Anticancer agents in medicinal chemistry

Anticancer agents

1. Anti neoplastic Agents
Antineoplasticagentsusedforthetreatmentofcancer
Neoplasm(inGreek,‘neo’means‘new’and‘plasm’means
‘formation'referstoagroupofdiseasecausedbyseveral
agents-namely,chemicalcompoundsandradiantenergy.
Cancerischaracterizedbyabnormalanduncontrolled
divisionofcells,whichproducetumorsandinvadeadjacent
normaltissues.
Often,cancercellsseparatethemselvesfromtheprimary
tumoursandcarriedbylymphaticsystem,reachdistantsites
oforgans,wheretheydivideandformsecondarytumours
(metastasis)
Cancerisclassifiedaccordingtothetissuesandtypeofcells
inwhichnewgrowthoccurs.

2. 1.Carcinoma:Malignanttumoursderivedfromepithelialcells.
2.Sarcoma:Malignanttumoursderivedfromconnective
tissue
3.Lymphoma andleukemia:Malignancyderivedfrom
hematopoietic(blood-forming)cells
4.Germcelltumour:tumoursderivedfromtotipotentcells.
1.Blastictumour:Atumour(usuallymalignant)that
resemblesanimmatureorembryonictissue.Manyofthese
tumoursaremostcommoninchildren

3. Treatment of cancer includes surgical intervention , radiation, immunotherapy, and
chemotherapy using neoplastic drugs.
Some type of tumours are currently treated first with chemotherapeutic agents.
Cancer chemotherapy is generally non –specific-means drugs kill not only cancerous
cells but also normal cells.
Special strategies developed to increase the potential of destroying cancerous cells and
lessening toxic effects on normal tissue.
CLASSIFICATION
1) Alkylating agents
i) Nitrogen mustard:
Mechlorithamine Melphalan Chlorambucil
Estramustine UracilmustardCyclophosphamide
Ifosphamide

4. ii) Nitrosourea-Carmustine, Lomustine, Semustine, Chlorozotocin
iii) Aziridines-Thiotepa, Benzotepa, Altretamine
iv) Alkyl sulfonates-Busulphan
v) Methyl hydrazine-Procarbazine
vi) Miscellaneous-Dacarbazine, streptozocine
2) Antimetabolites
i)Folic acid antagonist and analogues-Methotrexate, Trimetrexate,
Azathioprine
i)Purineantagonist and analogues -6-mercaptopurine
6-Thioguanine
Fludarabine,
Pentostatineand Cladribine
iii) Pyrimidineantagonist and analogues -5-Flurouracil and Cytarabine
Floxuridineand Capecitabine
3) Antibiotics
i) Anthracyclines-Daunorubicine, Doxorubicine, Carminomycin, Idarubicine
and Epirubicine
ii) Miscellaneous-ActinomycineD, Mithramycine, Bleomycine, MitomycinC

5. 4) Plant Products : Vincaalkaloids-Vincristineand Vinblastine
: Epipodophyllotoxins-EtoposideTeniposide
: Taxol: Paclitaxel, Docetaxel
: Miscellaneous-Camptothecin, Topotecan, Irinotecan,
Colchicine
5) Enzymes : L-Asparaginase, Pegaspargase
6) Hormones : Mitotane, Megestrol, Tamoxifen, Letrozole,
Dromostanolone, Pipobroman
7) Immunotherapy : Interferon α-2a, Interferon α-2b, Interferonα-n3
Aldesleukin, Diftitox, denileukin, Bacillus Calmette-Guertin(B C G)
8) Monoclonal Antibodies: Rituximab, Gentuzumabozogamicin
9) Radiotherapeuticagents: Chromic Phosphate P 32, Sodium phosphate P 32, Sodium
iodide I 132 , Strontium 89 chlorite
10) Cytoprotectiveagents: Mesna, Amifostine, Dexrazoxane
11) Miscellaneous : Cisplatin, carboplatin, hydroxyurea ete.,

6. Alkylatingagents
Chemotherapeuticalkylatingagentshavethecommon
propertyofbecomingstrongelectrophilesthroughthe
formationofcarboniumionintermediates,whichinturnreact
withnucleophilicmoietiesofthetargetmolecule(DNA).
Itactsbytransferofalkylgroupstobiologicallyimportant
constituentssuchasamino,sulfhydrylorphosphategroup
whosefunctionisthenimpaired.
Underphysiologicalcondition,alkylatingagentsarepositively
chargedandtheyreactwithnegativeorhighelectrondensity
region.

