase

TS: thymidylate synthase

5-formyl-tetrahydrofolate

MTX

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

The Oncologist 2002;7:288-323

Oral 5-FU

UFUR

Capecitabine

Clinical Colorectal Cancer 2002;2(1):16-23

Capecitabine (Xeloda)

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 synthesisMost sensitive in S phaseCross BBB in high dose (7-14% of serum level)Clinical: solid & hematological malignancyToxicity: myelosuppression, cerebellar, N/VProphylactic steroid for rash and conjunctivitis

PPO 7th edition

Gemcitabine (Gemzar)

• dFdCdCKdFdCMPdFdCTP=>DNA termination

• Toxicity: BM, transient flu-like in 45% patients, asthenia, liver, lung, HUS

• Clinical: NSCLC, pancreatic, bladder cancer

PPO 7th edition

Gemzar(dFdC)

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

PPO 7th edition

Topoisomerase Inhibitors

• Topoisomerase I inhibitor– Topotecan– Irinotecan

• Topoisopmerase II inhibitor– Etoposide– Anthracyclins:

• Doxorubicin• Idarubicin• Epirubicin• Daunorubicin

PPO 7th edition

Camptothecin-Mechanism

Topo-II Function

PPO 7th edition

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

Irinotecan• derivatives of natural

camptothecin• As a prodrugSN-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

PPO 7th edition

Camptotheca acuminate 喜樹

( 喜樹鹼 )

Etoposide (Vepesid)

Current Medicinal Chemistry, 2004, 11, 2443-2466

• 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

Topo-II poison

PPO 7th edition

Podophyllum peltatum八角蓮

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…

PPO 7th editionSource: Streptomyces peucetius var. caesius 放線菌目鏈黴菌科

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

Antimicrotubule Agent

• Vinka alkaloid: prevent microtubule formation– Vincristine– Vindesine– Vinblastine– Vinorelbine

• Taxane: stablize microtubule formation– Paclitaxel– Docetaxel

Structure of Microtubule

Lancet Oncol 2005; 6: 229–39PPO 7th edition

Cancer Chemotherapy & Biotherapy 4th edition

• 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

( － )

( ＋ )

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

PPO 7th edition

日日春 , 長春花

Dose capping: 1.4mg/m2

Up to 2mg (due to toxicity)

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

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

PPO 7th edition

Taxus baccata 歐洲紫杉

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Other

Bleomycin (Bleocin)

• 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)

Source: Streptomyces verticillus 放線菌目

PPO 7th editionCancer Chemotherapy & Biotherapy 4th edition

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) 。

臨床腫瘤學Cancer Chemotherapy & Biotherapy 4th edition

Combination chemotherapy

• Alkylating agent: Cyclophosphamide:

• Topoisomerase II inhibitor: Doxorubicin

• Anti-microtubule: Vincristine

• Prednisolone

CHOP