alkylating and antimetabolites.ppt

8/19/2019 Alkylating and antimetabolites.ppt

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General rules ofchemotherapy

Aggressive high-dose chemotherapy

•Cyclic regimens - repeated administrations with

appropriate intervals for regeneration of normalcells (e.g., bone marrow cells)

•Supportive therapy - to reduce toxicity

hematotoxicity – bone marrow transplantation,

hematopoietic growth factorsSpecic antagonists! antifolate (methotrexate)– folate (leucovorin)

"#S$% –(Mercapto Ethane Sulfonate sodium) donor of –S& groups, decreased urotoxicity ofcyclophosphamide. 'etoxifying agent.

dexraoxane! chelates iron, reducedanthracycline cardiotoxicity

amifostine! reduces hematotoxicity, ototoxicity

and neurotoxicity of alylating agents


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• "#S$% is an ad*uvant used in cancer chemotherapy involvingcyclophosphamide and ifosfamide. +t is mareted by axter asromitexan and "esnex. "#S$% is an acronym for -"ercapto#thane Sulfonate sodium. +t is a detoxifying agent.

• %mifostine is a cytoprotective ad*uvant used in cancerchemotherapy involving '$%-binding chemotherapeutic agents.%lso commonly nown as /0-1234 in its active form. +t ismareted by "ed+mmune under the trade name #thyol.

• 'exraoxane is used to protect the heart against the cardiotoxicside e5ects of anthracyclines, such as doxorubicin.

• %mifostine is used therapeutically to reduce the incidence of

neutropenia-related fever and infection induced by '$%-bindingchemotherapeutic agents including alylating agents (e.g.cyclophosphamide) and platinum-containing agents (e.g.cisplatin). +t is also used to decrease the cumulativenephrotoxicity associated with platinum-containing agents.%mifostine is also indicated to reduce the incidence of xerostomiain patients undergoing radiotherapy for head and nec cancer.


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•6ombination of several drugs with di5erent mechanisms of

action, di5erent resistance mechanisms, di5erent dose-limiting toxicities.

•Adjuvant therapy: %dditional cancer treatment givenafter the primary treatment to lower the ris that the cancer

will come bac. %d*uvant therapy may includechemotherapy, radiation therapy, hormone therapy,targeted therapy, or biological therapy.


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•Supportive therapy of chemotherapy!-%ntiemetics (4-&78 -antagonists)

-%ntibiotic prophylaxis and therapy

-9rophylaxis of urate nephropathy (allopurinol)

-#nteral and parenteral nutrition

-9ain – analgesic drugs

-9sychological support


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Alkylating agentsTopoisomeraseinhibitors Antimetabolites

Molecularlytargeted

busulfan dactinomycin cytarabine erlotinib

carboplatin daunomycin clofarabine imatinib

carmustine doxorubicin fludarabine sorafenib

cisplatin etoposide gemcitabine sunitinib

cyclophosphamide etoposide phosphate mercaptopurine tretinoin

dacarbazine idarubicin methotrexate Herceptin

ifosfamide irinotecan nelarabine Miscellaneous

lomustine liposomal daunomycin thioguanine arsenic trioxide

mechlorethamine liposomal doxorubicin Tubulin binders asparaginase

melphalan mitoxantrone docetaxel bleomycin

oxaliplatin teniposide ixabepilone dexamethasone

procarbazine topotecan vinblastine hydroxyurea

temozolomide vincristine mitotane

thiotepa vinorelbine PEGasparaginase

paclitaxel prednisone

Antineoplastic Agents


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Classical alkylating agents 7hey destroy proliferating cancer cells by adding an alylgroup to '$% molecule and preventing its replication.

7he following three groups are almost always considered:classical:.

