anticancer drugs.12.may.2011

7/28/2019 Anticancer Drugs.12.May.2011

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CHEMOTHERAPEUTICS

OF MALIGNANT DISEASES

A. Koht
http://edcenter.med.cornell.edu/CUMC_PathNotes/Female_Genital_Tract/854.gif


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Carcinogenesis

DNA mutation

hereditary

acquired

radiation viruses chemicals drugs


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Categories of genetic changes

resulting in malignity

a) inactivation of tumor

supressor genes:

mutation

binding to a virus protein

binding to a mutated

cellular protein

b) activation of

protooncogenes to

oncogenes:

point mutation

(single nucleotide

polymorphisms-SNPs)

gene amplification

chromosome

translocation

virus interaction


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Oncogenes

autonomy of cell growth

Oncogenes interfere with:

mechanisms of proliferation

mechanisms of differentiation

by means of:

production secretion of autocrinegrowth factors

receptors for growth factors

cytosolic nuclear signal pathways

transduction systems controling cell cycle


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Characteristics of tumour cells

uncontrolled proliferation

dedifferentiation loss of function invasiveness

metastatic potential


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Therapeutic effect of anticancer drugsa. The therapeutic effect of anticancer drugs may require total

tumor cell kill, which is the of all neoplastic cells.b. Achievement of a therapeutic effect often involvs drugs that have

a narrow therapeutic index (TI).

c. A therapeutic effect is usually achieved by killing activellygrowing cells, which are most sensitive to this class of agents.

d. Because normal cells and cancer cells have similar sensitivity tochemotherapeutic agents, adverse effects are mostly seen innormally dividing non-neoplastic cells, sach as:

hair follicles, bone marrow, sperm.

e. To minimize the adverse effects and resistance, often is used

combination of several agents with different mechanism ofaction.

f. Achievement of a therapeutic effect may involve the use of drugs,sometimes sequentially (at specific stages of cell cycle).


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PRODRUGS

1. Cyclophosphamide 4-Hydroxyphosphamide (liver)2. Procarbazne dacarbazine (liver)3. Merkaptopurine 6-merkaptopurine ribozophosphate4. Tioquann 6-tioquann-ribzophosphate5. Fluorouracil 5-fluoro-deoxy- uracil monophosphate7. Mitomycin (only at the hypoxic tissue of tumors)

8. Doxorubicin idarubicin


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SENSITIVITY OF TUMOURS TO

CHEMOTHERAPY

chemosensitive tumours

intermediary chemosensitive

tumours

chemoresistanttumours


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Chemosensitive tumours

generally sensitive to several drugs

combined chemotherapy is prefered

chemotherapy is always indicated


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Intermediary chemosensitive

tumours

complete remission rate about 10%

high partial response (about 50%)

combined chemotherapy is slightly

more effective

chemotherapy could be used

(no as first-choice therapy)


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Chemoresistant tumours

low response rate (about 20%)

complete remission is rare

chemotherapy has only adjuvant role

neoadjuvant therapy

F t i fl i


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Factors influencing

chemotherapy response

fraction of proliferating cells

cell cycle rate

synchronisation of cell cycle within tumour

tumour mass

large tumours are relatively less sensitive:

1. a lot of cells in G0 2. penetration of drugs

kinetics of cell killingcytotoxic drugs kill only a part of cells of certain type

resistance of tumour cells


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Mechanisms of resistance I.

Defect activation

cyc lophosphamideneeds metabolic activation metothrexateneeds conversion to MTX-

polyglutamate in cells

Increased inactivation sulfhydryl substances - glutathion, metalothionein scavenge

reactive molecules

aldehyde dehydrogenase inactivation of cyc lophosphamide

Increased nucleotide levels can affect the effectiveness of antimetabolites

Changes in DNA repare repare mechanisms, elimination of cross-links b leomycine other DNA-interfering drugs


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Mechanisms of resistance II.

Changes in target structure active enzyme with lower drug affinity:

DFR-metothrexate

Reduced quantity of target structure amount of topo II: etoposide

Gene amplification

metothrexate: DFR requires more MTXto block the activity


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Mechanisms of resistance III.

