Anti Cancer Final 14

8/20/2019 Anti Cancer Final 14

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Antineoplastic agents


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Overview

Introduction

Malignant disease accounts for a high proportion

of deaths in industrialised countries.

The treatment of anticancer drug is to give

palliation, induce remission and, if possible,

cure.


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Overview

Introduction Cancer occurs after normal cells have been

transformed into neoplastic cells through alteration oftheir genetic material and the abnormal expression ofcertain genes. Neoplastic cells usuall exhibitchromosomal abnormalities and the loss of their

differentiated properties. These changes lead touncontrolled cell division and man result in theinvasion of previousl unaffected organs, a processcalled metastasis.


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Advances in Cancer Chemotherap

Treatment options of cancer!

"urger! before #$%%

&adiotherap! #$%%'#$(%

Chemotherap! after #$(%Immunotherap and )ene therap


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Advances in Cancer ChemotherapThe treatment of a patient with cancerma aim to!

give palliation, for example prompt relief ofunpleasant smptoms such as superior vena cava

obstruction from a mediastinal tumorinduce *remission+ so that all macroscopic and

microscopic features of the cancer disappear,though disease is nown to persist

cure, for which all the cells of the clone mustbe destroed.


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Cancer Chemotherap

-isease Name % ears "urvival &ateChildhood Acute /mphoblastic /euemia %0'102Adult Acute /mphoblastic /euemia 30'(02Childhood Acute Meloblastic /euemia 30'(02Adult Acute Meloblastic /euemia #0'302

4reast Cancer（ 5remenopausal）

#0'3024reast Cancer（ 5ostmenopausal） 0'#%26odgin+ s lmphoma 7 80'102


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Cancer Chemotherap

-isease Name % ears "urvival &ate "mall Cell /ung Cancer （ /imited "tage） #0'302

（ 9xtensive "tage ） 0'%2Non:6odgin+ s lmphoma 7 80'(%2Ovarian Cancer 80'(02 Children "olid Tumor ;Nephroblastoma, &habdomosarcoma, /mphoma， Osteosarcoma） 7 (0'$02 Trophoblastoma （ Chorion 9pithelioma） 77 10'$02 "eminoma of Testis77 (0'$02 9mbronic Carcinoma of Testis (0'102

Note ： * Combination with other therapeutics **Chemotherapy Level of our country is high


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The Classification of Anticancer-rugs According to chemical structure andAccording to chemical structure and

resource of the drug


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The Classification of Anticancer

-rugs According to chemical structure andAccording to chemical structure andresource of the drug!!

Allating Agents,, Antimetabolite,,

Antibiotics, 5lant 9xtractsAntibiotics, 5lant 9xtracts 6ormones

Others.Others.


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-rugsAccording toAccording to biochemistr mechanisms ofanticancer action!

4loc4loc nucleic acid biosnthesis -irect influence

the structure and function ofthe structure and function of

-NA-NA Interfere transcription and bloc &NA snthesis

Interfere protein snthesis and function Influence hormone homeostasisOthers


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-rugs According to the ccle or phasespecificit of the drug!

Cell ccle nonspecific agents ;CCN"A=

Cell ccle specific agents ;CC"A=


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The 4asic Concept of

Cell )eneration Ccle

The ccle of cell replication includes!

M（ Mitosis） phase

)#（ )ap#, period before "） phase

"（ -NA snthesis） phase

)3（ )ap3,period after "） phase

)rowth >raction ;)>）


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)rowth >raction ;)>=

)>＝5roliferating cell group5roliferating cell group

Total tumor cell groupTotal tumor cell group

CCN"ACCN"A drugs that are activedrugs that are active

throughout the cell ccle.throughout the cell ccle.

CC"A!CC"A! drugs that act during a specificdrugs that act during a specific

phase of the cell ccle.phase of the cell ccle.


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CC"A and CCN"A Cell Ccle Nonspecific Agents ;CCN"A=

drugs that are active throughout the celldrugs that are active throughout the cell

ccle ccle

Allating Agents 5latinum Compounds

AntibioticsAntibiotics


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CC"A and CCN"A Cell Ccle "pecific Agents ;CC"A= drugs that act during a specific phase ofdrugs that act during a specific phase of

the cell ccle the cell ccle " 5hase "pecific -rug! Aantimetabolites, Topoisomerase Inhabitors M 5hase "pecific -rug!

