PRINCIPLES OF CYTOTOXIC PRINCIPLES OF CYTOTOXIC CHEMOTHERAPYCHEMOTHERAPY

Dr.Erdem GökerDr.Erdem GökerEge Üniversitesi Tıp FakültesiEge Üniversitesi Tıp FakültesiTÜLAY AKTAŞ ONKOLOJİ TÜLAY AKTAŞ ONKOLOJİ

HASTANESİHASTANESİ

Choice of Cancer ChemotherapyChoice of Cancer Chemotherapy

uu Is it a science, art or voodoo Is it a science, art or voodoo medicine?medicine?

BEST Tx OF CANCER

‘Historically‘Historically mostmost anticanceranticancer agentsagents havehave beenbeen usedused withoutwithoutanan understandingunderstanding ofof theirtheir mechanismmechanism ofof actionaction.. HoweverHowever thethepotentialpotential rewardsrewards ofof suchsuch understandingunderstanding areare enormous,enormous, forforthethe practicalpractical applicationapplication ofof thethe drug,drug, thethe discoverydiscovery ofof moremoreselectiveselective agents,agents, andand forfor fundamentalfundamental knowledgeknowledge..’’

GeorgeGeorge Hitchings,Hitchings, 19681968

An overviewAn overview

ll Role of chemotherapy in treatment of cancersRole of chemotherapy in treatment of cancers

ll Scientific basis of anticancer therapy Scientific basis of anticancer therapy

ll Major classes of antiMajor classes of anti--cancer drugscancer drugs

ll Common toxicitiesCommon toxicities

ll Choice of chemotherapy: Principles and examples Choice of chemotherapy: Principles and examples

Curative intent (30%)

Chemotherapy alone (5%)

Adjuvant chemotherapy (15%)

Neo-adjuvant chemotherapy (5%)

Chemoradiotherapy (5%)

Palliative intent (70%)

Role of anti-cancer drugs

Therapeutic EndpointsTherapeutic Endpoints

ll Efficacy without toxicityEfficacy without toxicity–– Palliative therapyPalliative therapy

ll Efficacy AND toxicityEfficacy AND toxicity–– Curative therapyCurative therapy

ll Toxicity without efficacyToxicity without efficacy–– Tentative administrationTentative administration–– Drug ResistanceDrug Resistance

ll Neither toxicity nor efficacyNeither toxicity nor efficacy

An overviewAn overview

ll Role of chemotherapy in treatment of cancersRole of chemotherapy in treatment of cancers

ll Scientific basis of anticancer therapyScientific basis of anticancer therapy

ll Major classes of antiMajor classes of anti--cancer drugscancer drugs

ll Common toxicitiesCommon toxicities

ll Choice of chemotherapy: Principles and examples Choice of chemotherapy: Principles and examples

Scientific basis of cancer chemotherapy

•The concept of log-cell kill

•The concept of dose intensity and density

•The concept of drug resistance.

•The concept of tumor growth and detection

Therapeutic PrinciplesTherapeutic Principles

Diagnosis&

DrugSelection

INPUT

AbsorptionDistributionMetabolismElimination

Toxicity&/OR

Efficacy

Pharmacokinetics Pharmacodynamics

Pharmacokinetic End PointsPharmacokinetic End Points

ll Peak drug concentrationPeak drug concentrationll AUC (Concentration X Time)AUC (Concentration X Time)ll Time above target concentrationTime above target concentrationll Cumulative dose or cumulative AUCCumulative dose or cumulative AUCll Dose “intensity”Dose “intensity”

Peak ConcentrationPeak Concentration

0102030405060708090

0 6 12 18 24

Concentration

Intensity / Time AboveIntensity / Time Above

0102030405060708090

0 6 12 18 24

Concentration

Pharmacokinetic PatternsPharmacokinetic Patterns

ll AbsorptionAbsorptionll ActivationActivationll DistributionDistributionll EliminationElimination

AbsorptionAbsorption

ll OralOral–– Variable concentration X time profileVariable concentration X time profile–– Typical factors affecting oral absorptionTypical factors affecting oral absorption

•• Presence of foodPresence of food•• Concurrent diseaseConcurrent disease

–– Likely produces a different efficacy / toxicity profileLikely produces a different efficacy / toxicity profile•• Etopside oral vs. IVEtopside oral vs. IV•• Oral FluoropyrimidinesOral Fluoropyrimidines•• Oral VinorelbineOral Vinorelbine