• $itrogen mustards• 6yclophosphamide

• "echlorethamineor mustine (HN2) (tradename "ustargen

• ramustine or uracilmustard

• "elphalan• 6hlorambucil• +fosfamide• endamustine

•$itrosoureas

•6armustine•


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Alkylating-like•9latinum-based chemotherapeutic drugs (termed

platinum analogues) act in a similar manner. 7hese agents do not have an alyl group, butnevertheless damage '$%. 7hey permanentlycoordinate to '$% to interfere with '$% repair, sothey are sometimes described as :alylating-lie:.

•6isplatin•6arboplatin•$edaplatin•=xaliplatin

•Satraplatin• 7riplatin tetranitrate

• 7hese agents also bind at $> of guanine.


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DNA

RNA

Proteintubulin

Purines andPyrimidines

Asparaginase

Tubulin binders

Alkylating agentsTopoisomerase Inh.

Antimetabolites

6hemotherapy! "echanisms of %ction


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%lylating %gents

Largest class of antineoplastics

General Properties/Mechanism:• !ll are electrophilic molecules that covalently modify nucleophilic

molecules in cells• "#! most important target $#% and &' of Guanine) for

anticancer propertiesGeneral Types of Alkylating Agents:

• Monofunctional• (ause single strand "#! breas

• Bifunctional• *nhibit "#! replication and transcription by crosslining "#!

Subtypes:

• itrogen mustards

• itrosoureas

• Platinum !ompounds


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H2N

O

N

N

HN

N

HO

O

OP

O

NH2

O

N

NNH

N

O

OP

OH

O

N

R

H2N

O

N

N

HN

N

HO

O

OP

O

NH2

O

N

NNH

N

OO

P

OH

O

N

R

Crosslinking: Joining two or more molecules by a covalent bond. Tiscan eiter occur in te same strand !intrastrand crosslink" or in teopposite strands o# te DNA !interstrand crosslink". Crosslinks also

occur between DNA and protein. DNA replication is blocked bycrosslinks$ wic causes replication arrest and cell deat.

An %&ample o# DNA Crosslinking


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$itrogen "ustards

"echlorethamine ("ustargen)&odgin?s@other lymphomasand chronic leuemias.A "=99 regimen

6hlorambucil (


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1 )ustargan serves as a prototype #or te mustards !and

oter alkylating agents" because o# its spectrum o#activity$ its to&icities and its mecanism o# action. 2t isigly unstable and reactive + still in use in combinationterapy$ )*PP$ -/ response$ 34/ cure

1 To&icity: Nausea and vomiting !N5(". Dose limitingto&icity !D6T" is bone marrow suppression$ wite bloodcells$ esp. granulocytes. )a& suppression at 7870 days$recovery around 90 days.

1 AD)%: t70 less tan ; min.$ admin in #ree #lowing

cateter

1 Analogs: Clorambucil !6eukeran"$ Cronic 6ympocytic

6eukemia< )elpalan !Alkeran"$ )ultiple )yeloma !longeral#8lives .o.

"echlorethamine ("ustargan)


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*fosphamide $"sophosphamide# "fe$)

+ung, breast, ovarian, lymphomas

(yclophosphamide $!yto$an)Malingnant lymphomas, various carcinomas-• !ctivated by P./0 enzymes

• Most versatile nitrogen mustard• 1etter bone marro2 recovery than

Mustargen

Most (ommon #itrogen MustardsMost (ommon #itrogen Mustards


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Cyclopospamide is a nitrogenmustard tat re=uires

bioactivation. Te circulating #orm$aldopospamide$ degenerates intote active posporamide mustard

and te to&ic acrolein. Aldeydeo&idase protects te liver and otertissues #rom aldopospamide tat

doesn>t di##use out.


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A se! "ost widely used alylating agent. $on-&odginCs lymphomas , reast (increases > yrsurvival form 81D to EF D)

A 7oxicity! $B, anaphylactic shoc. bone marrosuppression, max 12-1 days, recovery by 1days (relatively platelet sparing)H alopecia,hemorrhagic cystitis (minimied by diuresis), etc.