?inca Alaloids, Taxanes )3 5hase "pecific -rug! 4bleomcin


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Mechanism of Anticancer -rugs4loc nucleic acid ;-NA, &NA= biosnthesis

-irectl destro -NA and inhibit -NA

reproduction

Interfere transcription and bloc &NA snthesisInterfere protein snthesis and function

Influence hormone homeostasis


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4loc Nucleic Acid ;-NA, &NA=4iosnthesis

Antimetabolites!

>olic Acid Antagonist! inhibit dihdrofolate reductase

;methotrexate=

5rimidine Antagonist! inhibit thmidlate snthetase

;fluorouracil= < inhibit -NA polmerase ;ctarabine=

5urine Antagonist! inhibit interconversion of purine

nucleotide ;mercaptopurine=&ibonucleoside -iphosphate &eductase Antagonist!

;hdroxurea=


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Interfere 5rotein "nthesis

Antitubulin! vinca alaloids and taxanes<

Interfere the function of ribosome! harringtonines；

Influence amino acid suppl! /:asparaginase

4ind tubulin, destro spindle to producemitotic arrest.


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Interfere Transcription and 4loc

&NA "nthesis4ind with -NA to bloc &NA production. doxorubicin


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Influence the "tructure and

>unction of -NAAllating Agent! mechlorethamine,cclophosphamide and thiotepa

5latinum! cis:platiniumAntibiotic! bleomcin and mitomcin C

Topoismerase inhibitor! camptothecine

andpodophllotoxin


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Influence 6ormone 6omeostasis

These drugs bind to hormone receptors to blocthe actions of the sex hormones which results in

inhibition of tumor growth.9strogens and estrogen antagonistic drugAndrogens and androgen antagonistic drug5rogestogen drug

)lucocorticoid druggonadotropin:releasing hormone inhibitor! leuprolide, goserelin

aromatase inhibitor! aminoglutethimide,anastra@ole


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Anticancer -rugs

Allating AgentAntimetaboliteAntibiotics

Alaloid

6ormonesOthers（cis:platinum carboplatin， lobaplatin）


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Allating AgentsOne of the frightening developments of orld

ar I was the introduction of chemical

warfare. These compounds were nown as the

nitrogen mustard gases. The nitrogen mustards

were observed to inhibit cell growth, especiall

of bone marrow. "hortl after the war, these

compounds were investigated and shown to

inhibit the growth of cancer cells.


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Allating Agents

Mechanism of Action

Nitrogen mustards inhibit cell reproduction b

binding irreversibl with the nucleic acids ;-NA=.The specific tpe of chemical bonding involved is

allation . After allation, -NA is unable to

replicate and therefore can no longer snthesi@e

proteins and other essential cell metabolites.ConseBuentl, cell reproduction is inhibited and

the cell eventuall dies from the inabilit to

maintain its metabolic functions.


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Classification of Allating Agents 4is Chloroethl Amines： Cclophosphamide, Chlormethine, Chlorambucil,

"arcolsine Nithrosoureas： Carmustine， /omustine 9theneammonium or A@iridines： Thiotepa， triethlene melamine Alsulfonates： 4usulfan


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&esistance of Allating Agents &esistance to allating agents has severalcauses!

Membrane transport ma be decreased. The drug ma be bound b glutathione ;)"6=via )"6:":transferase or metallothioneins in

the ctoplasm and inactivated. The drug ma be metaboli@ed to inactivespecies.


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Adverse 9ffects of Allating AgentsMelosuppression is the dose:limitingadverse effect for allating agents.

Nausea and vomiting are common as areteratogenesis and gonadal atroph,although in the latter cases these are

variable, according to the drug, itsschedule, and route of administration.

Treatment also carries a maor ris of

leuemogenesis and carcinogenesis.


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Allating AgentsDDMustineMustine must be inected intravenouslbecause it is highl reactive. Itdisappears ver rapidl from the blood,the activit of Mustine lasts onl a fewminutes.The main indication for Mustine is intreatment of 6odgins disease and

lmphomas, but it ma also be useful inother malignancies.