7. AlkylatingagentsknowntoreactwithDNA,RNAand
proteintheirreactionwith DNAisbelievedtobe
mostimportant.
Alkylatingagentsactbyalkylationonnucleophilicsitei.e.,
InDNA7-nitrogenatomofguanineisparticularly
susceptibletoformcovalentbondwithalkylatingagents.
nu –H + Alkyl –y alkyl –nu + H
+
+ Y
-

8. Meclorethamine
MeclorethamineHcloccurs as hygroscopic leaflets –very
soluble in water
Dry crystals stable at room temp up to 40
0
C.
Very irritating to mucous membranes and harmful to eyes.
It is supplied in rubber stoppered vials containing mixture
of MeclorethamineHcland sodium chloride.
It is diluted with 10 ml of sterile water immediately before
injection in to a rapidly flowing i.vinfusion.
Intra cavity injsometimes given to control malignant effusion2HCN
CH
2CH
2Cl
CH
2CH
2Cl
2,2' - Dichloro -N- methyl diethyl amine

9. Aziridium ion formed from Meclorethamine in body
fluids is highly reactive.
Itactsonvariouscellularcomponentswithinminsof
admn.
Lessthan0.01%recoveredunchangedintheurine,but
morethan50%isexcretedainactivemetabolitesinthe
first24h.

10. Med uses
MeclorethamineiseffectiveinHodgkin’sdisease.
Prescribedincombinationwithotheragents
Combnwithvincristin(Oncovin),procarbocinandprednisone,
knownasMOPPregimen-considertreatmentofchoice.
LymphomasandmycosiscanbetreatedwithMeclorethamineO
CH3 N
CH
2CH
2OH
CH
2CH
2OH
CH2NH2
CH3 N
CH
2CH
2Cl
CH
2CH
2Cl
Ethylene oxide N-metyl diethanol amine Mechlorethamine
SOCl2
Synthesis

11. Toxicity
1.Bone marrow depression
2.Emesis and anorexia
3.Effect on GIT

12. CYCLOPHOSPHAMIDEO
P
HN
O
(ClH
2CH
2C)
2
.H2O
Itsmonohydrateformislowmeltingsolid
Verysolubleinwater
Suppliedas25and50mgwhitetablets
Aspowder(100,200,or500mg)insterile
vials
Forreconstitution5ml/100mgofsterile
WaterforInjUSP added
OraldoseofCYCLOPHOSPHAMIDE 90%
bioavailablewith8% firstpassloss.
Itmustbemetabolisedbylivermicrosomes
tobecomeactive.

13. Amongthemetabolites,PHOSPHAMIDE mustardhasanti
tumouractivityandacroleinistoxictourinarybladder.
Acroleintoxicitydecreasedbyi.v.ororaladmnofsod.Salt
of2-mercaptoethanesulfonicacid(mesna)
Meduses
1.CYCLOPHOSPHAMIDE hasadvantagesoverother
alkylatingagents–activeorallyandparenteralandgivenin
fractionateddosesoverprolongedperiods.

14. 2.Activeagainstmultifullmyelomaofchildren,
3.Incombinationwithotherchemotherapeuticagents,
hasgivencompleteremissionsandevencuresin
Burkett’slymphoma andacutelymphoblastic
leukemia(ALL)inchildren.
Toxic effects
1.Alopecia and nausea and vomiting
2.Leukopenia
3.Sterile haerrhagic cystitis
4.Gonadal suppression

15. MelphalanN
ClH
2CH
2C
ClH
2CH
2C
COOH
NH
2
SynthesisN
ClH
2CH
2C
ClH
2CH
2C
COOH
NH
2
COOH
NH
2
HNO3
H2SO4
C2H5OH/HCl
COOC
2H
5
NH
2
O
2N
Phthalic anhydride[H]
COOC
2H
5
N
H
2N
OO
O
1.
2.SOCl2
3.HCl/NH2NH2