A %'"#! "ay be administered parenterally, in alarge range of doses. 0esistant cells may havealdehyde oxidase (lie the liver)

A %nalog! +sofosfamide (+fex)

6yclophosphamide (6ytoxan)


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#itrosoureas#itrosoureas

!ompound?iscloronitrosourea$!armustine# B!%)

(hloroethylcyclohexylnitrosourea

$Lomustine# !!%)

B!% and !!%s: 1rain tumors, Hodgin3s disease,

melanoma-•+ipid soluble4 $(#S active)•&' of Guanine preferred alylation site•Prolonged cummulative myelosuppression•5eratogenic


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A se! 9rimary glioblastoma (with surgery andradiation can increase live span from 2 wees to 42wees)

A 7oxicity! $B. bone marrow suppression, max IdaysH recovery by E days.

A %'"#! %dministered by in*ection. niJue amongantineoplastics for its high oil-to-water partition

coeKcient (very lipophillic) and low ioniation atphysiological p& – ris of hematological toxicity persistdue to storage in the liver adipose tissue

A %nalog! 66$ (lomustine), may be administered

orally. 7emoolomide (7emodar) is a new non-

6$ (6armustin)


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Platinum compoundsPlatinum compounds(isplatin $Platinol)• testicular, ovarian, head and nec, lung,

bladder cancer • (urative in combination for metastatic testicular cancer

(arboplatin $Paraplatin)

• ovarian, nonsmall cell and small cell lung cancers• less toxic $6./7) than cisplatin but is generally less active

*&aliplatin !%lo&atin"• broad anticancer activity4 colorectal, ovarian, pancreatic, nonHodgins lym, breast, lung, prostate, etc• +acs crossresistance 2ith other platinum compounds• Generally less toxic than other platinum compounds


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*&aliplatin: Tird generation platinum analog. 2tsactivity and to&icity pro#iles di##er #rom bot cisplatinand carboplatin$ and tus$ it lacks cross8resistance wittese compounds. *&aliplatin contains a bulky carrierligand$ 7$08diaminocycloe&ane !DAC@"$ not present ineiter cisplatin or carboplatin. nlike cisplatin orcarboplatin$ o&aliplatin is not associated wit signi#icantrenal or auditory to&icity$ and ematological to&icity is

usually mild. *&aliplatin as a large spectrum o#antineoplastic activity$ including colorectal cancer$ovarian cancer$ pancreatic cancer$ non8@odgkinBslympoma$ breast cancer$ lung cancer$ prostate cancer$

germ8cell carcinomas$ and malignant mesotelioma.Canges in mismatc repair and enanced replicativebypass do not appear to contribute to o&aliplatinresistance as compared to cisplatin or carboplatin.


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se: )ost used in combination terapy 8 testiculartumors !-4/ curative"

To&icity: neproto&icity$ can be treated wit Ami#ostine !a

tiopospate" )aor N5($ earing loss at ig end.

AD)%: Administered i.v. a#ter 780 liters saline andmannitol !cloride diuresis"

Analog: Carboplatin !Paraplatin"$ *&aliplatin !%lo&atin" isnow a #irst line drug #or combination terapy o# coloncancer

6isplatin (9latinol)

• Cisplatin induced as been largely abrogated by ade=uate


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• Cisplatin8induced as been largely abrogated by ade=uatepretreatment ydration and diuresis. Ami#ostine !%T@*6" is atiopospate cytoprotective agent tat is labeled #or tereduction o# renal to&icity associated wit repeated administrationo# cisplatin. Ami#ostine is deposporylated by alkaline

pospatase to a parmacologically active #ree tiol metabolite.

