Lecture4&5.Cancer.chemotherapy

8/13/2019 Lecture4&5.Cancer.chemotherapy

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Neoplasia : New growth

uncontrolled proliferation / multiplication of cells

Cancer Characteristics :

growthnot subjected to normal restriction of

that tissue

defective differentiation

local invasiveness

metastasis


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Different approaches to treat Cancer

Surgery

Radiotherapy

Chemotherapy

Endocrinal therapy

Immunotherapy- immunostimulantscan behelpful in eradicating residual cancer cells after

chemotherapy


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Novel approaches for Cancer

chemotherapy

Manipulation of immune system

STIMULATE IMMUNITY AGAINSTPARTICULAR CELLS

Induction of differentiation CANCER CELLS LOSE DIFFERENTIATION

Anti-angiogenesis:cutting off blood supply

CA CELLS HAVE THEIR OWN COLLATERALBLOOD SUPPLY

Gene Therapy(UPCOMING FIELD)

Biologic response modifiers


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Principles of cancer chemotherapy

Log-kill hypothesis Cytotoxic actions of anti-cancer drugs follow first-

order kinetics

Means cytotoxic drugs kill constant fraction(not afixed number of cells) (log kill effect)of cells(rationale for drug combination)

Drugs are relatively selectively toxic to the cancercells

Cytotoxicity is proportional to total drug exposure


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Principles of cancer chemotherapy

Growth fraction

Cytotoxic drugs are more effective againsttumors that have a high growth fraction

(large percentage actively dividing)

Normal cells with high growth fraction

(e.g., bone marrow, GI cells, hair follicles)are also more sensitive to anticancer drugs


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Main mechanisms of Anti-cancer drugs

Damage the DNA of the affected cancer cellsapoptosis

Inhibit the synthesis of new DNAinhibition ofincorporation of purine or pyramidine

nucleotides

Inhibit mitosis,CAUSE METAPHASEARREST


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Anti-Cancer Drugs

Different Groups of anti-cancer Drugs:

Alkylating agents

Antimetabolites Microtubule inhibitors

Topoisomerase Inhibitors

Cytotoxic Antibiotics Hormones

Monoclonal antibodies


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Mechanisms ofanti-cancer drugs

**** ACT BY INIHBITING MITOSIS

SO MORE ACTIVE IN THE M PHASE.


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Cell cycle**

All cells (normal and cancer cells) go

through growth cycle which can be divided

into 4 cycling phases named, G1, S, G2and

M. Cells which are in the resting phase are

said to be in phase G0

DNA synthesis takes place in S Phase.


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**Cell cycle specific drugs (CCS)

Cell cycle specificanticancer drugs act on

tumor stem cells only when they are

traversing the cell cycle(replicating cells)

e.g.,

Anti-metabolites (METHOTREXATE)

Vinca alkaloids(VINCRISTINE)Taxanes

Bleomycin


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**Cell cycle non-specific drugs

(CCNS)Cell cycle non-specificanticancer drugs act on

dividing as well as resting tumor cells.

However, they exhibit most activity in rapidly

replicating cells

e.g.,

Alkylating agents

Platinum analogs

Antibiotics


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Mechanisms of drug resistance

Abnormal transport P-glycoprotein dependent efflux, THROWS OUT ALL

DRUGS THAT ENTERS CANCER CELLS

Increased cellular inactivation

Enhanced DNA repair Altered target protein

Decreased cellular retention

Chances of resistance can be decreased by

short term but intensive intermittent therapywith combination of different drugs


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Benefits of combination

chemotherapy

Increases maximum cell kill and decreasestoxicity

Kills cells in tumors with heterogeneous cellpopulations

Reduces the chances of development ofresistant clones***


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Side effects of cancer

chemotherapyCytotoxic effects result mainly from inhibition ofcell replication in tissues which have a high cellturnover rate

Bone marrow

Gastrointestinal epithelium

Hair follicle

Gametogenesis in gonads (INFERTILITY)


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Toxicity of cancer chemotherapy

Bone marrow*** Myelosuppression: results ingranulocytopenia,

lymphocytopenia,

thrombocytopenia and anemia

Gastrointestinal

epithelium (MOUTH TO ANUS)

Mucositis, Diarrhea, bleeding,

Emesis (Cisplatin)

Hair follicle Alopecia

Gametogenesis in

gonads

Infertility

Secondary malignancies

-drug can acutally create

cancer!