AbsorptionAbsorption

ll IntramuscularIntramuscular–– VERY few antiVERY few anti--cancer drugs can be given cancer drugs can be given

this waythis way–– Cytotoxicity associated with tissue damage Cytotoxicity associated with tissue damage

at injection siteat injection site–– Used by this route:Used by this route:

•• Hormonals (leuprolide, glucocorticoids)Hormonals (leuprolide, glucocorticoids)•• LL--asparaginase (lower toxicity than IV)asparaginase (lower toxicity than IV)

ActivationActivation

ll HepaticHepatic–– e.g. cyclophosphamide, doxorubicin, e.g. cyclophosphamide, doxorubicin,

daunorubicin, othersdaunorubicin, othersll Intracellular phosphorylationIntracellular phosphorylation

–– e.g fludarabinee.g fludarabinell Tissue metabolism with free radical Tissue metabolism with free radical

productionproduction–– e.g. doxorubicine.g. doxorubicin

DistributionDistribution

ll Most target intraMost target intra--cellular sitescellular sites–– Combination solubility (water:lipid)Combination solubility (water:lipid)

ll Small number penetrate bloodSmall number penetrate blood--brain barrierbrain barrierll Protein bindingProtein binding

–– High protein binding increases interaction High protein binding increases interaction potentialpotential

–– May or may not limit tissue “penetration”May or may not limit tissue “penetration”•• Consider both plasma and tissue proteinsConsider both plasma and tissue proteins

DistributionDistribution

ll Active Metabolite distributionActive Metabolite distribution–– Ifosfamide metabolites cross bloodIfosfamide metabolites cross blood--

brain barrierbrain barrierll Consider local factorsConsider local factors

–– Tumor vascularityTumor vascularity–– PP--glycoprotein cell membrane pump glycoprotein cell membrane pump

(drug efflux pump)(drug efflux pump)

EliminationElimination

ll Hepatic MetabolismHepatic Metabolism–– P450 metabolismP450 metabolism

ll Catabolism (especially antiCatabolism (especially anti--metabolites)metabolites)–– Normal degradation pathways for Normal degradation pathways for

amino acids etc. to carbon dioxide and amino acids etc. to carbon dioxide and waterwater

ll HydrolysisHydrolysisll Renal elimination unchangedRenal elimination unchanged

Dosing ChemotherapeuticsDosing Chemotherapeutics

ll What are we really doing in patients?What are we really doing in patients?–– Dosing for palliation in most casesDosing for palliation in most cases–– Critiquing dose regimes with more Critiquing dose regimes with more

emphasis on toxicity than efficacyemphasis on toxicity than efficacy–– Specifics of the approach to dosing Specifics of the approach to dosing

become more important as the therapy become more important as the therapy becomes more aggressive.becomes more aggressive.

Dosing ChemotherapeuticsDosing Chemotherapeutics

ll Traditional dosing on Body Surface AreaTraditional dosing on Body Surface Area–– Correlates with metabolic rate, volume Correlates with metabolic rate, volume

of distributionof distribution–– Correlation with tissue concentrations?Correlation with tissue concentrations?

•• Efficacy and toxicityEfficacy and toxicity–– Extrapolated (with enthusiasm from Extrapolated (with enthusiasm from

human dose recommendations)human dose recommendations)–– Probably correct for SOME and not Probably correct for SOME and not

ALL protocolsALL protocols

Dosing ChemotherapeuticsDosing Chemotherapeutics

ll Body surface areaBody surface areall mg/kgmg/kgll Total doseTotal dosell Dose to pharmacokinetic targetDose to pharmacokinetic target

–– AUC, Peak, etc.AUC, Peak, etc.–– Implies therapeutic monitoring for Implies therapeutic monitoring for

chemotherapeuticschemotherapeutics

Dose Form ManipulationDose Form Manipulation

ll LiposomesLiposomes–– Drug contained in lipid spheresDrug contained in lipid spheres

•• Essentially artificial liposomal Essentially artificial liposomal membranesmembranes

•• Actively acquired by some cell linesActively acquired by some cell lines–– Improved therapeutic indexImproved therapeutic index

•• Reduced cardiotoxicityReduced cardiotoxicity•• Enhanced activityEnhanced activity