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Allating AgentsDD

CclophosphamideCclophosphamide can also be given orall.Indications：

It is used in the treatment of chronic lmphoccticleuemia, non:6odgin+s lmphomas, breast andovarian cancer, and a variet of other cancers.

It is also a potent immunosuppressant, it is used inthe management of rheumatoid disorders and

autoimmune nephritis.Adverse 9ffects! Alopecia, nausea, vomiting, melosuppression, and

hemorrhagic cstitis.


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Allating AgentsDDNitrosoureasCarmustine, /omustine, "emustine

5harmacoinetics!

Nitrosoureas are highl lipophilic andreach cerebrospinal fluid concentrationsthat are about E02 of plasmaconcentrations.

Indications!4ecause of their excellent CN"penetration, carmustine and lomustine have

been used to treat brain tumors.


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Allating AgentsDD

5henlalanine Nitrogen MustardMelphalan is a nitrogen mustard that isprimaril used to treat multiple meloma

;plasma cell meloma=, breast cancer, and

ovarian cancer.


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Allating AgentsDD Alsulfonates

4usulfan FMleranG Indications!

4usulfan is administered orall to treat chroicgranuloctic leuemia and other meloproliferativedisorders.

Adverse 9ffects!4usulfan produces advers effects related to

melosuppression. It onl occasionall producesnausea and vomitting. In high doses, it producesa rare but sometimes fatal pulmonar fibrosis,Hbusulfan lungH.


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Allating AgentsDDThiotepa Thiotepa is converted rapidl b livermixed:function oxidases to its active

metabolite triethlenephosphoramide

;T95A=< it is active in bladder cancer.


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Antimetabolites

)eneral Characteristics

Antimetabolites are " phase:specific

drugs that are structural analogues of

essential metabolites and that interfere

with -NA snthesis.Melosuppression is the dose:limiting

toxicit for all drugs in this class.


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Classification of Antimetabolites >olic acid Antagonists! MT

5urine Antagonists! (M5 (T) 5rimidine Antagonists： %>J

araC

6J


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AntimetabolitesDD>olic Acid Antagonist

Methotrexate （ MT ）

Mechanism of Action：

The structures of MT and folic acid aresimilar. MT is activel transported into

mammalian cells and inhibits dihdrofolate

reductase, the en@me that normall convertsdietar folate to the tetrahdrofolate form

reBuired for thmidine and purine snthesis.


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AntimetabolitesDD>olic Acid AntagonistMethotrexate （ MT ）Indications：

The use of MT in the treatment of

choriocarinoma, a trophoblastic tumor, was thefirst demonstration of curative chemotherap.

It is especiall effective for treating acute

lmphoctic leuemia and for treating the

meningeal metastases of a wide range oftumors.


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AntimetabolitesDD>olic Acid Antagonist

Methotrexate （ MT ）Adverse 9ffects：

MT is melosuppressive, producing severeleuopenia, bone marrow aplasia, andthromboctopenia.

This agent ma produce severe gastrointestinal

disturbances. &enal toxicit ma occur because of precipitation

;crstalluria= of the K:O6 metabolite of MT.


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AntimetabolitesDD

5urine Antagonists(:Mercapapurine （ (:M5 ） The drugs are believed to act similarl to inhibit

purine base snthesis, although their exact

mechanisms of action are still uncertain.Indications!Mercaptopurine is used primaril for the maintenance

of remission in patients with acute lmphocticleuemia and is given in combination with MT forthis purpose.

Adverse 9ffects!ell tolerate.Melosuppression is generall mild with

thioguanine./ong:term mercaptopurine use ma causehepatotoxicit.


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AntimetabolitesDD

5rimidine Antagonists

%:>luorouracil ;%:>J= Mechanism of Action：

>luorouracil is an analogue of thmine in which the

methl group is replaced b a fluorine atom. It has

two active metabolites! %:>dJM5 and %:>dJT5. %:

>dJM5 inhibits thmidlate snthetases and preventsthe snthesis of thmidine, a maor building bloc of

-NA. %:>dJT5 is incorporated into &NA b &NA

polmerase and interferes with &NA function.


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AntimetabolitesDD5rimidine Antagonists%:>luorouracil ;%:>J= Indications：

>luorouracil is exclusivel used to treat

solid tumors, especiall breast,colorectal, and gastric tumors and

sBuamous cell tumors of the head and

nec.