Decreased accumulation

Decreased uptake

MTX- protein transporter melphalan/leucine transport

Increased efflux

multidrug resistance (MDR):

- most often for natural drugs doxorubic ine,

etopos ide, act inom yc ine D, vinc a alcaloids

- Pgp is normally expressed in some cells, e.g. stem

cells in bone marrow


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Combination chemotherapy

tumours have tendency to be resistant tosome drug (cell heterogeneity)

resistance is often required during therapywith only one drug (proliferation of mutatedcells)

several sites of effect are possible with

drugs with different side effects

cummulative biochemical damageappear in cancer cells


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MODALITIES OF ANTICANCER

CHEMOTHERAPY

1. Intermittent application period for bone marrow regeneration

period for immunity regeneration

2. Continual therapy during maintenance therapy

(chlorambucilin CLL, busulfan in CML, hormones orantagonists in prostate or breast carcinoma)

3. Special applications instilation in malignant secretions (bleomycine, thiotepa)

(can be palliative by volume reduction)

intrathecal (metothrexate)

(infiltration of CNS in leukemia)


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INDIVIDUALISATION OF

CANCER THERAPY

Type of tumour: selection of anticancer drug

combination (or not)

Repeated evaluation of clinical status:

continuation (or not) in agressive therapy

Continual monitoring of bone marrow:

before & during therapy

reduction (or not) of therapeutic regimenintensity

The use of drugs modifying unwanted side effects:

antiemetics, colony-stimulating factors

increase in therapeutic:toxic ratio


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PRACTICAL USE OF

ANTICANCER DRUGS

the doses are expressed in

mg per m2

of body surface

(more precise dose/effect ratio)

Toxic effects


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Toxic effects

of anticancer chemotherapeutics

myelotoxicity

alopecia

loss of appetite &

weight nausea & vomitus

taste change

stomatitis,

esophagitis,constipation, diarrhea

fatigue

cardiotoxicity

neurotoxicity

lung damage

sterility &teratogenicity

hepatotoxicity &nefrotoxicity

wound healing growth (children)

carcinogenicity


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ANTICANCER DRUGS


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Mechanism of action - cell cycle

intercalation

blockade of metabolic

steps in DNA

synthesis

of enzymesregulating cell cycle

RNA synthesis protein synthesis microtubular

functions


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Cell cycle intervals &

anticancer drugs interferrence


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Anticancer drugs

1. alkylating agents(cyclophosphamide, cisplatin)2. antimetabolites(methotrexate)

3. cytotoxic ATB (antracyclines)

4. mitosisinhibitors (vincristine, taxans)

5. topoinhibitors (topotecan, etoposide)

6. hormones(corticoids, tamoxifen, flutamide)

7. enzymes & other drugs(asparaginase,procarbazine, hydroxyurea)

8. PTKinhibitors (imatinib)

9. monoclonal antibodies(rituximab,trastuzumab)


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I. Alkylating agents

cyc lophosphamide

platinum derivatives

derivatives of nitrosourea ( lomust ine,

carmust ine)

estramust in

melphalan

ch lorambuci l

busu lphan

dacarbazine


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Mechanism of action

inter- or intra-chain cross-linking

interference with transcription &

replication (S phase & G2 block)

apoptosis


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Alkylating agents

Side effects

myelosuppresion

GIT toxicity

inhibition of gametogenesis

(sterility-males)

secondary malignities

(acute leukemias)


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Cyclophosphamide

(mustard gas)

frequently used

also asimmunosupressiveagent

P-450 activation

p.o., i.v, i.m.

derivative - ifosfamide


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Cyclophosphamide

Side effects

myelosuppression

GIT toxicity

hemorrhagic cystitis

acroleineN-acetylcyst.,mesna


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Cisp lat in , carbop lat in

platinum complex

2 chlorid ions

2 amonium groups

cross-linking,

DNA denaturation

solid tumors - testes

& ovarial


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Cisplat in

Kineticsslow i.v. perfusion

(water soluble)

Side effects

myelosuppression

GIT toxicity

nephrotoxicity emetogenity

ototoxicity

neuropathies


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II. Antimetabolites

Antagonists of folic acid

Pyrimidine derivatives

(thymine, cytosine, uracil)

