Sss.35. Farmakologi Anti Cancer Drug

8/12/2019 Sss.35. Farmakologi Anti Cancer Drug

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Dr. Datten Bangun MSc,SpFK

Dept. Farmakologi dan Terapeutik, Fakultas Kedokteran

Universitas HKBP Nomensen

ANTI CANCER DRUGS



SITOSTATIKACYTOSTATICS

INTRODUCTION :

Cyto : CellsStatic : statisSynonim : - Cancer chemotherapy

- Cytotoxics- Antineoplastics



The cell cycle 2 key events :I. S phase : Synthesis of DNA

II. M phase : Division of parent cell intotwo daughter cells duringmitosis.

G1 (gap) : Synthesis of cellularcomponents needed for

DNA synthesis.G 2 : Synthesis of cellular

components for mitosis



IMPORTANCE OF CELL CYCLE KINETICSBased on informations of cell cycle cytotoxicdrugs are devided into two classes.

1. Cell cycle - specific agents = CCS - agentsCCS drugs most effective in :

- Haematologic malignancies

- Solid tumors which are proliferatingor are in growth fraction.2. Cell cycle- Nonspecific agents=CCNS -agents

CCNS drugs are useful in :- Low growth fraction solid tumorsNote : Growth fraction = the ratio of the number of

cells that are proliferating to the total numberof cells in the tumor.



General principles in the use: cytostatics interfere with several different stages

of the cell cycle and so open the way to therational use of drug combinations .

Cycle non-specific drugs act at all stages inthe proliferating cell cycle(but not in the G 0 resting phase)

Phase-specific drugs act only at a specific phase :the more rapid the cell turnover the more effectivethey are.



CANCER CHEMOTHERAPY A. Concepts

1. Cell cycle kinetics : Cell cycle-specific (CGS) drugsact on tumor cells during the mitotic cycle and areusually phase specific. Most anticancer drugs are cellcycle-nonspecific (CCNS), killing tumor cells in both

resting and cycling phases.2. Log kill : Antitumor drug treatment kills a fixedproportion of a cancer cell population rather than aconstant number of cells. A 3-log-kill dose of a drug

reduces cancer cell numbers by three orders ofmagnitude.

3. Resistance : Established mechanisms of tumor cellresistance to anticancer drugs.

4. Toxicities : Drug-specific toxicities.



DNA synthesis

Antimetabolites

DNA

DNA transcription DNA duplication

Mitosis

Alkylating agents

Spindle poisons

Intercalating agentsCellular level

Principles of chemotherapy

Action sites of cytotoxic agents



6-MERCAPTOPUR

INE

6-THIOGUANINE

METHOTREXATE

5-FLUOROURACIL

HYDROXYUREA

CYTARABINE

PURINE SYNTHESIS PYRIMIDINE SYNTHESIS

RIBONUCLEOTIDES

DEOXYRIBONUCLEOTIDES

DNA

RNA

PROTEINS

MICROTUBULESENZYMES

L-ASPARAGINASE

VINCA ALKALOIDS

TAXOIDS

ALKYLATING AGENTS

ANTIBIOTICS

ETOPOSIDE

Principles of chemotherapy Action sites

of cytotoxic agents



CYTOTOXIC DRUGS

1. Mechanisms of action : The alkylatingagents are CCNS drugs.

a. They interact covalently with DNA bases,

especially at the N-7 position of guanine.

b. Nucleic acid functions are disrupted dueto cross-linking, abnormal base pairing,

and DNA strand breakage.

A. Alkylating Agents



1. A L K Y L A T I N G AGENTS: Cyclophosphamide,Ifosphamide, Chlorambucil, Nitrosoureas

Cell- cycle-nonspecific drugs• combine with DNA of both malignant and normal cells and

thus damage not only malignant cells but also dividing normalcells (the bone marrow and the GIT)

• mechanisms: the alkyl groupings (ethyleneimine ions andpositively charged carbonium ions) are highly reactive, so thatcombine with susceptible groups in cells and in tissue fluids(SH, PO 4)

The alkylating action on DNA leads to abnor mal basepair ing or intr a and interstrand li nks with DNA molecul e

• cytotoxic, mutagenic and teratogenic effects may resultfrom interaction with DNA



A

DNA

T

C G

CG

GAT

G C

A

C

G

C

A

T

G

C

G

T

i.e.Alkylatingagent

Mechanism of intramolecular bridging of DNA by alkylating agents.