Leukemia (alkylating agents)

-it creates an onocogenic gene

and cause leukemia

Infections Opportunistic infections


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Tumor lysis syndrome

Increased uric acid productionGout

***Role of Allopurinol

Doses of chemotherapeutic agents which are

metabolized by Xanthine oxidase (eg, 6-Mercaptopurine)should be decreased while

giving Allopurinol


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Anti-cancer drugs


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Anti-Cancer Drugs

Different Groups of Anti-cancer Drugs:

Alkylating agents

Antimetabolites Microtubule inhibitors

Topoisomerase inhibitors

Cytotoxic Antibiotics

Hormones

Monoclonal antibodies


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Alkylating agents


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Alkylating agents:

They areCell cycle non-specific drugs(CCNS)

**Nitrogen

mustards

Nitrosoureas

(for brain

tumors)

Others

Cyclophosphamide

Mechlorethamine

ChlorambucilMelphalan

Carmustine

Lomustine

Busulfan

Cisplatin

ProcarbazineDacarbazine


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ALKYLATING AGENTS

Mechanism of action They undergo intramolecular cyclization to

form either an ethyleneimoniumor a

carboniumion which are strongly electrophilic

These intermediates can alkylate (transfer ofalkyl groups) various cellular constituents byformation of covalent bondswith nucleophilegroups***


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ALKYLATING AGENTS

Mechanism of action

The position N7of guanineresidues in DNA issusceptible

Alkylation results in cross linking/abnormal base pairing / scission of DNAstrand.

Alkylation of guanine of a single strand of theDNA molecule results in miscoding.


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ALKYLATING AGENTS :

Mechanism of action

Alkylation of guanine of both strands of theDNA molecule results in cross-linking----

Cytotoxic action. CAUSES DNADAMAGE!!


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ALKYLATING AGENTS :

Directly damage the DNA

***Active against proliferating and non-proliferating cells(CCNS); however, proliferatingcells are more sensitive to the drug,

Dose limiting Myelosuppression

***Genotoxic and increase risk of leukemia


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Alkylating agents: Resistance

Resistance occurs due to

decreased permeability of the drug

increased conjugation with thiols suchas glutathione , and

increased DNA repair


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Mechlorethamine

Administration:given IV because of itsvesicant activity (blistering agent)

Extravasationmay cause tissue necrosisand sloughing

**Clinical uses : Hodgkins disease

(MOPP regimen)

C l h h id /


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Cyclophosphamide /Ifosfamide

- Cyclophisphamide:most commonly usedalkylating agent

Mode of action:

***It is a prodrug-convert to the activemetabolite by hepatic mixed function oxidase

Pharmacokinetics:

- preferred orally- does not have vesicant effects- cytotoxic metabolite is acrolein


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Cyclophosphamide /


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Toxicity :- causes hemorrhagic cystitis*** (due toacrolein)

This can be decreased by adequatehydration as well as by the use of

MESNA***(2- mercaptoethane sulfonate)

Ifosfamide has a less potential to causehemorrhagic cystitis

Cyclophosphamide /


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Clinical uses : Cancer of breast, Ovary, CLL and Non-

Hodgkins lymphoma (CHOP regimen)

As Immunosuppressant in autoimmuneconditions (e.g. SLE)


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Melphalan

Can be given orally

***Therapeutic Use:

multiple myeloma

***Side effects:

Bone marrow suppression, Pancreatitis


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Chlorambucil

***Therapeutic Uses:

CLL- Chronic Lymphocytic Leukemia(agent of choice)

Produces less severe BMSthan othernitrogen mustards


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Nitrosoureas

***Carmustine & Lomustine :

highly lipophilic; easily enter the brain,SO PRIMARILY USED FOR BRAIN TUMORS

- LIMITED USE IN THE TREATMENT OFOTHER CANCERS.