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AntimetabolitesDD

5rimidine Antagonists%:>luorouracil ;%:>J= Adverse 9ffects：>luorouracil ma cause nausea and vomiting,

melosuppression, and oral and gastrointestinalulceration. Nausea and vomitting are usuallmild.

ith fluorouracil, melosuppression is more

problematic after bolus inections, whereasmucosal damage is dose:limiting with continuousinfusions.


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AntimetabolitesDD

5rimidine Antagonists

Ctarabine Indications：

Ctarabine has a narrow clinical spectrum and isprimaril used in combination with daunorubicin orthioguanine for the treatment of acute nonlmphocticleuemia.

Adverse 9ffects!6igh doses of ctarabine can damage the liver, heart,and other organs.


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Classification of Antibiotics!Adriamcin ;Anthracaline Antibiotics=

Mitomcin C

4leomcin

Actinomcin -


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Adriamcin and -aunorubicin ：5roperties!

Adriamcin and -aunorubicin are tetraccline rings withthe sugar daunosamine. The are -NA intercalatingagents that bloc the snthesis of -NA and &NA.

These agents are primaril toxic during the " phase of

cell ccle.These agents imparts a red tinge to the urine.Adramcin is used to treat acute leuemias, lmphoma,

and a number of solid tumors.


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Mitomcin C!Mechanism!Mitomcin C is an antineoplastic antibiotic that

allates -NA and thereb causes strandbreaage and inhibition of -NA snthesis.

Indications!It is primaril used in combination with vinvristine

as salvage therap for breast cancer.Adverse 9ffects!Mitomcin produces delas and prolonged

melosuppression that preferentiall affectsplatelets and leuoctes.


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Actinomcin -!Actinomcin - intercalates -NA and thereb

prevents -NA transcription and messenger &NAsnthesis.

The drug is given intravenousl, and its clinicaluse is limited to the treatment of trophoblastic;gestational= tumors and the treatment of

pediatric tumors, such as ilms+ tumor and9wing+s sarcoma.


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4leomcin!Mechanism!The drug has its greatest effect on neoplastic cell in

the )3 phase of the cell replication ccle.Althoughbleomcin intercalates -NA, the maor ctotoxicit isbelieved to result from ironcatal@ed free radicalformation and -NA strand breaage.

Indications!It is useful in 6odgin+s and non:6odgin+s lmphomas,

testicular cancer, and several other solid tumors.Adverse 9ffects!4leomcin produces ver little melosuppression. The

most serious toxicities of 4leomcin are pulmonar andmucocutaneous reactions.


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Anti:Cancer 5lant AllaloidsTubulin:4inding Agents

?inca Alaloids! The cellular mechanism of

action of vinca alaloids is the prevention of

microtubule assembl, causing cells to arrest in

the late )3 phase b preventing formation of

mitotic filaments for nuclear and cell division.


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Anti:Cancer 5lant Allaloids

Tubulin:4inding Agents?inca alaloids!

?inblastine,vincristin, vindesine and vinorelbine are all alaloids derived

from the periwinle plant ;?inca rosea=.Indications!

?inblastine is used in combination with 4leomcin and Cisplatinfor metastatic testicular tumors.

?incristine is used in combination with prednisone to induceremission in childhood leuemia.

?inorelbine is used to treat non:small:cell lung cancer andbreast cancer.


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Anti:Cancer 5lant AllaloidsTubulin:4inding Agents5aclitaxel!

Taxanes enhance all aspects of tubulinpolmeri@ation, an action that is the opposite tothat of vinca alaloids, but the are alsoctotoxic, emphasi@ing the dnamic importance of

tubulin polmeri@ation as a target for ctotoxicdrugs.

5aclitaxel, Taxotere


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Anti:Cancer 5lant Allaloids

Interfere the >unction of &ibosome!

Cephalotaxus Alaloids ! 6arringtonine

6omoharringtonine


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5latinum CompoundCisplatin!Mechanism of Action!

Cisplatin binds to guanine in -NA and

&NA, and the interaction is stabili@ed bhdrogen bonding. The molecular

mechanism of action is unwinding and

shortening of the -NA helix.