Dose Form ManipulationDose Form Manipulation

ll ChemoembolizationChemoembolization–– Arterial infusion of methylcellulose Arterial infusion of methylcellulose

micromicro--capsules filled with capsules filled with chemotherapeuticschemotherapeutics

ll Implantible polymersImplantible polymers–– Surgical implantation of Surgical implantation of

biodegradeable polymers containing biodegradeable polymers containing chemotherapeuticschemotherapeutics

*Drug resistance: De novo or acquired

*Lack of selectivity: Between normal and cancer cells

*Cytokinetics: Low growth fraction of cancer

*Pharmacokinetics: Poor bioavailability

*Sanctuary sites: Central nervous system.

Reasons for failure of anti-cancer chemotherapy

An overviewAn overview

ll Role of chemotherapy in treatment of cancers Role of chemotherapy in treatment of cancers

ll Scientific basis of anticancer therapyScientific basis of anticancer therapy

llMajor classes of antiMajor classes of anti--cancer drugscancer drugs

ll Common toxicitiesCommon toxicities

ll Choice of chemotherapy: Principles and examples Choice of chemotherapy: Principles and examples

ll Interview with a cancer survivor.Interview with a cancer survivor.

An overview:Mechanisms of action of anticancer drugs

DNA, RNA &proteins are targets of anticancer drugs

Cell Cycle Specific Agents

• Antimetabolites

• Bleomycin

• Podophyllin Alkaloids

• Plant Alkaloids

Cell Cycle Non-Specific Agents

• Alkylating Agents

• Antibiotics

•Cisplatin

• Nitrosoureas

Major classes of anti-cancer drugs

*Alkylating agents

*Antimetabolites

*Natural products/antibiotics

*Hormones

*Molecularly-targeted therapy.

Alkylating AgentsAlkylating AgentsMMechanism of Actionechanism of Action

ll Alkylate within DNA at the N7 position of Alkylate within DNA at the N7 position of guanineguanine

ll Resulting in miscoding through abnormal Resulting in miscoding through abnormal basebase--pairing with thymine or in pairing with thymine or in depurination by excision of guanine depurination by excision of guanine residues, leading to strand breakageresidues, leading to strand breakage

ll CrossCross--linking of DNA and ring cleavage linking of DNA and ring cleavage may also occurmay also occur

Alkylating AgentsAlkylating AgentsMechanism of ActionMechanism of Action

*Mechlorethamine (Nitrogen mustard): A component of MOPP for Hodgkin’s

lymphoma

*Cyclophosphamide (Cytoxan): A component of CMF, AC, CHOP.

Alkylating agents

Alkylating agents: Examples

Nitrogen MustardsNitrogen Mustards

ll CyclophosphamideCyclophosphamidell IfosfamideIfosfamidell MechlorethamineMechlorethaminell MelphalanMelphalanll ChlorambucilChlorambucil

Cyclophosphamide MetabolismCyclophosphamide Metabolism

AlkylatingAlkylating--Related AgentsRelated Agents

ll ProcarbazineProcarbazinell DacarbazineDacarbazinell AltretamineAltretaminell CisplatinCisplatinll CarboplatinCarboplatin

*Cisplatin: Highly emetogenic; may cause renal dysfunction, neuropathy, hearing loss

A component of PEB for testicular cancer

*Carboplatin: An analog of cisplatin with less side-effects.

Alkylating agents

Platinum Coordination ComplexesPlatinum Coordination Complexes

These compounds alkylate N7 of guanine. They cause nephro- and ototoxicity.

To counteract the effects of nephrotoxicity, give mannitol as an osmotic diuretic,

or induce chloride diuresis with 0.1% NaCl.

AntimetabolitesAntimetabolites

SFolate analogs

SPyrimidine analogs

SPurine analogs.