16. 2mgtabavailablefororaladministrationassolution.
Oralabsorptioniserraticandincompletewithabsolute
bioavailabilityrangingfrom25to89%
Apreparationkitisprovidedforparenteralformulation
Itcontains100mgMelphalan,whichisdissolvedin1ml
acid–alcoholsolutionandthencombinedwithfinaldiluents
containing108mgofdipotassiumphosphate,5.4mlof
propyleneglycol,andsterilewaterforinjectionUSP.This
prepnshouldbeusedpromtply.
Thereisnosignificantfirst-passeffectwtihmelphalanbut
drugisgraduallyinactivatedbynonenzymatichydrolysisto
monohydroxyanddihydroxyderivatives.

17. Elimination is biphasic, with half-lives of 6 to 8 min
and 40 to 60 min
Med Uses
1.Active against multiple myeloma
2. Also active against breast, testicular and ovarian
carcinoma
Toxicity
1.Hematological –blood count must be followed
carefully
2.Nausea and vomiting infrequent
3.Alopecia

18. ChlorambucilN
ClH
2CH
2C
ClH
2CH
2C
(CH
2)
3COOH
Solubleinetherandaqueousalkali
Itsoralabsorptionisefficientandreliable
Sugarcoated2mgtabletsaresupllied
Itactsmostslowlyandistheleasttoxicofanymustard
derivativeinuse.
ItisindicatedespeciallyinthetreatmentofCLLand
primaryglobulinemia
OtherindicationsarelymphosarcomaandHodgkin’s
diseases.

19. Manypatientsdevelopprogressive,butreversible
lymphopeniaduringtreatment
Mostpatientalsodevelopadoserelatedandrapidly
reversibleneutropenia
Forthesereasons,weeklybloodcountsaremadeto
determinethetotalanddifferentialleukocytelevel
TheHemoglobinlevelsarealsodeterminedfor
monitoringbothtoxicityandefficacy

20. BUSULPH
AN
CH
3SO
2(CH
2)
4 O SO
2CH
3
Synthesis
HO (CH
2)
4OH + 2CH
3SO
2Cl
CH
3SO
2O (CH
2)
4OSO
2CH
3
Occursascrystalandsolubleinacetoneandalcohol
Althoughpracticallyinsolubleinwater,itslowlydissolves
onhydrolysis
Stableindryair
Itissuppliedas2mgtablets
Wellabsorbedorallyandmetabolizedrapidly
Muchofthedugsundergoesaprocessknownas“sulphur
stripping”inwhichthiolcompoundssuchasglutathioneor
cysteineresultsinlossoftwoequivalentsof
methanesulphonicacidandformationofasulphonium
intermediateinvolvingthesulphuratomofthethiol.

21. Suchsulphoniumintermediatesarestablein-vitro,
butin-vivotheyarereadilyconvertedinto
metabolite,3-hydroxythiolane-1,1-dioxide.
Oraldoseofbusulfanarewelltolerated
Absorptionhaszeroorderkinetics
Thehalflifeis2.1to2.6hours

22. Med Uses
TreatmentofGranulocyticleukemia
Usedforbonemarrowtransplantationinpatients
withvariousleukemia
Toxicity
Depletionofthrombocytesmayleadto
haemorrhageBloodcountmustbecheckedatleast
weekly
Rapiddestructionofgranulosides

23. THIOTEPAN P N
N
S
Tri-(1-aziridinyl) phosphine sulfide
White powder and water soluble
Suplied in vials containing 15mg of thiotepa, 80mg
of NaCl and 50g of NaHCO
3
Sterile water used to make an isotonic solution

24. Bothvialsandsolutionmustbestoredat2-8
o
Cand
thissolutionmaybestored5dayswithoutlossof
potency
Thiotepabloodlevelsdeclineinarapidbiphasic
manner
ItisconvertedintoTEPAbyoxidativedesulferization,
andTEPAlevelsexceedthoseofthiotepa2hours
afteradmn
Aziridinemetabolismalsooccurswithliberationof
ethanolamine