DNA RNA

Purine derivatives(adenine, guanine)


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Methothrexate(antifolate)

Mechanism of action

folates purine nucleotides thymidilate DNA

reduction to FH4 DHFR - high affinitt forFH4 -key enzyme

transport of monocarbon groups uracile methylation to 2-deoxyuridylate

(DUMP) & thymidylate (DTMP)

DNA synthesis


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Methothrexate

Kinetics low liposolubility

p.o., i.v., i.m., i.t.

folate transport

(in the cell)

polyglutamation

(intracellular)

higher affinityto DHFR as FH2

FH4 depletion

Side effects myelosuppression,

GIT, pneumonitis,

nephrotoxicity (tubular

precipitation - hydratation)

high doses followed

by folic acid


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Fluo rou raci l (5-FU)(pyrimidine (uracile) derivative)

Mechanism of action

interference with

thymidylate & DNAsynthesis

fluorodeoxyuridine

monophosphate

formation (FDUMP)

parenteral application

mainly solid tumors

(GI)

Side effects

GI epithelial damage

myelotoxicity

C t bi


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Cytarabine

(pyrimidine (cytidine) derivative)

Mechanism of action

intracellular

phosphorylation

DNA & RNAincorporation

DNA polymerase

inhibition

Inhibition ofreplication &reparation

Kinetics & indications

s.c. (myelodysplastic

syndrome), i.v., i.t.

AML, CML remission,lymphoma,

myelodysplast. sy

Side effects myelosuppression, GIT,

nausea, vomiting


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III. Cytotoxic ATB

Anthracyclines

(daunorubicine, doxorubicine,epirubicine,

idarubicine)

Bleomycines


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Daunorubic ine

(anthracycline)

Mechanism of action

intercalating ATB

topo II inhibition

Indications

induction therapy

ALL, AML,CML blast. trans.

Kinetics

i.v. infusion

metab. & excretion(mainly liver)

Side effects myelotoxicity

accumulative cardio-

toxity (free radicals)

alopecia

local necrosis(extravascular appl.)
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Doxorubic ine

(anthracycline)

Mechanism of action

intercalating ATB

inhibition of topo II

much broaderindication spectrum asdau

Hodgkin, NHL,myeloma, at least alllocalizations of solidtumors

i.v. perfusion,intravesically

Side effects myelotoxicity

cardiotoxicity(dexrazoxan)

alopecia, mucositis,necroses in mouth & ifapplied paravenously

Bl i
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Bleomycines(glycopeptide ATB-radiomimetic)

Fe ion chelatation,interaction with O2

superoxide &

hydroxyl radicals

degradation ofpreformed DNA

chain fragmentation

radiomimetic effect

most effective in G2 &M phase, as well as G0

testicular tumors &malignant lymphomas

orofacial tumors, cavulvae, penis, skin

i.v., i.m.

Side effects

shivering, fever

lung fibrosis allergies, mucocutaneous

reactions

low hemat. tox.


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IV. Mitosis inhibitors

Vinca alcaloids

(vincristine,vinblastine, vinorelbine)

Taxans

(paclitaxel, docetaxel)

M h i f ti


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Mechanism of action

Inhibition of polymerisation:

colchicin

vinca alcaloids

Tubuline Microtubulus

Stimulation of polymerisation Inhibition of depolymerisation

taxans

Vincr ist ine ( )


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Vincr ist ine(vin blast ine, vin orelbine)(mitosis inhibitors)

Mechanism of action inhibition of tubuline polymerisation

inhibition of mitotic spindleformation

effective in G2/M phase

Side effects

myelosuppression

phagocytosis, chemotaxy ofleukocytes

axonal transport in neurons paresthesies, neuromuscular

abnormalities

Vi i t i i b l t i


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Vinc r ist ine, vinb last ine

Indications

Vincr ist ine

ALL & AML

Hodgkin lymphoma, NHL

multiple myeloma

combination therapy in some solid tumors

Vinblast ine

Hodgkin lymphoma, NHL

testicular tumors

choriocarcinoma

Grawitz tumor

P lit l d t l


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Pac li taxel, docetaxel(mitosis inhibitors)