• *toto&icity caused by cisplatin is una##ected by diuresis and ismani#ested by tinnitus and ig8#re=uency earing loss. Teototo&icity can be unilateral or bilateral$ tends to be more #re=uent

and severe wit repeated doses$ and may be more pronounced incildren. )arked nausea and vomiting occur in almost all patientsand usually can be controlled wit 48ydro&ytryptamine !48@T;"antagonists$ neurokinin87 !NE7" receptor antagonists$ and ig8dose corticosteroids !see Capter ;F". At iger doses or a#ter

multiple cycles o# treatment$ cisplatin causes a progressiveperiperal motor and sensory neuropaty$ wic may worsen a#terdiscontinuation o# te drug and may be aggravated by subse=uentor simultaneous treatment wit ta&anes or oter neuroto&ic drugs.Cisplatin causes mild8to8moderate myelosuppression$ wittransient leukopenia and trombocytopenia. Anemia may becomeprominent a#ter multiple cycles o# treatment


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=ther %lylators

• Streptoocin (Lanosar), a nitrosourea• se! "alignant pancreatic insulinoma, pancreatic carcinoid,

doubles 1 yr survival rates ($ausea and vomiting notable,renal toxicity in @8 cases – bone marrow suppression in M2D)

• 9rocarbaine ("utalane)• se! &odgin?s 'isease ("="9 protocol)• New reports of cross resistance, minor toxicities (bone

marrow suppression), psychic disturbances, nausea,vomiting, /ea "%= inhibitor - available orally

• 'acarbaine ('7+6)• 7emoolomide '7+6 are metabolied to same active

compound! 4-amino-imidiole-E carboxamide - thought to bethe active alylating species

• '7+6 se! "elanoma, &odgin?s disease , dose i.v.• 7emoolomide se! malignant gliomas

• Streptococci is used in the management of pancreatic islet cell


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• Streptococci is used in the management of pancreatic islet cellcarcinoma, carcinoid tumor, colorectal cancer, and pancreaticadenocarcinoma. +t seems to have specic activity only in pancreaticcancers and some gastrointestinal tumors. 'ue to the presence of asugar moiety, streptoocin has a mared specicity for beta- and

exocrine cells of the pancreas, and its uptae by these cells isenhanced.

• 9rocarbaine is an oral, cell cycle-phase specic antineoplastic agentused in the treatment of &odginCs disease, non-&odginCs lymphomas,brain tumors, and lung cancers. +t has been described as a nonclassic

alylating agent and is not cross-resistant with the other alylatingagents. 9rocarbaine must be activated by chemical decomposition orby microsomal oxidation via the hepatic cytochrome 9-E42 enymesystem to exert its cytotoxic e5ects. Several active metabolites canform including species capable of binding to '$% and free radicals.0esistance to procarbaine develops rapidly after exposure to the drug.

• 'acarbaine is a cell cycle-phase nonspecic antineoplastic drug that isbelieved to be an alylating agent. 'acarbaine is unlie conventionalalylating agents such as cyclophosphamide or chlorambucil. +t is usedin the treatment of metastatic malignant melanoma, osteogenic

sarcoma, soft-tissue sarcoma, and &odginCs disease. +t reJuiresactivation by the cytochrome 9-E42 system to its alylating form.

#$ echanism 2$ Clinical &$ 'oute $ Side eects


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#$ echanismo% Action

2$ Clinicalapplication

&$ 'oute $ Side eects

a. NitrogenMustards

A$"echlorethamine

'$% cross-lins, resultingin inhibition of'$% synthesisand function

&odgin?s and non-&odgin?s lymphoma

"ust begiven =rally

$ausea and vomiting,decrease in9< count, "depression, bleeding,alopecia, sinpigmentation,pulmonary brosis

*$

6yclophosphamide

Same as above reast, ovarian, 6


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Action application

b. AlkylSulfonates

A$ usulfan %typical alylating

agent.