25. MedUses
Triedagainstmanytypeofcancer,most
consistentresultobtainedinbreast,ovarian,
andbronchogeniccarcinomasandmalignant
lymphomas
Itisalsousedtocontrolintracavityeffusion,
resultingfromneoplasms
Toxicity
Highlytoxictobonemarrowandbloodcounts
arenecessaryduringtherapy

26. Antimetabolites
Antimetabolites–Compoundspreventbiosynthesisoruseofnormal
cellularmetabolites.Chemicalsubstancesthattakepartincellular
metaboliteknownasmetabolites
Antimetabolitesexerttheiractionbyactingasfalseprecursorfor
enzymes.
ManyAntimetabolites-enzymeinhibitors.Thesedrugsare
usuallystructuralanaloguesofnormalbodymetabolite,derived
fromincorporatingoneortwoiso-stericgrouporotherstructural
changesofmetabolites
Structural modification of these metabolites may be on the
pyrimidine ring

27. PosisbleMOA :
1.Inhibition of kinase or enzyme involved in
biosynthesis of pyrimidine
2.Incorporation into DNA or RNA leading to
miscoding
3.Inhibition of polymerase

28. Mercaptopurine
PURINE ANALOGUESHN
N
N
H
N
SH
Purine -6-thiol HN
N
N
H
N
SH
Purine -6-thiol
HN
N
N
H
N
OH
HN
N
N
H
N
Cl
POCl3
Pyridine
HN
N
N
H
N
SCN
NaSCN
-NaCl
H2O-HCN
SYNTHESIS

29. Yellowcrystalofmonohydrate,Poorwatersolublity
Dissolvesindilutealkalibutundergoesdecomposition.Suppliedas50mgtab
Injformulationofvialscontains500mgsodsaltof6-mercaptopurine,whichis
reconstitutedwith48.5mlofwaterforinj
Itisnotactiveuntilitisanabolizedtothephosphorylatednucleotide.Inthis
formitcompeteswithendogenousribonucleotideforenzymesthatconvert
inosinicacidintoadenine-andxanthinebasedribonucleotide
Futhermore,itisincorporatedintoRNA,whereitinhibitsfurtherRNA
synthesis.
Oneofitsmainmetaboliteis6-methylmercaptopurineribonucleotide,
whichisalsoapotentinhibitoroftheconversionofinosinicacidtopurines
Poorabsorption,lowbioavailability,firstpassmetabolismbyliverandhas
oralabsorption

30. Peak plasma levels reached 2h after ingestion
It is metabolisedby S-methylationfollowed by 8-
hydroxylation
It also oxidisedto 6-thiouricacid
Tolerated dose varies with individual patients
Medicinal Use
1.Primarily treating acute leukemia, Children respond better
than adults
Toxic effect
1.Leukopenia
2.Thrombocytopenia and bleeding occurs with high dose

31. THIOGUANINEHN
N
N
H
N
SH
2-AminoPurine -6-thiol
H
2N
Supplied as 40 mg tab
Oralthioguaninepoorlyabsorbed
Injformissuppliedin75mgvials
Itisreconstitutedbyadding5mlNaClforinjUSP
Itisconvertedbyhypoxanthineguaninephosphoribosyl
transferaseintonucleotideformthatinhibitsanumberof
reactioninDNAandRNAsynthesis
Cross-resistanceexistbetweenthioguanineand
mercaptopurine

32. Med Use
1.Treating acute leukemia especially in
combination with cytarabine
Toxic effects
1.Bone marrow depression
2.Leukopenia
3.Thrompocytopenia
4.bleeding

33. PRIMIDINE ANALOGUES
1.FlurouracilHN
N
H
F
O
O
5-Fluro-2,4-pyrimidinedione
Synthesis
Supplied in 10ml ampuls containing 500mg in water for inj
Stored at room temp and protected from light
It is potent inhibitor of thymidylate synthetase
It is also converted into flurouridine triphosphate, which is
incorporated into RNA and DNA
Plasma levels erratic after oral admn and high after parenteral
dosing
Extensively metabolised in the liver and main metabolite is
dihydrofluorouracil
Most of admnd dose is excreted in urine as alpha –fluoro-beta-
alanine HN
N
H
F
O
O
5-Fluro-2,4-pyrimidinedione
HN
N
H
F
O
O
2,4-pyrimidinedione
CF3OF
Fluorination