Mechanism of action

microtubular

stabilisation final effect like

vinca alcaloids

Kinetics very low water

solubility

only as i.v. perfusion


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Pac li taxel, docetaxel

Side effects

myelosuppression

neurotoxicity

hypersensitivity

(premedication with

steroids & antihistaminics)

Indications

metastatic tumors

(breast) progressive ovarial

tumors

NSCLC

Kaposi sarcoma (AIDS)


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V. Topoisomerase inhibitors

topo I inhibitors

(topotecan,irinotecan)

topo II inhibitors(etopozide,tenipozide)

Topotecan ( i i t )


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Topotecan( i r inotecan)(topo I inhibitors)

Mechanism of action

topo I inhibition

its levels are duringthe whole cell cycle

Side effects

diarrhea, reversible

myelosuppression relatively low toxicity

Indications

metastatic ovarial

tumors in case of firstline therapy failure( topotecan)

colorectal ca inprogress ( ir inotecan)

Etopozide ( tenipozide)


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Etopozide( tenipozide)(topo II inhibitors)

Mechanism of action

Inhibition of

mitochondrial

functions &

nucleoside transport

topo II inhibition

Side effects

nausea, vomitus myelosuppression,

alopecia

Indications solid tumors

(lung-SCLC, testicular,

trophoblast, ovarial,

urinary blader)

malignant lymphoma,

acute non-lymphatic

leukemia


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VI. Hormones

Glucocorticoids

(prednisolone, dexamethasone)

Antihormones

(tamoxifen, flutamid)

T if ( t i f )


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Tamoxifen( toremifen)

Mechanism of action nonsteroidal

antiestrogene

inhibits estradiol

binding to receptors

Indications

p.o. appl. in breast

cancer with positive

estrogene receptors

Side effects

metrorhagies

thrombophlebitis

flush

alopecia

estrogene

endometrial effect


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VII. Enzymes

& other chemotherapeutics

Enzyme

(asparaginase)

Other chemotherapeutics

(procarbazine, hydroxyurea)


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Asparaginase(enzyme)

Mechanism of action, kinetics, indications

cleaves asparagine, useful in malignitieswhere the cells lost possibility of itssynthesis

i.m., i.v. in ALL

Side effects

weak myelosuppression, GIT toxicity &alopecia

nausea, vomiting, CNS depression,anaphylaxis, hepatotoxicity

VIII PTK inhibitors


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VIII. PTK inhibitors

(imatinib mesylate)

Mechanism of action, kinetics, indications

PTK inhibition

phosphate group transport from ATP& phosphorylation of tyrozine residues in substrate

proteins

Inhibition of transduction signals transmission

p.o. appl. in therapy of CML & GIST

Side effects

nausea, vomiting, diarrhea

edema, headache & muscle pain

neutropenia & thrombocytopenia

IX Monoclonal antibodies


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IX. Monoclonal antibodies(rituximab, trastuzumab)

Rituximab monoclonal antibody only for i.v. appl.

indicated in lymphoma therapy

Trastuzumab monoclonal antibody only for i.v. appl.

indicated in HER2 Neu positive breast ca therapy

Side effects

pseudoinfluenza sy. fever

headache, chest, abdominal, muscle & joint pain

nausea, vomiting, diarrhea & exanthema


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Angiogenesis in cancer


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Vasculogenesis vs Angiogenesis

Formation of blood vesselsfrom differentiatingangioblasts and theirorganization into aprimordial vascular

network, consisting of themajor blood vessels of theembryo

Formation of vascularsprouts from pre-existing vessels

Vasculogenesis

Agiogenesis


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Physiological versus pathological

angiogenesisPhysiologicalangiogenesis

Pathological angiogenesis

Therapeutic goal

Inhibition of angiogenesis Stimulation ofangiogenesis

Embryogenesis

Female reproductive

system

Development offollicles

Corpus luteum

formation

Embryo implantation

Successful wound

healing

Hemangiomas

Psoriasis

Kaposi's sarcoma

Ocular neovascularizationRheumatoid arthritis

Endometriosis

Atherosclerosis

Tumor growth

and metastasis

Myocardial ischemia

Peripheral ischemia

Cerebral ischemia

Wound healingReconstructive surgery

Ulcer healing

Established tumorProgression of Cancer


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Initiation

Promotion

Dormant in situ Cancer

1 kg

1 g

1 mg

1mg

1 ng

Established tumor

Dormant cancer cells

regain tumorigenic

potentialSuzuki M et al AJP 169: 673-681

Angiogenic switch

Hypoxia crosstalk

Accessorycells


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Hanahan D & Folkman J. Cell. 86:353, 1996