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Nitrosoureas

Carmustine : Toxicity :

Aplastic anemia on prolonged use,

hepatitis(carmustine)

**Clinical uses :

Brain tumors***

R/A:Carmustine (IV)

Lomustine (Oral)


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Procarbazine, Dacarbazine

They are converted to active intermediatesthat can alkylate DNA.

Clinical uses:

Hodgkins disease CURRENT REGIMEN: ***ABVD

(Adriamycin=Doxobubicin, Bleomycin,Vinblastine, Dacarbazine )

MOPP (Procarbazine)old regimen

Malignant Melanoma


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Temozolamide


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Temozolamide Related to Dacarbazine

Differences are:

Temezolamide can cross BBB, but Dacarbazine cannot

Temezolamide given orally, whereas DacarbazineIV

approved recently for brain tumors(treatment-resistant gliomas, anaplastic astrocytomas)

also has the property of inhibiting the repair enzyme therefore less chance of resistance

Adv effects:Nausea and vomiting, myelosuppression


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Cisplatin

a small platinum coordination complex

Mechanism of Action

- inhibits DNA synthesis by formation ofboth, interstrand and intrastrand**cross-links(adjacent guanines are mostfrequently crosslinked)


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Cisplatin

***Adverse effects :

*Nephrotoxicity (ameliorated byhydration and diuresis)(antidote:

amifostine) Strong emetic effect (use Ondansetron)

Neurotoxicity (deafness)

***Therapeutic Uses :

testis, ovary,bladder and lung cancer


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Carboplatin

Similar but less severe toxicities than

cisplatin

Also causes myelosuppression (dose-

limiting)


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Anti-metabolites

Folate analogs

Purine analogsPyrimidine analogs

A ti t b lit


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Antimetabolites:

They are cell cycle specific (CCS) agents. They are

structural analogs of essential cellular metabolites

(folic acid, purine & pyrimidine bases)and

competitively inhibit the essential enzymes

involved in DNA synthesis.

Folateanalogs

Purine analogs Pyrimidineanalogs and

others

Methotrexate 6- Mercaptopurine

6- Thioguanine

Fludarabine

Cladribine

5-Fluorouracil

Cytarabine

Gemcitabine

Capecitabine


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Anti-metabolites

Mechanism of action

They are structural analogues of folic acid

/ purine / pyrimidine bases found in DNA

act as anti-metabolites to inhibit enzymes

required for DNA synthesis.


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Anti-metabolites

M imic cellular essential metabolites

* * Active against prol iferating cells * (S phase

specific)

Myelosuppressionis the dose-limiting toxicityfor all drugs in this class.

Teratogenicbut not leukemogenic* * *(not

genotoxic)


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Anti-metabolites

All are CCS agents.

All need to be activated before they can act

Some are used as immunosuppressants:

-in autoimmune diseases, organ

transplantation


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Folate analogs

Methotrexate

Methotrexate


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Methotrexate

structurally related to folic acid


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M th t t


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Methotrexate

Mode of action : inhibits dihydrofolate reductase

leading to inhibition of tetrahydrofolate

(THF) synthesis

Deficiency of THF causes inhibition of one-carbon transferreactions required for the

synthesis of deoxynucleotides &ribonucleotides; leading to depressed DNA,RNA, and protein synthesis and ultimatelycell death.


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***Methylene tetrahydrofoate is


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***Methylene- tetrahydrofoate is

required for:

Purine synthesis (for RNA & DNA synthesis)

Conversion of dUMP to dTMP (for DNA

synthesis)

Synthesis of methionine, serine


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Methotrexate

- can be given Orally, IV, IM and

Intrathecally.

