Chemotherapeutic Agents -Introduction

Alkylating agent Platium Antimetabolite Topoisomerase poison Antimicrotubule Others

Cell Cycle
DNA duplication

DNA damage: Radiation, Platiums alkylating agent topoisomerase inhibitors Anti-metabolites

Protein G1 synthesis Mitosis

G2

Protein synthesis

G0

Anti-microtubules

Alkylating Agent
Nitrogen mustard Cyclophosphamide Ifosfamide BCNU/CCNU Busulfan Temozolomide Tiotepa DTIC

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Alkylation Site

O6AT: O6-alkyltransferase

 Cytotoxicity: forming covalent interstrand cross-links in DNA

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Cyclophosphamide

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hemorrhagic cystitis

Clinical: lymphoma, breast, lung.. (100%) Toxicity: hemorrhagic cystitis (), bone marrow, heart, GI mucosa, gonad, lung, alopecia, carcinogenesis

Micromedex

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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-urotoxic compounds

BCNU: bischloroethylnitrosourea

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:,,, ,,
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Busulfan
Mechanism

Alkyl Sulfonate Toxicity: venoocclusive disease of the liver, , ,,, , Clinical: CML, high dose C/T before BMT
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Mitomycin (Mitomycin C)
, 1958 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
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CDDP: cis-diamminedichloroplatinum (II)

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Cisplatin (Platinex)
1965, Rosenberg Toxicity: neurotoxicity (cumulative, usually reversible), nephrotoxicity, emesis, ototoxicity (cumulative and irreversible), myelosuppression
Mechanism like alkylating agent Must dilute in normal saline

cis-diamminecyclobutanedicarboxylato platinum (II)

Carboplatin (Paraplatin)
Less renotoxicity Similar anti-cancer spectrum to cisplatin

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1,2-diaminocyclohexaneoxalato platinum (II)

Oxaliplatin
chloride-free solutions (5-FU) Indication: colorectal cancer(unlike cisplatin) Toxicity: myelosuppression, peripheral neuropathy (pharyngolaryngeal dysesthesia, sensory neuropathy), N/V
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Semin Oncol 30 (suppl 6):78-87; 2003

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 High dose MTX: monitor drug level & leucovorin rescue
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Pemetrexed (Alimta)
Polyglutamation Toxicity: mucositis, BM, skin rash, liver =>reversed by folic acid 350ug po qd, and vit B12 1000ug im 13wks before Tx=> not reduce its activity Clinical: mesothelioma, NSCLC-2nd line
PPO 7th edition Cancer 2003;97(8 Suppl):205663.

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

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bolus

CIF
5-formyl-tetrahydrofolate

DPD: dihydropyrimidine dehydrogenase

TS: thymidylate synthase

MTX

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

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

Oral 5-FU
UFUR

Capecitabine
The Oncologist 2002;7:288-323

Capecitabine (Xeloda)

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

Cytarabine (Ara-C)
Cytidine deaminase Ara-U Ara-C DCK Ara-CMP
dCMP-K Ara-CDP NDP-K Ara-CTP dCMP deaminase Ara-UMP
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
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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
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Gemzar (dFdC)

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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

Topoisomerase Inhibitors
Topoisomerase I inhibitor
Topotecan Irinotecan

Topoisopmerase II inhibitor
Etoposide Anthracyclins:
Doxorubicin Idarubicin Epirubicin Daunorubicin

Camptothecin-Mechanism

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Topo-II Function

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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

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Irinotecan
derivatives of natural camptothecin As a prodrugSN-38 Metabolism: liver (major)
()

Toxicity:

Camptotheca acuminate

early-onset diarrhea: cholinergic symptoms (flushing, diaphoresis, cramping, and vomiting) late-onset diarrhea myelosuppression, alopecia; N/V; mucositis; fatigue
UGT1A1 polymorphism: SN-38 glucuronidation

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Topo-II poison

Etoposide (Vepesid)

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 Podophyllum peltatum sarcoma, and neuroblastoma, BMT
PPO 7th edition Current Medicinal Chemistry, 2004, 11, 2443-2466

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
Source: 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)
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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

Structure of Microtubule

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Lancet Oncol 2005; 6: 22939

( )

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, Dose capping: 1.4mg/m2 Up to 2mg (due to toxicity) alopecia
Catharanthus roseus G. Don

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Paclitaxel
Taxus brevifolia

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 polyvinyl chloride(PVC)!!

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Docetaxel
Taxus baccata

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

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Other

Bleomycin (Bleocin)
Source: Streptomyces verticillus

, 1962Streptomyces verticillus 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

Bleomycin-Lung Toxicity
:
> 70 > 26 units/m2 > 400 units

Incidence 3-5% in total dose <450U Diagnosis: biopsy 10%; 1-2% , , corticosteroid (eosinophilia)
Cancer Chemotherapy & Biotherapy 4th edition

Combination chemotherapy
Alkylating agent: Cyclophosphamide: Topoisomerase II inhibitor: Doxorubicin Anti-microtubule: Vincristine Prednisolone

CHOP