anticancer drugs.12.may.2011
TRANSCRIPT
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CHEMOTHERAPEUTICS
OF MALIGNANT DISEASES
A. Koht
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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