chemotherapy introduction

7/28/2019 Chemotherapy Introduction

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Chemotherapeutic Agents

-Introduction


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Alkylating agent

Platium

Antimetabolite

Topoisomerase poison

Antimicrotubule Others


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Cell CycleS

G1 G2

M

Protein

synthesisProtein

synthesis

DNA duplication

Mitosis

DNA damage:

Radiation, Platiumsalkylating agent

topoisomerase inhibitors

Anti-metabolites

Anti-microtubulesG0


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Alkylation Site

PPO 7th edition

O6AT: O6-alkyltransferase


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Cytotoxicity: forming covalent interstrand

cross-links in DNA PPO 7th edition


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Cyclophosphamide

Clinical: lymphoma, breast, lung..

(100%)

Toxicity: hemorrhagic cystitis (), bone marrow,heart, GI mucosa, gonad, lung, alopecia, carcinogenesis

PPO 7th edition

hemorrhagic cystitis


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Ifosfamide

Structural isomer of cyclophosphamide

Endoxan(cross-resistance)

More potent than cyclophosphamide?

Hemorrhagic cystitis:

Mesna (Sodium 2-mercaptoethane sulfonate)

reacts with acrolein and other urotoxic

metabolites to form non-urotoxiccompounds

PPO 7th editionMicromedex


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BCNU

Characteristic: BCNU,blood-brain barrier

Mechanism:DNA(chloroethylate)(cross-links)

Resistance:alkylating agent

Clinical: hematologic malignancy (high dose C/T

before BMT), brain tumor Toxicity:,,,,,

BCNU: bischloroethylnitrosourea

PPO 7th edition


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Busulfan

Alkyl Sulfonate

Toxicity: veno-occlusive disease

of the liver,,,,,,

Clinical: CML, highdose C/T beforeBMT

PPO 7th edition

Mechanism


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Mitomycin (Mitomycin C)

,1958

Streptomyces caespitosus

Structure: aziridine ring

Mechanism: activated especiallyin hypoxic status; causing DNA

cross-links

Indication: H/N (MEPFL), breast,GI, cervical cancers

Toxicity: GI, kidney, prolonged

myelosupression, lung

PPO 7th edition


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Carboplatin (Paraplatin)

Less renotoxicity

Similar anti-cancer spectrum to cisplatin

PPO 7th edition

cis-diamminecyclobutanedicarboxylato platinum (II)


14/43Semin Oncol 30 (suppl 6):78-87; 2003

Oxaliplatin

chloride-free solutions

(5-FU)

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


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Methotrexate

Polyglutamation: inhibitors ofDHFR, TS, aminoimidazolecarboxamide ribonucleotideand glycinamide ribonucleotide

transformylases Toxicity:myelosuppression,kidney, liver,lung

PPO 7th edition

High dose MTX: monitor drug level & leucovorin

rescue


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Pemetrexed (Alimta)

Polyglutamation

Toxicity: mucositis, BM,

skin rash, liver

=>reversed by folicacid 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):205663.PPO 7th edition


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5-FU (Fluorouracil)

Developed by Heidelbergerand patented in 1957

remains at the very core ofmost chemotherapeutic

approaches to colorectalcancer

effectively metabolized bythe same enzymaticpathways as uracil

Leucovorin

PPO 7th edition


19/43Clinical Colorectal Cancer 2002;1(4):220-9

CIF

bolus

DPD: dihydropyrimidine dehydrogenase

TS: thymidylate synthase

5-formyl-tetrahydrofolate

MTX


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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 anddo best supportive care


21/43The Oncologist 2002;7:288-323

Oral 5-FU

UFUR

Capecitabine


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

Capecitabine (Xeloda)


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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


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Gemcitabine (Gemzar)

dFdCdCKdFdCMP

dFdCTP=>DNA

termination

Toxicity: BM, transient

flu-like in 45% patients,

asthenia, liver, lung, HUS

Clinical: NSCLC,

pancreatic, bladder

cancer

PPO 7th edition

Gemzar

(dFdC)

PPO 7th edition


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Fludarabine (Fludara)

Mechanism: metabolized to F-ara-ATP asDNA chain terminator, inhibitor ofRNA

function, processing, mRNA translation and

an inhibitor of DNA polymerases, DNA

primase, DNA ligase I, and ribonucleotidereductase

Clinical: CLL, NHL, PLL, CTCL, WM

Toxicity: myelosuppression,

immunosuppression, lymphopenia,opportunistic infection, lung, skin

PPO 7th edition


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Topoisomerase Inhibitors

Topoisomerase I inhibitor

Topotecan

Irinotecan

Topoisopmerase II inhibitor

Etoposide

Anthracyclins:

Doxorubicin

Idarubicin

Epirubicin

Daunorubicin


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PPO 7th edition

Camptothecin-Mechanism


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Topo-II Function

PPO 7th edition


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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


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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

()

Topo II poison


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Etoposide (Vepesid)

Current Medicinal Chemistry, 2004, 11, 2443-2466

derivative of the natural podophyllotoxin ()

Target: topoisomerase IIcause ds and ss

DNA breaks

: 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

Podop hyl lum pel tatum


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Doxorubicin (Adriblastina)

Target: topo-II, 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


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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


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Antimicrotubule Agent

Vinka alkaloid: prevent microtubule formation

Vincristine

Vindesine

Vinblastine

Vinorelbine

Taxane: stablize microtubule formation

Paclitaxel

Docetaxel

Cancer Chemotherapy & Biotherapy 4th edition


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Structure of Microtubule

Lancet Onco l2005; 6: 22939PPO 7th edition

py py


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Treadmilling:

net growth at one end andnet shortening at the otherend

Dynamic instability:

the plus end switchspontaneously between slogrowth and rapid shortening

()

()


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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

,

Dose capping: 1.4mg/m2

Up to 2mg (due to toxicity)


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Paclitaxel

Mechanism: enhance microtubule polymerization,cause delay or blockage of mitosis

Toxicity: myelosuppression (non-cumulative),hypersensitivity (Cremophor EL), symmetricneuropathy, alopecia, myalgia, arthralgia

CDDP->Phy(24hr) => neutropenia

Phy(24hr)->Adria =>cardiotoxicity/neutropenia/mucositis

Premedication: corticosteroids / H1+H2-receptorantagonists for prevention of hypersensitivity

polyvinyl chloride(PVC)!!

Taxus b revifol ia

PPO 7th edition


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Docetaxel

Clinical: NSCLC, breast, prostate, gastric cancer

Toxicity: neutropenia, hypersensitivity (not due to

Cremophor EL), fluid retention (increased capillarypermeability), 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


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Other


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Bleomycin (Bleocin)

, 1962Streptomycesverticillus

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 & skinrash/ulceration, thrombophlebitis, N/V, anaphylaxis;caution in Ccr


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Bleomycin-Lung Toxicity

:

> 70

> 26 units/m2

> 400 units

Incidence 3-5% in total dose


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Combination chemotherapy

Alkylating agent: Cyclophosphamide:

Topoisomerase II inhibitor: Doxorubicin

Anti-microtubule: Vincristine

Prednisolone

CHOP

chemotherapy introduction

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