34. Med Uses
1.Effective in palliative management of carcinoma of the breast,
colon, pancreas, rectum, and tomachin patients who can not
cured by surgery or other means
2.Topical formnused for the treatment of premalignant
keratosesof the skin and superficial basal cell carcinomas.
Toxic effects
1.Parenteraladmnproduces –Leukopenia
2.GI Heamorrhage
3.Stomatitis, Esophagopharyngitis, diarrhea, nausea , vomiting
4.Alopecia and dermatitis
5.Topical admncontraindicated in patients develop
hypersentivity
6.Prolonged exposure to ultraviolet radiation may increase the
intensity of topical inflammation reactions

35. H
H
CH
2OH
OH
H
H H
O
HN
NO
F
O FLOXURIDINE
Supllied in 5ml vials containing 500mg of floxuridine as sterile powder
and reconstitution by addition of 5ml sterile water and resulting solu stored
under refrigeration for NMT 2 weeks
It is prodrug of 5-Fluorouracil and freely soluble in water than 5-
Fluorouracil
It is admsd by continuous regional intra arterial infusion
When given in this manner , it has significant advantages over
Fluorouracil
Metabolically deoxy sugar moiety of floxuridine cleaved to give 5-
Fluorouracil
Med Use
Gastro intestinal Adenocarcinoma

36. CYTARABINEH
H
CH
2OH
OH
H
H OH
O
HN
NO
NH
2
1-Beta-D-Arabinofuranosylcytosine
Itispyrimidineantimetaboliteinwhichsugarhasmodified
Itissuppliedasfreezedriedsolidinvialscontaining100or
500mg
Itisreconstitutedwithsterilewatercontaining0.9%benzyl
alcoholtogive20mg/mlcytarabine
Solutionmaybestoredatroomtempfor48h

37. N
N N
N
NH
2
CH
2 N CONHCH(CH
2)
2COOH
CH
3 COOH
H
2N METHOTREXATE
MOA:Sequentialactionofdeoxycytidinekinaseanabolizescytarabineto
triphophorylatednucleotide,whichactsascompetitiveinhibitorofDNA
polymerase,afterincorporationintoDNAchainleadstomiscoding
ItisspecifictheS-Phaseofthecellcycle
MedUses
1.Treatmentofacuteleukemia,chronicmyelocyticleukemia,meningeal
leukemia,acutelympholyticleukemia(ALL)andchroniclympholytic
leukemia(CLL)

38. SYNTHESIS
N
N
NH
2
NH
2
NH
2
H
2N
+
HC-CH2Br
Br
CHO
2,3- Dibromopropionaldehyde
N
N
NH
2
NH
2
NH
H
2N
-HBr
CH CH
2Br
O
Cyclization
Dehydration
-H2O
N
N
NH
2
N
NH
H
2N
CHCH
2Br
N
N
NH
2
N
N
H
2N
C CH
2BrDehydrogenation
HN CONHCH(CH
2)
2COOH
CH
3
COOH
+
-HBr
N
N N
N
NH
2
CH
2 N CONHCH(CH
2)
2COOH
CH
3 COOH
H
2N
Methotrexate

39. It is isolated as monohydrate as yellow solid
Soluble in alkali solution, but decompose in them
It is supplied as 25 mg tab and in vials containing either 5
or 50 mg of methotrexate sodium in 2ml of solution
5mg sample contains 0.9% benzyl alcohol as preservative
50 mg sample contains 0.9% benzyl alcohol , 0.26%
sodium chloride and sodium hydroxide to give pH 8.5
A preservative –free lyophilized preparation is
recommended for intra thecal admn to prevent or treat
tumour cells in CNS

40. After oral admn , it is rapidly but incompletely absorbed
Approximately 50 to 60% of the absorbed drug is bound
to plasma proteins.
Cytotoxic levels are found in cerebrospinal fluid when
high doses of methotrexate given
Most of the drug given is excreted in the urine
unchanged.
Plasma level decay is biphasic or possibly triphasic