A = adenineC = cytosineG = guanineT = thymidine



Cyclophosphamide• an inactive prodrug• can be given orally

is activated by the CYP450 in liver as well as in tumors.

with time, the active metabolite and also acrolein areformed. The latter compound is responsible forbladder toxicity (chemical hemorrhagic cystitis).

a wide spectrum antitumor and immunosuppressiveactivity used as a part of combination therapyregimens to treat lymphoma, breast cancer, bladdercancer, ovarian cancer

and various children malignancies



T o x i c i t i e s: bone marrow depression, granulocytopenia,thrombocytopenia.

urotoxicity appears with chronic therapy -M e s n a … dimesna (2-mercaptoethane sulfonate sodium) protects theurinary tract against the irritant effects by supplyingsulfhydryl groups to form a stable thioether withacrolein. Mesna is given by IV injection or by mouth

The nitrosoureas: Carmustine and Lomustine are potebone marrow toxins. Hepatotoxicity and nephrotoxicity.

Broad spectrum of activity (solid tumors, in particular

brain tumors).



B. Antimetabolites1. Mechanisms of action : Antimetabolites are CCS

drugs.

a. They are structurally similar to endogenouscompounds.b. Anticancer and immunosuppressive actions result

from interference with the metabolic functions offolic acid, purines, and pyrimidines.

2. Methotrexate (MTX) is an analog of folic acid thatinhibits dihydrofolate reductase and other enzymesin folic acid metabolism.

a. It is used (orally and intravenously) in acuteleukemias, breast cancers, and non- Hodgkin’s andT-cell lymphomas.

b. Folinic acid (leucovorin ) is used to reverse MTX

toxicities and full hydration is needed to preventcrystalluria.



3. Mercaptopurine (6-MP) inhibits purine metabolismfollowing its activation by hypoxanthine guaninephosphoribosyl transferase (HGPRT). a. Resistant cells may lack HGPRT.b. 6-MP is used mainly in regimens for acute

leukemias. 4. Cytarabine (Ara-C) is activated by tumor cell

kinases to form a nucleotide that inhibits pyrimidinemetabolism. a. Resistant cells may lack such kinases.b. Ara-C is used mainly in regimens for acute

leukemias.

5. Fluorouracil (5-FU) is activated to a metabolite thatinhibits thymidylate synthase causing “thymine -lessdeath” of tumor cells. a. Changes in this enzyme may results in resistance.

b. 5-FU is widely used, mainly for the treatment of solidtumors.



3. Vinblastine and vincristine act in the Mphase to block mitotic spindle assembly.

a. They are widely used in combinationregimens for acute leukemias, Hodgkin’s andother lymphomas, Kaposi’s sarcoma,neuroblastoma, and testicular cancer.

b. Vincristine is neurotoxicc. Vinblastine suppresses bone marrow.



D. Antibiotics

1. Bleomycin is a glycopeptide mixture (CCS)that alters nucleic acid functions via freeradical formation.

a. It is used in regimens for Hodgkin’s and otherlymphomas and squamous cell and testicularcancers.

b.Pulmonary toxicity, skin thickening, and byhypersensitivity reactions are distinctive.



2. Doxorubicin and daunorubicin areanthracyclines (CCNS) that intercalate withDNA, inhibit topisomerases, and form freeradicals.

a.Doxorubicin is widely used in breast,endometrial, lung, and ovarian cancers and inHodgkin’s lymphoma.

b.Daunorubicin is used in leukemias.

c. Myelosuppression is marked, butcardiotoxicity is dose limiting.



3. Other antibiotics include dactinomycin andmitomycin.

a.Dactinomycin (CCNS) inhibits DNA-dependent RNA synthesis and is used inmelanoma and Wilms’tumors.

b.Mitomycin (CCNS) is biotransformed to analkylating agent and is used for hypoxictumors.

c. Both of these agents cause bone marrowsuppression.`



F. Miscellaneous Anticancer Agents.

1. Asparaginase depletes serum asparagine and

is used in auxotrophic T-cell leukemias andlymphomas. It causes bleeding, hypersensitivityreactions, and pancreatitis.