What are Antifolates?What are Antifolates?

ll Substances that interfere with the action Substances that interfere with the action of folate intermediates are known as of folate intermediates are known as antifolatesantifolates

ll Can be divided into three basic categories Can be divided into three basic categories based on the enzyme they inhibitbased on the enzyme they inhibit–– Dihydrofolate Reductase (DHFR)Dihydrofolate Reductase (DHFR)–– Serine Hydroxymethyl Transferase Serine Hydroxymethyl Transferase –– Thymidylate SynthaseThymidylate Synthase

Dihydrofolate Reductase AntifolatesDihydrofolate Reductase Antifolates

N

HN

N

N

H2N

O

HN

O COOH

HOOC

Target molecules for inhibiting this enzyme must be structurally similar to Folic Acid

Serine Hydroxymethyl Transferase Serine Hydroxymethyl Transferase AntifolatesAntifolates

N

HN

N

N

H2N

O

HHN

R

H

HH

Tetrahydrofolate

Must have structural similarities to THF

Thymidylate Synthase AntifolatesThymidylate Synthase Antifolates

NH2C N

HNN

HN

H2N

OR

N5,N10-Methylene-THF

HN

N

O

O

OH2C

O3PO

HO

-2

H

Uracil

Target antifolates that inhibit this enzyme must have structural similarities to Uracil or the cofactor

N

NN

NH2N NH2

N

CH3

Methotrexate (MTX)

O

NH

COOH

HOOC

Clinically available in 1953

Still the most widely used drug in chemotherapy

Therapeutic index of 1

Dihydrofolate reductase inhibitor

AntifolatesAntifolatesll Utilised since 1940 in the treatment of cancerUtilised since 1940 in the treatment of cancerll Methotrexate standard in regimens for:Methotrexate standard in regimens for:

–– Neoplastic Diseases: ALL, NHL, Neoplastic Diseases: ALL, NHL, Osteosarcoma, Breast Ca, Head&Neck, Osteosarcoma, Breast Ca, Head&Neck, ChoriocarcinomaChoriocarcinoma

–– NonNon--neoplastic: Rheumatoid Arthritis, neoplastic: Rheumatoid Arthritis, GVHDGVHD

ll Cellular resistance to MTX is frequentCellular resistance to MTX is frequentll Other antifolates: Trimetrexate, Edatrexate, Other antifolates: Trimetrexate, Edatrexate,

RaltitrexedRaltitrexed, , PemetrexedPemetrexed

TRANSPORTTRANSPORT

How Drugs Get Into Cells

Diffusion Transport Endocytosis

e.g., immunotoxins

D

D

D D

D

vinblastine, doxorubicin

e.g., nucleoside analogs

e.g.,

D

D

Mechanisms of Folate TransportMechanisms of Folate Transportll InfluxInflux

–– Folate ReceptorsFolate Receptors-- activates an energy dependent, endocytic activates an energy dependent, endocytic

pathway.pathway.–– Reduced Folate CarrierReduced Folate Carrier

-- bidirectional anion exchange mechanism.bidirectional anion exchange mechanism.–– Low pH folate transporter (?) (Biochem Pharmacol Low pH folate transporter (?) (Biochem Pharmacol

53;22353;223--31, 1997).31, 1997).ll EffluxEfflux

–– At least two energy dependent efflux systems have At least two energy dependent efflux systems have been identified (Biochem Pharmacol 51;975been identified (Biochem Pharmacol 51;975--82, 82, 1996).1996).

POLYGLUTAMYLATIONPOLYGLUTAMYLATION

MTX MTX

FH4

PurineBiosynthesis

Lysosome

CH FH2 4 dUMP

TMP

FH2

MTX

MTX (glu)n

FPGS

GAR and AICARTransformylase

DHFR

MTX

EXTRACELLULAR INTRACELLULAR

CELL MEMBRANE

GGH

TS

STUDYING POLYGLUTAMYLATIONSTUDYING POLYGLUTAMYLATION

ll Functional Assay: Using HFunctional Assay: Using H33--MTX and MTX and HPLCHPLC

ll Enzyme Study: Levels of Enzyme Study: Levels of Folylpolyglutamyl Synthase (FPGS) and Folylpolyglutamyl Synthase (FPGS) and Gamma Glutamyl Hydrolase (GGH)Gamma Glutamyl Hydrolase (GGH)

ll Molecular Studies: Expression and Molecular Studies: Expression and Mutational Screen for FPGS and GGHMutational Screen for FPGS and GGH

Therapeutic Implications of Methotrexate Therapeutic Implications of Methotrexate StudiesStudies

•• Administering high dose methotrexate is Administering high dose methotrexate is expensive and results in morbidity/mortality.expensive and results in morbidity/mortality.

•• Trimetrexate an inhibitor of dihydrofolate Trimetrexate an inhibitor of dihydrofolate reductase is transported into cells by a different reductase is transported into cells by a different mechanism.mechanism.