The balance hypothesis for the

angiogenic switchVEGF familyFGF family

PDGF

TGF family

Angiogenin

Angiopoietin-1/Tie2TNF-a

HGF/scatter factor

IGF family

IL-8

Nitric oxide

ProstaglandinsTissue factor

MMPs

.

.

.

Angiostatin/otherplasminogen kringles

Antithrombin (cleaved)

Endostatin

Fibronectin fragments

PEX

16-kDa Prolactin

Prothrombin kringle-2

Maspin

Restin

Vasostatin

IL-1, -4, -10, -12, -18

IFNs

TIMPs

1,25-(OH)2-vitamin D

2-MethoxyestradiolAngiopoietin-2

EMAP-II

gro-b

IP-10

.

.

.

Normal Blood Vessels vs Tumor Blood Vessels


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McDonald & Choyke Nat Med 2003


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Bevacizumab

Recombinant, humanized monoclonal

antibody that binds to VEGF-A

Approved for first-line treatment of Non-SmallCell Lung Cancer in combination with

Carboplatin and Paclitaxel

Adding bevacizumab to chemotherapy results

in increased median Progression FreeSurvival by 33%


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Concerns

Since bevacizumab is expected to inhibit new

angiogenic growth, concerns have been

raised regarding postoperative wound-healing

and bleeding complications in patients who

undergo surgery within 1 to 2 months of

Bevacizumab therapy


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Side efects

Gastrointestinal (GI) perforation

Wound healing complication

Hemorrhage

Neutropenia


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Immunosuppressant drugs

- inhibit interleukin-2 production or action


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- inhibit interleukin-2 production or action

cyclosporin, tacrolimus, sirolimus

- inhibit cytokine gene expressioncorticosteroids

-inhibit purine and pyrimidine synthesis

azathioprine

- block the T cell surface molecules involved in

signalling

polyclonal and monoclonal antibodies

- act by cytotoxic mechanisms

cyclophosphamide, chlorambucil


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Usage in therapy:

- autoimmune disease (some forms ofhaemolytic anaemia, glomerulonephritis)

- prevention /or therapy of

transplant rejection (kidneys, bonemarrow, heart, liver, etc.)

Hazard:

- decreased response to infections

- facilitation of emergence of

malignant cells


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Cyclosporin

-a fungal polypeptide with potentimmunosuppresive activity

Pharmacokinetics- i.v., oral absorption

- hepatic metabolism-metabolites excreted in

the bile

-accumulation in most tissues at conc. 3 to 4times that seen in the plasma


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Unwanted reactions:

- nephrotoxicity

- hepatotoxicity

- hypertension


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Tacrolimus

-a macrolide antibiotic- i.v., orally

- metabolized by the liver

Unwanted reactions:- neurotoxicity

- GIT upsets, metabolic disturbances

(hyperglycaemia) reversible by reducing the

dosage


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Glucocorticoids- restrain the clonal proliferation of Th cells through

decreasing transcription of the gene for IL-2

- decrease the transcription of many other

cytokine genes in both the induction and effectorphases of the immune response


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Azathioprine

is activated to 6-mercaptopurine (a pure analogue

antimetabolite - that inhibits DNA synthesis)

by a cytotoxic action on dividing cells inhibits clonalproliferation in the induction phase of the immune

response

Unwanted reactions:- depression of the bone marrow,

- nausea and vomiting


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Mycophenolate mofetil

A semisynthetic derivative of a fungal antibiotic

bioactivated to mycophenolic acid

Action(fairly selective):

-restrains proliferation of both T and B lymphocytes

- reduces the production of cytotoxic T cells

Kinetics:

Well absorbed from the GITEnterohepatic circulation-inactive glucuronides

anticancer drugs.12.may.2011

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