41. Methotrexatebindstightlytodihydroflolate
reductase,blockingthe reductionof
dihydrofolatetotetrahydrofolate-activeformof
coenzyme.
ItisspecificfortheSphaseofcellcycle
Methotrexateundergoespolyglutamation
intracellularly,formingapoolofcompoundsthat
isretianedformonths
Rsistancetomethotrexatedevelopsby
increasingdihydroflolatereductase,which
resultsfromgeneamplificationorbydefective
transfortintotumorcells

42. Med
MMedUses
Uses
1.Itwasthefirstdrugtoproducesubstantialremissionsin
leukemiaandtreatmentoflymphocyticleukemiaandALL
2.Usedinthetreatmentandprophylaxisofmeningeal
leukemia
3.Usedincombinationchemotherapy forpalliative
managementofbreastcancer,epidermiscancersofhead
andneckandlungcancer
4.Itisalsousedagainstseveredisablingpsoriasis
Toxicities
Toxiceffects
1Ulcerativestomatitis,leukopenia,andabdominaldistress
2.Renalfailureinsomepatients.Thisconditionisthoughtto
beresultfromcrystallizationofthedrugoritsmetabolitesin
acidicurine

43. 
AZATHIOPRINEN
N
N
H
N
S
N
N
H
3C NO
2
It is supplied as 50 mg tab
Injectable salt available in 20 ml vials containing 100mg of
Azathioprine
Well absorbed when taken orally
It is converted extensively to 6-mercaptourine

44. ThemainindicationofAzathioprineisasan
adjuncttopreventtherejectionofhetero
transplants
Itiscontraindicatedinpatientswhoshow
hypersensitivitytoit
Toxiceffects
1.Hematologicaldisorderexpressedasleukemia,
anemiaandThrombocytopenia
2.ShouldnotbetakenwithAllopurinol

45. ANTICANCER ANTIBIOTICS
Ninedifferent antibiotics or their semisynthetic analogues are established clinical
anticancer agents , and other anibiotics under going clinical development
Some of these agents approved recently, however others are known for long time
1. Dactinomycin ( actinomycin D) (1940, Walksman)
2. Plicamycin ( Aureolic acid) (1962) (Mithramycin)
3. Actinomycins
4. Bleomycins
5. Mytomycin C
6. Doxorubicin
Antracyclines
7. Doxorubicin
8. Daunorubicin
9. Idarubicin
10. Carminomycin
Actinomycinscompriselargenoofcloselyrelatedstructures.Allofthemcontains
chromophore-asubstituted3-phenoxazone-1,9-dicarboxylicacidknownas
actinomycin

46. Anthracycline
Antracyclines–largeandcomplexfamilyof
antibiotics
Occurasglycosideofanthracyclinone
Glycosidiclinkageusuallyinvolves7-hydroxyl
groupoftheanthracyclinoneandbetaisomer
ofsugarwithL-configurations
Becauseoftheconjguatedanthraquinone
nucleus,theanthrayclines–reddishincolor
andimpartredcolortotheurineofthepatient

47. MOA
anthraquinonenucleusoftheanthracyclinesintercalate
withDNA,whichleadstosingleanddoublestrandedDNA
breaks
Inaddition,anthraquinoneisalsocapableofgenerating
reactiveoxygenspeciessuchashydroxyradical(-OH)
andsuperoxideradicalanion(-O–O)-
Thesefreeradicalsmayproducedestructiveeffect
uponthecellwhichmayincludedamageofDNA.
Generationoffreeradicalsleadstocardiotoxicity-a
majorsideeffectofanthracyclines

48. O
CH
2 R
2
O
O
O
OH
O
NH
2
OH
CH
2
R
1
R1 R2
Daunorubicin OCH3
Doxorubicin
OCH3
H
OH
Idarubicin
H
OH
Carminomycin
OH
H
1
2
3
4
5
76
8
9
101112