•• Trimetrexate with simultaneous leucovorin is Trimetrexate with simultaneous leucovorin is safe and effective in the treatment of human safe and effective in the treatment of human transport defective leukemia cell lines transport defective leukemia cell lines xenografted into SCID mice.xenografted into SCID mice.

HighHigh--Dose Methotrexate in OsteosarcomaDose Methotrexate in Osteosarcoma

ll Standard treatment is highStandard treatment is high--dose therapy as data suggests dose therapy as data suggests it is more effective than conventional dose.it is more effective than conventional dose.

ll The literature suggests it is the peak level not the AUC The literature suggests it is the peak level not the AUC that correlates with therapeutic response in that correlates with therapeutic response in osteosarcoma. The peak level is predominantly osteosarcoma. The peak level is predominantly determined by dose.determined by dose.

–– Ferrari S, et al: J Chemother 5:135Ferrari S, et al: J Chemother 5:135--41, 199341, 1993–– Graf N, et al: J Clin Oncol 12:1443Graf N, et al: J Clin Oncol 12:1443--51, 199451, 1994–– Delepine N, et al: Anticancer Res 15:489Delepine N, et al: Anticancer Res 15:489--94, 199594, 1995–– Bacci G, et al: J Clin Oncol 16:658Bacci G, et al: J Clin Oncol 16:658--63, 199863, 1998–– OthersOthers

ll Impairments in methotrexate transport are frequent in Impairments in methotrexate transport are frequent in osteosarcoma tumor samples, which can be overcome by osteosarcoma tumor samples, which can be overcome by achieving a high peak level.achieving a high peak level.

Pyrimidine AntagonistsPyrimidine Antagonists

ll Fluorouracil Fluorouracil ll Cytarabine Cytarabine ll GemcitabineGemcitabinell CapecitabineCapecitabine

Pyrimidine analogs:

5-Fluorouracil(5-FU) Cytosine arabinoside (Ara-C) Gemcitabine

Activation of 5Activation of 5--FUFU

Mechanism of Action 5Mechanism of Action 5--FUFU

ll 55--FU inhibits thymidylate synthase FU inhibits thymidylate synthase therefore causing depletion of therefore causing depletion of ThymidylateThymidylate

ll 55--FU is incorporated into DNAFU is incorporated into DNA

ll 55--FU inhibits RNA processing FU inhibits RNA processing

Pyrimidine analogs

•5-Fluorouracil (5-FU) Inhibits thymidylate synthase A component of CMF in the treatment of breast cancerCapecitabine (Xeloda): given orallyTegafur (UFT)

•Cytosine arabinoside (Ara-C) Inhibits DNA polymerase Therapy for AML

•Gemcitabine (Gemzar)Analog of Ara-C Therapy for solid tumors, i.e. pancreatic cancer.

PemetrexedPemetrexed

ll Continuing his work with the synthesis of antifolate molecules, Continuing his work with the synthesis of antifolate molecules, Edward C. TayEdward C. Tayllor has synthesized the drug known as Pemetrexed or has synthesized the drug known as Pemetrexed in 2000. in 2000.

HN

NH2N

O

NH

O

NH

CO2H

CO2H

PemetrexedPemetrexed

ll This is a unique antifolate in that it has been shown to This is a unique antifolate in that it has been shown to inhibit at least five of the major folateinhibit at least five of the major folate--dependent dependent enzymes enzymes –– thymidylate synthasethymidylate synthase–– dihydrofolate reductasedihydrofolate reductase–– glycinamide ribonucleotide formyltransferaseglycinamide ribonucleotide formyltransferase–– aminoimidazole ribonucleotide formyltrasnferaseaminoimidazole ribonucleotide formyltrasnferase–– CC--1 tetrahydrofolate synthetase1 tetrahydrofolate synthetase

ll Pemetrexed is an extraordinarily effective antiPemetrexed is an extraordinarily effective anti--tumor tumor agentagent..

Purine analogs:

Fludarabine

2-Chlordeoxyadenosine

Purine analogs

•2-Chlorodeoxyadenosine (Cladribine) Curative treatment for hairy cell leukemia

• Fludarabine (Fludara) Therapy for CLL and low-grade lymphoma.