- does not enter the brain (has to be given

intrathecally to get to CNS)

Therapeutic Uses :

ALL, Choriocarcinoma***, Burkittslymphoma in children, breast cancerRheumatoid arthritis, Psoriasis

M th t t


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MethotrexateToxicity :

Most common:

Bone marrow suppression (BMS)

Mucositis, Stomatitis

Alopecia

Leucovorin rescue:BMS can be reduced byadministration of folinic acid(Leucovorin / N5

formyl THF / Citrovorum factor)which by-passthe dihydrofolate reductase step intetrahydrofolate synthesis. This agent can rescuehost cells but not cancer cells. Dose of leucovorinmust be kept minimal to avoid

possible interference with the antitumor action of MTX

M th t t


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Methotrexate

Toxicity :

Renal damage (Crystalluria): Alkalinization of

the urine and hydration prevent this problem


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Purine analogs

6-Mercaptopurine

6-Thioguanine

Fludarabine

Cladribine


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Purine analogs

6-Mercaptopurine and 6-Thioguanine

* * *Mercaptopur ine,analog of adenine,inhibits the biosynthesis of purinenucleotides.

* * *Thioguanineis an anti-metabolite in thesynthesis of guanine nucleotides.


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Purine analogs


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Purine analogs

Purine analogs : Anti-metabolites

M/A

6-Mercaptopurine and 6-Thioguanine aremetabolized by hypoxanthine-guanine

phosphoribosyltransferase***(HGPRT)to toxic nucleotides, thio-IMP and then tothio-GMP.

thio-IMP and thio-GMP inhibit enzymesinvolved in purine nucleotideinterconversion

Purine analogs


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Purine analogs

Purine analogs : Anti-metabolites

M/A

Thio-GMP, after phosphorylation to di-

and triphosphates can be incorporatedinto DNA, resulting in non-functional RNAand DNA synthesis


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Resistance: 6 MP

Generally due to deficiency in tumor

cells of HGPRT (for example, in Lesch-

Nyhan Syndrome, in which patients

lack this enzyme) Increased dephosphorylation (th io-IMP is

phosphory lated to work as inhib i tor), or

Increased metabolism of the drug tothiouric acid or other metabolites


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Purine analogs

6-Mercaptopurine:

***6-MP is metabolized by xanthine oxidase toinactive metabolites.

***Simultaneous therapy with Allopurinol and 6-MPresults in excessive toxicity unless the dose of 6-MP isreduced to 25%

(***Not with 6-TG because as it is not metabolized byxanthine oxidase. 6-TG is metabolized by S-methylation).


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Purine analogs

Clinical uses of Purine analogs :

6-Mercaptopurine :ALL

6-Thioguanine :AML


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Purine analogs

Fludarabine (Fluoro-adenine arabinoside ) Interferes with DNA synthesis and induces

cellular apoptosis

***Used in CLLand non-Hodgkins lymphoma

Given IV

Main adverse effect:myelosuppression

Cladribine(Chlordeoxyadenosine)

***Used in hairy cell leukemiaand CLL


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Pyrimidine analog

5-Fluorouracil

Pyrimidine analog


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Pyrimidine analog

5-Fluorouracil: a thymidine antimetabolite.

5-Fluorouracil is converted into FdUMP which

inhibits thymidylate synthaseandleads tothymine less death of cell.So no DNA synthesis,because thymine is required for synthesis.

The failure to synthesize the thymidinenucleotide results in little or no production ofDNA.


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Pyrimidine analog


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Pyrimidine analog

5- FU administered IV or topically

* * *Leucovorin is administered with 5-FU

to enhance its effect. (by allowingthymidylate synthase to work)

* * *Uses :

Breast, colorectal, ovarian, pancreaticand gastric carcinomas

***Basal cell carcinoma of skin(topically).

Pyrimidine analog


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Pyrimidine analog

5- FU: Adverse effects GI symptoms: Nausea, vomiting, diarrhea, severe

ulceration of oral and GI mucosa

BMS

O h i b li


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Other anti-metabolites

Cytarabine(Cytosine arabinosideara C) is

phosphorylated to ara CTP that inhibits DNA

polymerase and also causes DNA strandbreakage.