49. DAUNORUBICIN
ObtainedfromfermentationofStreptomycepeucetiuss
Hclsaltredcrystallinepowder,solubleinwaterandalcohol
Availableaslyophilizedpowderin20mgvials,inthisform
stableatroomtemp,butafterreconstitutionwith5to10ml
sterilewateritshouldbeusedwithin6h
AnewliposomalformulationofDaunorubicinknownas
DaunoXome,isinphasetwoclinicaltrials
Significantlyreducedtoxicity,includingcardiotoxicityhas
beenclaimedforit
LongterminalplasmahalflifeofDaunorubicinresultsfrom
extensivetissuebinding.
ItisreadilymetabolisedtoDaunorubicinolbyreductionof
its13-ketogroup.This metaboliteone-tenthasactiveas
Daunorubicin
Druganditsmetaboliteeliminatedbyhepatobiliaryexcretion

50. MOA:
Anoofcellularlesionsmaycontributetothe
antitumoractivityofDaunorubicin
ItintercalatesintoDNAandRNAandinhibitthe
ligaseactivityoftopoisomeraseII
Redoxcyclingofquinonefuctionalitygenerates
hydroxylandsuperoxideradicals, which
peroxidizelipidsanddamagecellularmembranes
Thiseffectmayproducecardiotoxicitybecause
heartcellsrelativelydeficientin antioxidant
defenses

51. Usual dose of admn is 30 to 45mg /m
2
It is admnd i.v taking care to prevent extravasation
Med Use
Treatment of acute lymphocytic and granulocytic leukemia
Toxic effects
Bone marrow depression
Stomatitis
Alopecia
And GI disturbances
At higher dose cardiac toxicity may develop
Severe and progressive congestive heart failure may follow initial
tachycardia and arrhythmiasis

52. DOXORUBICIN (Adriamycin)
ObtainedfromculturesofStreptomycespeucetius
Orangeredcolorneedlesaresolubleinwaterandalcohols
Suppliedasfreezedriedpowderintwodifferentsizes:10mgplus50mg
oflactoseUSPand50mgplus250mgofLactoseUSP
Theseamountsarereconstitutedwith5and25mlrespectively,ofNaCl
injUSP
Afteradmnitrapidlydistributedtobodytissues,withabout75%ofit
bindingtoplasmaproteins
Itisextensivelymetabolisedandeliminatedprimarilyasglucoronide
conjugatesoftheparentaglyconeor13-hydroxylreductionproduct,
doxorubicinol
Dispositionandeliminationcanbeexplainedbytwo-comparmentora
threecompartmentmodel
Liposome-encapsulateddoxorubicin(LED)isavailableinseveral
formulationforclinicaltrials
Dose:60to75mgbyi.vat21-dayinterval
MOA: Similar to those described for daunorubicin

53. Med Uses
Combinationtherapywithvarietyofotherreagentsisbeing
developedforspecifictumors
Toxicity
Mylosupptressionandcardiotoxicity
Bonemarrowdepression,primarilyofleukocytes
Redbloodcellsandplateletsalsomaybedepressed,socarefulblood
countsessential
Acuteleftventricularfailure
Usetoproduceregressioninacuteleukemias,Hodgkin’sdiseaseand
otherlymphomas,Wilmstumor,neuroblastoma,soft-tissue,andbone
sarcomas,breastcarcinoma,transitionalcellbladdercarcinoma
Cardiomyopathyandcongestiveheartfailuremaybeencounteredseveral
weeksafterdiscontinuinguseofAdriamycin

54. 
Toxicityaugmentedmainlybyimpairedliverfunction,becausethissiteof
metabolism
Evaluationofliverfunctionisbyconventionallaboratoryisrecommended
beforeindividualdosing
IDARUBICIN HCl
HClsaltformulatedinsingle–dosevialscontaining5mgor10mgoforange
lyophilizedpowderandisreconstitutedwith5or10mlNaClforinj
Thesesolustableatleast7daysunderrefrigeration
Admnisi.v,withcaretakentoavoidextravasationbecauseofthepotent
vesicantaction
Itdiffersfromdaunorubicinbylackofmethoxygroup
LikeDaunorubicin,itintercalatesDNAandinhibitstopoisomeraseII