Purine AntagonistsPurine Antagonists

ll MercaptopurineMercaptopurinell ThioguanineThioguaninell Fludarabine PhosphateFludarabine Phosphatell CladribineCladribine

Mercaptopurine/ThioguanineMercaptopurine/Thioguanine

ll Must metabolized by HGPRT to the Must metabolized by HGPRT to the nucleotide formnucleotide form

ll This form inhibits numerous enzymes of This form inhibits numerous enzymes of purine nucleotide interconversionpurine nucleotide interconversion

GemcitabineGemcitabine

ll Gemcitabine is SGemcitabine is S--phase specificphase specificll it is a deoxycytidine antimetaboliteit is a deoxycytidine antimetabolitell it undergoes intracellular conversion to it undergoes intracellular conversion to

gemcitabine monophosphate via the gemcitabine monophosphate via the enzyme deoxycytidine kinaseenzyme deoxycytidine kinase

ll it is subsequently phosphorylated to it is subsequently phosphorylated to gemcitabine diphosphate and gemcitabine diphosphate and gemcitabine triphosphategemcitabine triphosphate

GemcitabineGemcitabine

ll Gemcitabine triphosphate competes with Gemcitabine triphosphate competes with deoxycytidine triphosphate (dCTP) for deoxycytidine triphosphate (dCTP) for incorporation into DNA strandsincorporation into DNA strands

ll do to an addition of a base pair before do to an addition of a base pair before DNA polymerase is stopped, Gemcitabine DNA polymerase is stopped, Gemcitabine inhibits both DNA replication and repairinhibits both DNA replication and repair

ll GemcitabineGemcitabine--induced cell death has induced cell death has characteristics of apoptosischaracteristics of apoptosis

Natural Products/AntibioticsSAnthracyclines

SAntimitotic drugs

SEpipodophyllotoxins

SCamptothecins

SBleomycin.

Natural Products/Antibiotics: Anthracyclines

•Mechanisms of action: DNA intercalation and inhibition of

topoisomerase II ---double-strand DNA breaks

•Toxicity:Irreversible cardiomyopathy (> 500 mg/m2).

AnthracyclinesAnthracyclinesMechanism of ActionMechanism of Action

ll HighHigh--affinity binding to DNA through affinity binding to DNA through intercalation, resulting in blockade of intercalation, resulting in blockade of DNA and RNA synthesisDNA and RNA synthesis

ll DNA strand scission via effects on Top IIDNA strand scission via effects on Top IIll Binding to membranes altering fluidityBinding to membranes altering fluidityll Generation of the semiquinone free Generation of the semiquinone free

radical and oxygen radicalsradical and oxygen radicals

MitoxantroneMitoxantrone

ll Structure resembles the anthracyclinesStructure resembles the anthracyclinesll Binds to DNA to produce strand Binds to DNA to produce strand

breakage breakage ll Inhibits DNA and RNA synthesisInhibits DNA and RNA synthesisll Treats pediatric and adult acute Treats pediatric and adult acute

myelogenous leukemia, nonmyelogenous leukemia, non--Hodgkin’s Hodgkin’s lymphomas, and breast cancerlymphomas, and breast cancer

ll Causes cardiac toxicityCauses cardiac toxicity

MitomycinMitomycinMechanism of ActionMechanism of Action

ll Bioreductive alkylating agent that Bioreductive alkylating agent that undergoes metabolic reductive activation undergoes metabolic reductive activation through an enzymethrough an enzyme--mediated reduction to mediated reduction to generate an alkylating agent that generate an alkylating agent that crosscross--links links DNADNA

*

Natural Products/Antibiotics: Antimitotic agents

By interfering microtubule synthesis and degradation, these compounds inhibit cell division.

Antimitotics: Taxanes

Natural products/Antibiotics: Antimitotics

•Paclitaxel (Taxol): Stabilizes microtubulesCauses alopecia totalis, neuropathy

•Docetaxel (Taxotere): Stabilizes microtubules.

•Vinorelbine •Vinblastine•Vincristine

Inhibits polymerization of microtubules.