2. Interferons include interferon-alfa, which is used

in early-stage chronic myelogenous leukemia,hairy cell cancers, and T-cell lymphomas.Interferons cause myelosuppression andneurotoxicity.

3. Monoclonal antibodies.a. Gemtuzumab interacts with the CD33 antigen

and is used in CD33 + myloid leukemias; severe

myelosuppression is the major toxicity.



b. Rituximab interacts with a surface protein ofnon- Hodgkin’s lymphoma cells; toxicities includemyelosuppression and nypersensitivity

reactions.c. Trastuzumab is used for breast tumors that

overexpress the HER2 protein; toxicity includescardiac dysfunction.

d. Alemtuzumab, which targets the CD52 antigen,is used for treatment of B-cell chroniclymphocytic leukemia (CLL).

4. Imatinib is a protein designed to inhibit theabnormal tyrosine kinase created by thePhiladelphia chromosome abnormality in chronicmyelogenous leukemia (CML); toxicity includes

diarrhea, myalgia, and fluid retention.

PLATINUM COMPOUNDS



. PLATINUM COMPOUNDSCisplatin (cis-diaminedichlorplatinum) is an inorganicplatinum complex.

mechanism of action: DNA synthesis by formationof intra-and interstrand cross-links with DNA molecule.Adverse effects, toxicity:

severe vomiting nephrotoxicity is dose-related(acute distal tubular necrosis).

Prevention: the patients is fully hydrated by IV infusioncombined with manitol and furosemide.

hypomagnesemia ototoxicity develops in up to 30%.

Peripheral neuropathy can be disabling. myelosuppression



Cisplatinis the most effective single agentin testicular teratomas, but is usually given

in combination with other cytotoxic drugs.

Cisplatin has been used with some succes in head and neckand bladder cancers -IV .

Carboplatin is less toxic (renal toxicity or ototoxicity),neuropathy is rare and vomiting although common,is less severe than after cisplatin.

Oxaliplatin

5 HORMONES and antagonists



5. HORMONES and antagonistsHormon can cause remission in certain types of cancer(breast and prostate).

Ways in which hormones can affect malignant cells:a direct cytotoxi c action on the malignant cel ls. This is likely if cancer cells that are normally dependenton a specific hormone are exposed to a high concentration

of a hormone with the opposite effect (if a carcinomaarises from cells of the prostate that are testosteronedependent, ….estrogens in large doses are cytotoxicto the cancer)

a hormone may suppress production of the hormonesby a feedback mechanism .

Estrogens are used in the management of prostaticand breast carcinoma



Progestogens: = megesteron,= medroxy-progesteron acetate:

Indication:-adenocarcinoma of the body of the uterus- in advanced breast cancer,- carcinoma of the kidney.

G l u c o c o r t i c o s t e r o i d s:= are cytotoxic to lymphoid cells= are usedwith combination with other cytotoxic

agents in treating:lymphomas, myeloma and

to induce a remission in acute lymphoblastic



H o r m o n e a n t a g o n i s t s :• Anti-estrogens:

tamoxifen - in breast tissue competes withendogenous estrogens for the estrogen receptorsand inhibits the transcription of estrogen-responsivegenes.

= is remarkably effective in some cases ofhormone-dependent breast cancer

• Anti-androgens:

flutamide is used in prostate tumors• Adrenal hormone synthesis inhibitors: inhibitsex hormone synthesis. Aminoglutethimide.



Aminoglutethimide

inhibits adrenal synthesis of estrogens,glucocorticoids and mineralocorticoidsby inhibition of the enzyme producingtheir common precursor- pregnandione

inhibits tissue aromatase blocking conversionof androgens to estrogens.

Ovarian aromatase is resistant to

this inhibition, so aminoglutethimide is onlyuseful in postmenopausal women.



Pharmacokinetics: polymorphic acetylation to an inactive N-acetylmetabolite. Fast acetylators - slow acetylators.

Adverse effects:dizziness, lethargy are common on starting treatmentbut decline during chronic dosing

(probably due to enzyme induction).

