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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
7/28/2019 Chemotherapy Introduction
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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)
7/28/2019 Chemotherapy Introduction
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
7/28/2019 Chemotherapy Introduction
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
7/28/2019 Chemotherapy Introduction
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
7/28/2019 Chemotherapy Introduction
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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
7/28/2019 Chemotherapy Introduction
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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
7/28/2019 Chemotherapy Introduction
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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