55. 
Med Uses
1.I.V Idarubicinis approved for therapy of acute nonlymphocyticleukemia
in combination with Cytarabine
2.Active against blast phase of chronic myelogenousleukemia
Toxicity
1. Its dose limiting toxicity is Myelosuppression
2. Leukemia
3. It appears to be less cardiotoxicthan doxorubicin and daunorubicin
BLEOMYCIN SULFATE
Bleomycinsulfate–mixtureofcytotoxicglycopeptidesisolatedfroma
strainofStreptomycesverticillus
MaincomponentisbleomycinA2(lessthan65%)andbleomycin(less
than20to30%)
Itiswhitishpowder,readilysolubleinpowder
Occursnaturallyasbluecoppercomplex,butitremovedlaterin
formulation

56. Itissuppliedinampulscontaining15uitsofsterilebleomycin
sulfate
Bleomycinunitisbasedoninhibitoryactivityagainst
Mycobacteriumsmegmatisinculture
Bleomycinsulfateisreconstitutedbydissolutionin1to5mlof
sterilewater,ornormalsalineforInj
Itundergoesrapidinitialdistributionwithhalflife10to20min,
followedbyeliminationhalf-lifeof2to3h
Itisinactivatedreadilyinliverandkidneyandexcretedinurine
MOA:
InvolvesbindingtoDNAfollowedbysingleordouble–strand
cleavageTransferRNAalsomaybecleaved
Thesecleavagecausedbyactiveoxygenspeciesthatare
generatedinastepwiseprocessfrombleomycin–iron-oxygen
complexes
Theprocessiscellspecific,withmaineffectintheG
2andM
phase

57. MedUses
Palliativetreatmentofsquamouscellcarcinomasoftheheadand
neck,esophagus,skin,andcervixandvulva
Alsousedagaisttesticularcarcinoma,especiallyincombination
withcisplatinandvinblastine
Toxic effects: Mainly occurs in skin and lungs
1. Bone marrow depression
2. Pulmonary fibrosis
3. Toxicity in mucous membrane
4. Anaphylactoidreactions are possible in lymphoma patients
Dose;
0.2 to 0.50 units /kg given i.v, I.M or subcutaneous once or twice
weekly

58. ETOPOSIDE.

59. Semisyntheticderivativeofpodophyllotoxinandsuppliedin5-mLampuls
containing
20mg/rnLofthedrugpIus30mgofbenzylalcohol.80rngofpolysorbate,
650mgofpolyethyleneglycolandabsolutealcohol.
Thismixtureisdilutedwitheither5%dextroseorsalinetogiveafinal
concentrationof0.2or0.4mg/mL
Etoposidcalsoissuppliedas50-mgcapsuleswhichalsocontainsorbitol.
Theymustbestoredat36to46°F.
Thepharmacokineticsofetoposidcfitatwo-compartmentmodel.Aterminalhalf-
lifeof7hoursisindependentofthedoseandmethodofadministration.
Theprimarymetabolitesfoundinplasmaarepicrohydroxyacidsandpicro
lactone
themajorurinarymetaboliteis4‘-demethylepipodophyllicacid.Oral
bioavailabilityisabout50%
Eliminationhalf-fifeis4toIIhours.

60. MOA:
Etoposidehasmarkedscheduledependence,WithtoxiceffectsintheG2
phase.
Itcausesprotein-linkedDNAstrandbreaksbyinhibitingtopoisomeraseII
AlthoughEtoposidedoesnotbinddirectlytotheDNA.itstabilizes
covalentintermediateformoftheDNA—topoisontcrasceIIcomplex
Med Uses
Etoposideincombinationwithotherchemotherapeuticagentsisthefirst
choicetreatmentforsmallcelllungcancer

61. Italsoineffectiveincombinationwithother
agentsinrefractorytesticulartumors
ithasbeenusedaloneorincombination
againstacutenon-lymphocyticleukemias.
Hodgkin'sdisease.non-Hodgkin'slymphornas,
andKaposissarcoma.
TOXICITY
1.hypersensitivity.
2 Dose-limiting bone marrow depression is the
most significant toxicity

62. Thank you