Usage:A. is effective in about 30% of postmenopausal patients

with best effects on skin and breast disease.The response of bone metastases is also good.



Hormones

1. Glucocorticoids include prednisone, whichis used in combination regimens forHodgkin’s lymphoma and leukemias.

2. Gonadal hormones include the palliative use

(rare) of androgens in estrogen dependentcancers in women and the use of estrogensin prostate cancer.

3. Gonadal hormone antagonists includeestrogen receptor blockers ( tamoxifen andtoremifene ) and the androgen receptorblocker flutamide. They are used for tumors

responsive to gonadal hormones .



4. Gonadotropin-releasing hormone analogsinclude leuprolide and naferelin , whichdecrease follicle-stimulating hormone (FSH)and luteinizing hormone (LH) if used inconstant doses.

5. Aromatase inhibitors include anastrozole,which inhibits formation of estrogens fromandrostenedione and is used in advancedbreast cancer.



I NCREASED EF F I CACY

Different mechanisms of action Compatible side effectsDifferent mechanisms of resistance

ACTIVITY SAFETY

Principles of chemotherapy

Aim of combination therapy



Mucositis

Nausea/vomitingDiarrhea

Cystitis

SterilityMyalgia

Neuropathy

Alopecia

Pulmonary fibrosis

Cardiotoxicity

Local reaction

Renal failure

Myelosuppression

Phlebitis

Side effects of chemotherapy



TOXICITY OF ANTICANCER DRUGS

Normal cells with a high growth fraction (bonemarrow, gastrointestinal mucosa, ovaries, andhair follicles) are highly susceptible to thecytotoxic actions of anticancer drugs.Bone marrow suppression is common with bothalkylating agents and antimetabolites; it is oftenthe dose-limiting toxicity.Drug dosage is usually titrated to avoid

excessive neutropenia (granulocytes < 500/dl) orthrombocytopenia (platelets < 20.000/dl).The use of colony-stimulating factors decreasesthe infection rate and the need for antibiotics.

A ti d g ifi t i iti



Anticancer drug-specific toxicities.Drug Specific Toxicities

Bleomycin’ Pulmonary fibrosis, fevers, skinhardening and blisters, anaphylaxis.Cisplatin’ Nephrotoxicity, acoustic and

peripheral neurophathyCyclophosphamide

Hemorrhagic cystitis- ’mesna’ isprotective (traps acrolein); ifosfamideis similar to cyclophosphamide.

Doxorubicinanddaunorubicin

Cardiomyopathy (eg, delayed heartfailure)-dexrazoxane is protective(decreases free radical formation);

liposomal forms are less cardiotoxic.



Methorexate(MTX)

Myelosuppression (use”leucovorinrescue”) and mucositis; crystalluria;toxicity is enhanced by drugs thatdisplace MTX from plasma proteins(eg, salicylates, sulfonamides).

Vincristine’ Peripheral neuropathy (autonomic,

motor, and sensory); vinblastine isless neurotoxic; paclitaxel alsocauses sensory neuropathy

5. Procarbazine forms free radicals; it is used inHodgkin’s lymphoma, but may cause leukemia.



Problems With Cancer

Chemotherapy

• Drug Resistance• Drug Toxicity



Drug Resistance

De novo Resistance• Acquired Resistance• Multidrug Resistance (MDR)

De novo resistance:De novo resistance can be de novo genetic (i.e. the cellsare initially inherently resistant), orcan arise because drugs are unable to reach the target

cells because of permeability barriers such as the blood-brain barrier .



Drug Resistance

Acquired Resistance:• Acquired drug resistance may result from

genomic mutations, such as the induction ordeletion of enzymes involved in drug inactivationor drug activation, respectively.

Multidrug Resistance (MDR):P-glycoprotein transports many naturally

occurring drugs out of neoplastic cells, and itsinduction may lead to multidrug resistance.As scientific understanding of the mechanismsof drug resistance increases, new treatments

may be developed to counteract resistance.