***Cytarabine use is limited toAML *.


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Gemcitabine :

Inhibits DNA synthesis via chain

termination

Uses

***adenocarcinoma of pancreas

non-small cell lung cancer and bladder

carcinoma.

Oth ti t b lit


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Capecitabine :

Converted to 5-FU

Inhibits thymidylate synthetase

***Used for:

metastatic breast * and metastatic

colorectal cancer Common adverse effects:Dermatitis and

myelosuppression


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Anti-mitotic Drugs

Vinca alkaloids

Taxanes


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Antimitotic Drugs

(CCS drugs)

Vinca alkaloids

They Inhibit tubulin

polymerization

Taxanes

They promote assembly

of microtubules(tubulin

polymerization)&prevent microtubule

disassembly(PROMOTE

ASSEMBLY)

Vincristine

Vinblastine

Paclitaxel

Docetaxel


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Antimitotic Drugs


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Antimitotic Drugs

All are CCS agents.

All act on the ***M phaseof the cell cycle.

Mechanism of action

They inhibit Mitotic spindle formation thatis essential for equal partitioning of DNA

into two daughter cells.metaphase arrest


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A ti it ti D


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Antimitotic Drugs

Drug toxicity:

Cytotoxic effectsmainly on bone marrow,

gastrointestinal epithelium and the hairfollicle.

Emetic effectsdue to stimulation of CTZ.

Vinca alkaloids: Vincristine,


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Vinca alkaloids:Vincristine,Vinblastine

Obtained from Periwinkle plants

Mechanism of action :

- they inhibit tubulin polymerization,preventmicrotubule assembly and henceinhibit the formation of mitotic spindle

- Resistance is often accounted for P-glycoproteinthat transports drugs out ofcells


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Vinca alkaloids: Vincristine,


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Vinca alkaloids:Vincristine,Vinblastine

***Toxicity : Vincristine:peripheral

neuropathy(neurotoxicity)and

SIADH

Vinblastinecauses myelosuppression.

Vinca alkaloids:Uses


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Vinca alkaloids:Uses

Vincristine:(aka ONCOVIN)

Hodgkins disease (MOPP regimen), Non-

Hodgkins Lymphoma (CHOP regimen),ALL and Wilms tumor

Vinblastine :

Hodgkin's lymphoma (ABVD regimen)

and testicular cancer (PVB regimen)

T P lit l d D t l


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Taxanes:Paclitaxeland Docetaxel

They prevent microtubule disassembly & promotetubulin polymerization

***Toxicity :

- Neutropenia is dose limiting.Treat NEUTROPENIA with G-CSF (Filgrastim).

-Peripheral neuropathy

-Hypersensitivity reactions(esp Paclitaxel):Premedicate the patients with Dexamethasone,Diphenhydramine and H2blockers

- Docetaxel contraindiacted in patients with heartdiseases as it causes fluid retention

T P lit l d D t l


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Taxanes:Paclitaxeland Docetaxel

Clinical uses :

Advanced breast, lung and Ovarian cancer

Resistance :

- associated with expression of P-glycoprotein

(efflux)


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Topoisomerase Inhibitors


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Topoisomerse inhibitors


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pTopotecan is a camptothecin analogue

Etoposide is a podophyllin analogue.

Mechanism of action

DNA topoisomerases are enzymes that relieve thetorsional strain caused by the unwinding of the DNAduring the replication.

Topoisomerase I breaks and reseals single- DNA

strands, whereas topoisomerase II breaks and resealsboth strands of DNA.


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Topotecaninhibits topoisomerase I

Etoposide inhibits topoisomerase II

In this way, both prevent the resealing ofnicked strands of DNA.

The final result is accumulation of DNAbreaks and cell death.

They act mainly in the S and G2phases ofthe cell cycle***



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Topoisomerse inhibitorsEtoposideand Topotecan Both can cross the blood brain barrier.

Toxicity

Myelosuppression and alopecia

Uses

Topotecan is used for metastatic ovarian cancer

*,lung and colon cancer. ***Etoposide is used for testicular *,lymphoma

and lung cancers

T i id ALL

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Lecture4&5.Cancer.chemotherapy