6hronic granulocytic

leuemia

=rally e5ective one marrow

depression,pulmonary brosis,and hyperuricemia

c. Nitrosoureas #$ echanism o%Action

2$ Clinicalapplication

&$ 'oute $ Side eects

A$ 6armustine '$% damage, it cancross blood-brainbarrier

&odgins and non-&odgins lymphoma,brain tumors, G.+.

carcinoma

Given +.B. mustbe givenslowly.

one marrowdepression,6$S depression, renal

toxicity

*$


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%lylating %gents - Summary

•


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"etabolites and their%ntimetabolites

General 9roperties@"echanism!• %ntimetabolites resemble cellular metabolites and act tointerfere with '$% synthesis or the synthesis of '$%precursors.

• 7hese are classical cell cycle specic anti-cancer agents• "ost are prodrugs that must be activated throughincorporation into the normal biosynthetic pathways

• 7oxicities! only partially selective to tumor cell –toxic to all rapidly dividing normal cells

• one marrow and intestinal epithelium are particularlysensitive

•General 'rug classes!• %ntifolates

• %ntinucleotide analogs

•%ntimetabolites resemble cellular


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•%ntimetabolites resemble cellularmetabolites and act to interfere with '$%synthesis or the synthesis of '$%

precursors.

•%s with most antimetabolites,methotrexate is only partially selective fortumor cells and is toxic to all rapidlydividing normal cells, such as those of theintestinal epithelium and bone marrow.Nolate antagonists ill cells during the Sphase of the cell cycle and are moste5ective when cells are proliferatingrapidly.


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Methotre$ate# Amethopterin5rophoblastic choriocarcinoma, lymphoblastic leuemia,

1uritt3s

lymphoma•!lass4 8olate antagonist•Mechanism4 "ihydrofolate 9eductase inhibitor4 inhibits

d5MP synthesis- :ills in Sphase $G; and S 9#! and

protein synthesis)•To$icity4 bone marro2, G*, renal, alopecia, teratogen•&esistance4 increased


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/8luorouracil= /8> $'fude$)

(olorectal, breast, gastric, pancreatic colon cancers !;4/ decrease in

recurrence". sed topically #or premalignant skin lesions.•!lass4 Pyrimidine analog•Mechanism4 irreversible inhibition of thymidylate synthase $5S)-

*ncorporation into "#!


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•4 N is a prodrug that needs to betransported into the cell and activated

(metabolied) into the nucleotide pool. 7here are several parallel pathways toachieve this, but ultimately 4 N ismetabolied to Nd"9. Nd"9 is a substratefor thymidylate synthase, an enymeessential for the synthesis of thymidine (a'$% precursor). Nd"9 inhibits thymidylatesynthase and starves the cell for thymine,the so-called thymine less death.


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"ore nucleotide


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8)ercaptopurine< 8)P !Purinetol"Acute leukemias !9/ remission in cildren"1Class: Purine analogMechanism: @PRTase: @ypo&antine8guanineposporibosyltrans#erase makes te nucleosidepospate #rom te #ree base 8 inibition o# purine

syntesis< incorporation into RNADNA unclear. Eills inH8pase.1Toxicity: bone marrow$ nausea$ vomiting1Resistance: decreased @PRTase activity !needed to

incorporate 8)P into RNADNA"

'5hioguanine $5hioguanine)Same as 'MP

>sed against granulocytic +euemia2ith cytarabine

"ore nucleotideanalogsO

•3 "ercaptopurine is a purine prodrug that


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•3 "ercaptopurine is a purine prodrug that,once metabolied to the monophosphate, isan excellent feedbac inhibitor ofphosphoribosyl amidotransferase, the rstenyme in the purine de novo synthesispathway. /hile having antineoplastic activityof its own, probably its most important use isfor maintenance of remissions in %


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%ntimetabolites - Summary

•6lassical cell-cycle dependent agents

•0eJuire bioactivation

•6lasses•%ntifolates•%ntinucleotide analogs

•+nhibit enymes reJuired for '$%

synthesis• 7oxicities extend to tissues with higherrates of cellular turnover

alkylating and antimetabolites.ppt

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