RESISTANCEprimary: (non-responsive tumors)

aquired:

• reduced uptake of drugs• deletion of enzyme to activate drug• increased detoxication of drug• increased concentration of target enzyme• rapid repair of drug-induced lesion•

decreased number of receptors for drug• increased efflux



Mechanisms of cellular drug resistance

reduced uptakeof drugs

deletion of enzyme

to activate drug

increased

detoxication of drug

active

metabolite

inactivated

cytotoxic drugincreased efflux

(multidrug resistance)

C

increasedconcentration

of target molecules

T- cellular target

+T - gene amplification

+T

T

rapid repair of drug-induced lesion

defective cellular target

Resistance to anticancer drugs



Resistance to anticancer drugs

Mechanisms of Resistance Anticancer Drugs AffectedIncreased DNA repair Alkylating agentsFormation of trapping agents Alkylating agents

Changes in target enzymesor receptors

Etoposide, gonadalhormones, methotrexate,vincristine, vinblastine.

Decreased activation ofprodrugs

6-Mercaptopurine, 5-fluorouracil.

Formation of drug-inactivating enzymes

Purine and pyrimidineantimetabolites

Decreased drugaccumulation via increase inP-glycoprotein transporters.

Alkylating agents,dactinomycin, methotrexate

MULTIDRUG RESISTANCE (MDR)



MULTIDRUG RESISTANCE (MDR)

Resistance to multiple anticancer drugsmay occur from increased expression ofthe MDRI (MDR Type I) gene for cellsurface glycopreteins (P-glycoproteins)

involved in drug efflux.Such drug transporters (not limited tocancer cells) use ATP to drive drugmolecules out of a cell against aconcentration gradient.Verapamil (a calcium channel antagonist)inhibits these drug transporters.



Methotrexate

Mechanism of Resistance1. Decreased drug transport2. Altered DHFR3. Decreased polyglutamate formation4. Increased levels of DHFR

THE ABVD REGIMEN IN HODGKIN’S DISEASE



THE ABVD REGIMEN IN HODGKIN’S DISEASE

Chemotherapy in cancer commonly involves the use of drug combinations to enhance antitumor actions and to prevent development ofresistance.

The ABVD regimen includes doxorubicin(Adriamycin), bleomycin, vinblastine, anddacarbazine (an alkylating agent).

This drug regimen, used in cycles with totalnodal radiotherapy, has achieved up to 80%remission in stages III and IV of Hodgkin’s

disease.



Drug Toxicity•

The most common toxicities ofantineoplastic drugs result from inhibitionof cell replication in the bone marrow,

gastrointestinal epithelium, and hairfollicles.

• Many antineoplastic drugs also stimulatethe chemoreceptor trigger zone in themedulla and thereby elicit nausea and

vomiting.



Toxicities, which can be severe, includealopecia, gastrointestinal distress, neutropenia,thrombocytopenia, and possible sterility.In addition, patients on the ABVD regimen maysuffer the pulmonary toxicity of bleomycin and adelayed cardiomyopathy caused by doxorubicin.

Tabel. Anticancer drug-specific toxicities.



g p

Drug Specific Toxicities

Bleomycin’ Pulmonary fibrosis, fevers, skin hardening and

blisters, anaphylaxis.Cisplatin’ Nephrotoxicity, acoustic and peripheral neuropathy.

Cyclophosphamide

Hemorrhagic cystitis-mesna is protective (trapsacrolein); ifosfamide is similar to cyclophosphamide.

Doxorubicinanddaunorubicin

Cardiomyopathy (eg, delayed heart failure)-dextrazoxane is protective (decreases free radicalformation); liposomal forms are less cardiotoxic.

Methotrexate

(MTX)

Myelosuppression (use “leucovorin rescue”) and

mucositis; crystalluria; toxicity is enhanced by drugsthat displace MTX from plasma proteins (eg,salicylates, sulfonamides).

Vincristine’ Peripheral neuropathy (autonomic, motor, andsensory); vinblastine is less neurotoxic; paclitaxelalso causes sensory neuropathy.



M I S C E L L A N E O U S AGENTSProcarbazinedepresses DNA synthesis . Its main use is in treating Hodgkin´s disease.

I N T E R F E R O N Shairy cell leukemia, lowgrade non-Hodgkin´slymphoma, chronic myeloid leukemia.



HORAS

Sss.35. Farmakologi Anti Cancer Drug

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