Natural Products/Antibiotics: Antimitotics

Vinca AlkaloidsVinca AlkaloidsMMechanism of Actionechanism of Action

ll Binds to the microtubular protein tubulin in a Binds to the microtubular protein tubulin in a dimeric formdimeric form

ll The drugThe drug--tubulin complex adds to the forming end tubulin complex adds to the forming end of the microtubules to terminate assemblyof the microtubules to terminate assembly

ll Depolymerization of the microtubules occursDepolymerization of the microtubules occursll Resulting in mitotic arrest at metaphase, Resulting in mitotic arrest at metaphase,

dissolution of the mitotic spindle, and interference dissolution of the mitotic spindle, and interference with chromosome segregationwith chromosome segregation

ll CCS agentsCCS agents-- M phaseM phase

*

Topoisomerases: Cleavage, unwinding and re-annealing of DNA

Etoposide (VP-16):

• Inhibits topoisomerase II leading to double-strand DNA breaks

• A component of PEB for testicular cancer.

Natural Products/Antibiotics: Epipodophyllotoxin

Topotecan (Hycamtin) & Irinotecan (CPT-11, Camptosar):

• Inhibits topoisomerase I resulting in single-strand

DNA breaks.

Natural Products/Antibiotics: Camptothecins

CamptothecinsCamptothecins

ll TopotecanTopotecanll IrinotecanIrinotecan

CamptothecinsCamptothecinsMechanism of ActionMechanism of Action

ll Interfere with the activity of Interfere with the activity of Topoisomerase Topoisomerase II

ll Resulting in DNA damageResulting in DNA damage

ll IrinotecanIrinotecan-- a prodrug that is metabolized a prodrug that is metabolized to an active Top I inhibitor, to an active Top I inhibitor, SNSN--3838

Bleomycin

• Induces DNA strand breaks

• May cause pulmonary fibrosis

• A component of PEB.

Natural Products/Antibiotics: Peptide antibiotic

BleomycinBleomycin

ll Acts through binding to DNA, which results in Acts through binding to DNA, which results in single and double strand breaks following free single and double strand breaks following free radical formation and inhibition of DNA synthesisradical formation and inhibition of DNA synthesis

ll The DNA fragmentation is due to oxidation of a The DNA fragmentation is due to oxidation of a DNADNA--bleomycinbleomycin--Fe(II) complex and leads to Fe(II) complex and leads to chromosomal aberrationschromosomal aberrations

ll CCS drug that causes accumulation of cells in GCCS drug that causes accumulation of cells in G22

NitrosoureasNitrosoureasll CarmustineCarmustinell LomustineLomustinell SemustineSemustinell StreptozocinStreptozocin--naturally occuring sugar naturally occuring sugar

containingcontaining

M.O.A.M.O.A.-- crosscross--link through alkylation of DNAlink through alkylation of DNAAll cross the blood brain barrierAll cross the blood brain barrier

PodophyllotoxinsPodophyllotoxins

ll EtoposideEtoposide (VP(VP--16)16)ll TeniposideTeniposide (VM(VM--26)26)

ll SemiSemi--synthetic derivatives of podophyllotoxin extracted from the root synthetic derivatives of podophyllotoxin extracted from the root of the mayappleof the mayapple

PodophyllotoxinsPodophyllotoxinsMechanism of ActionMechanism of Action

ll Blocks cells in the late SBlocks cells in the late S--GG2 2 phase of the phase of the cell cycle through inhibition of cell cycle through inhibition of topoisomerase IItopoisomerase II

ll Resulting in DNA damage through Resulting in DNA damage through strand breakage induced by the strand breakage induced by the formation of a ternary complex of drug, formation of a ternary complex of drug, DNA, and enzymeDNA, and enzyme

Miscellaneous AntiCancer AgentsMiscellaneous AntiCancer Agents

ll AsparaginaseAsparaginasell HydroxureaHydroxureall MitoxantroneMitoxantronell MitotaneMitotane

HydroxyureaHydroxyurea

ll An analog of ureaAn analog of ureall Inhibits the enzyme ribonucleotide reductaseInhibits the enzyme ribonucleotide reductasell Resulting in the depletion of deoxynucleoside Resulting in the depletion of deoxynucleoside

triphosphate poolstriphosphate poolsll Thereby inhibiting DNA synthesisThereby inhibiting DNA synthesisll SS--phase specific agentphase specific agentll Treats melanoma and chronic myelogenous Treats melanoma and chronic myelogenous

leukemialeukemia

An overviewAn overview

ll Role of chemotherapy in treatment of cancers Role of chemotherapy in treatment of cancers

ll Scientific basis of anticancer therapy Scientific basis of anticancer therapy

ll Major classes of antiMajor classes of anti--cancer drugscancer drugs

ll Common toxicities.Common toxicities.

ll Choice of chemotherapy: Principles and examples Choice of chemotherapy: Principles and examples

ll Interview with a cancer survivor.Interview with a cancer survivor.