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5latinum CompoundCisplatin!Indications!Cisplatin has efficac against a wide range of

neoplasms. It is given intravenousl as a first:line drug for testicular, ovarian, and bladdercancer, and it is also useful in the treatment ofmelanoma and a number of other soild tumors.

Adverse 9ffect!Cisplatin produces relativel little

melosuppression but can cause severe nausea,vomiting, and nephrotoxicit.


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5latinum CompoundCarboplatin!Indication!Carboplatin has a similar spectrum of

activit, but it is approved onl as asecond:line drug for ovarian cancer.


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6ormones"everal tpes of hormone:dependent cancer;especiall breast, prostate, and endometrialcancer= respond to treatment with theircorresponding hormone antagonists.

9strogen antagonists are primaril used in thetreatment of breast cancer, whereas androgenantagonists are used in the treatment ofprostate cancer. Corticosteroids are particularluseful in treating lmphoctic leuemias andlmphomas.


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6ormones9strogens!9strogens inhibit the effects of endogenous

androgens and androgen:dependent metastatic

prostatic carcinoma. -iethlstilbestrol is usuallthe agent of choice.

Cardiac and cerebrovascular complications and

carcinoma of the male breast are potentialadverse effects.


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6ormones5rogenstins!5rogestins are useful in the management of

endometrial carcinoma and bac:up therap for

metastatic hormone:dependent breast cancer.


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6ormonesAntiestrogen! Tamoxifen Tamoxifen is the drug of choice in

postmenopausal women with or recovering frommetastatic breast cancer. It is most effective

in patients who have estrogen receptor:positivetumors.

Tamoxifen is also used as adunvctive therap tooophorectom to leuprolide or goserelin in

premenopausal women with estrogen receptor:positive tumors.


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6ormonesAndrogens!Androgen activit in breast cancer is similar to

that of estrogens, perhaps for the samemechanistic reasons.

?irili@ing effects and hepatic toxicit maethem unacceptable to most patients.

>luoxmesterone is the most widel used agent.-ana@ol has use in hematolog in aplastic anemia

and congenital anemias.


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6ormones)lucocorticoids!The are integral components of curative

therap for acute lmphoblastic leuemia, non:6odgin+s lmphoma, and 6odgin+s disease.

)lucocorticoids have essential roles in theprevention of allergic reaction, emesis control,relief of intracranial hpertension or spinal cordcompression in neurologic complications, and painrelief.


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5roblems ith Cancer

Chemotherap -rug &esistance

-rug Toxicit


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-rug &esistance

-e novo &esistance

AcBuired &esistanceMultidrug &esistance ;M-&=


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-rug &esistance

-e novo resistance!-e novo resistance can be de novo genetic ;i.e.

the cells are initiall inherentl resistant=, or

can arise because drugs are unable to reach thetarget cells because of permeabilit barriers

such as the blood:brain barrier.


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-rug &esistance

AcBuired &esistance!AcBuired drug resistance ma result from

genomic mutations, such as the induction ordeletion of en@mes involved in drug inactivation

or drug activation, respectivel.


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-rug &esistanceMultidrug &esistance ;M-&=!5:glcoprotein transports man naturall

occurring drugs out of neoplastic cells, and its

induction ma lead to multidrug resistance.

As scientific understanding of the mechanisms

of drug resistance increases, new treatments

ma be developed to counteract resistance.


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-rug Toxicit

The most common toxicities of antineoplastic

drugs result from inhibition of cell replication in

the bone marrow, gastrointestinal epithelium, and

hair follicles. Man antineoplastic drugs also

stimulate the chemoreceptor trigger @one in the

medulla and thereb elicit nausea and vomiting.


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Immunomodulating -rugs

Immunosuppressive Agents!

Act to suppress immune mechanisms and are usedto treat autoimmune diseases or to prevent graft

reection following tissue transplantation.

Ciclosporin, Tacrolimus, adrenocortical hormones,antimetabolites, allating agent, antilmphocte

globulin, Mcophenolate Mofetil


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Immunomodulating -rugsImmunopotentiator :9nhance antitumor immunit and are used to

treat neoplastic disease.

&ecombinant Interferons and Ctoines.

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Anti Cancer Final 14

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