Common toxicities of chemotherapy

Organs with active cell division are affected:

*Bone marrow*GI tract mucosa* Hair follicles

•These side-effects are often reversible.

Common toxicity

Bone marrow suppression:

• Leukopenia, thrombocytopenia and anemia

• Nadir WBC count typically occurs 7-14 days after treatment

• Caused by most anti-cancer drugs except: Bleomycin, vincristine, hormones, and most of the molecularly-targeted agents.

Common toxicity

*Gastrointestinal toxicity: -Nausea and vomiting:

Especially cisplatin, mechlorethamine, anthracyclines -Diarrhea: 5-FU, topotecan, irinotecan-Mucositis: 5-FU

*Alopecia (Hair loss): -Paclitaxel, carboplatin, anthracyclines etc.

*Renal toxicity: Cisplatin

*Pulmonary toxicity: Bleomycin (pulmonary fibrosis)

*Peripheral neuropathy: Cisplatin, paclitaxel, vincristine.

Common toxicity

Long-term complications

*Cardiomyopathy: Anthracyclines (Incidence exceeds 5% for doxorubicin dose > 500 mg/m2)

*Leukemia: Mechlorethamine, high-dose etoposide

*Infertility: Alkylating agents causing azoospermia.

Prevention and treatment of side-effects of anticancer drugs

Most of the side-effects can be effectively prevented and treated.

An overviewAn overview

ll Role of chemotherapy in treatment of cancers Role of chemotherapy in treatment of cancers

ll Scientific basis of anticancer therapy Scientific basis of anticancer therapy

ll Major classes of antiMajor classes of anti--cancer drugscancer drugs

ll Common toxicitiesCommon toxicities

ll Choice of chemotherapy: Principles and Choice of chemotherapy: Principles and examplesexamples..

ll Interview with a cancer survivor.Interview with a cancer survivor.

Principles for choice of anticancer drugsPrinciples for choice of anticancer drugs

uu Cancer type and stageCancer type and stageuu Curative or palliative intentCurative or palliative intentuu Patient status: Performance status, coPatient status: Performance status, co--

morbid conditions, organ functionsmorbid conditions, organ functionsuu Combination of drugs is the choice.Combination of drugs is the choice.

Principles of Combined ChemotherapyPrinciples of Combined Chemotherapy

ll Each drug is active against the cancerEach drug is active against the cancerll Each drug has a different mechanism of actionEach drug has a different mechanism of actionll Each drug has a different mechanism of Each drug has a different mechanism of

resistanceresistancell NonNon--overlapping toxicities among the drugsoverlapping toxicities among the drugs

ØØ Synergism and safety.Synergism and safety.

Principles of Combined ChemotherapyPrinciples of Combined Chemotherapy

ll Adoption of a new regimenAdoption of a new regimen

- Requires randomized clinical trials: Phase III study

- A comparison of the new regimen with the ‘standard’ therapy.

Examples of combined chemotherapyExamples of combined chemotherapy

• Non-Hodgkin’s lymphoma (NHL): CHOP

• Relapsed non-Hodgkin’s lymphoma: High-dose chemotherapy followed by autologous peripheral stem cells or bone marrow transplant

• Testicular cancer: PEB.

Success Stories of Clinical Trial Success Stories of Clinical Trial InvestigationInvestigation

ll Cure RatesCure Ratesll Limitation of ToxicityLimitation of Toxicityll Reduction of Treatment DurationReduction of Treatment Durationll Lower Treatment Intensity Lower Treatment Intensity

‘Historically‘Historically mostmost anticanceranticancer agentsagents havehave beenbeen usedused withoutwithoutanan understandingunderstanding ofof theirtheir mechanismmechanism ofof actionaction.. HoweverHowever thethepotentialpotential rewardsrewards ofof suchsuch understandingunderstanding areare enormous,enormous, forforthethe practicalpractical applicationapplication ofof thethe drug,drug, thethe discoverydiscovery ofof moremoreselectiveselective agents,agents, andand forfor fundamentalfundamental knowledgeknowledge..’’

GeorgeGeorge Hitchings,Hitchings, 19681968