NEOPLASIA V' Pathobiological basis of cancer therapy Dr' A' Jeney

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NEOPLASIA V.Pathobiological basis of cancer
therapyDr. A. Jeney

17. Octóber 2007
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PATHOLOGY UNLIMITED CELL PROLIFERATION RESULTS
IN TUMOR FORMATION PHARMACOLOGY TO DEVELOP
DRUGS AGAINST TUMOR CELL PROLIFERATION
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Site of actions of the cytotoxic drugs
MOLECULAR TARGETS
CYTOTOXIC DRUGS
Antimetabolites (5-Fluoruracil, methotrexate,
Ara-C, Gemcitabin)
NUKLEOTID BIOSYNTHESIS
Cyclophophamide, Platina compounds, Bleomycin

DNA
RNA
topoizomerase
Campto, etopozid, antracycins
Mitotic spindle
Vinca-alkaloidsok, taxans
DNADNA
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• Cytotoxic antitumor drugs
• Drugs damaging DNA
• (Cyclophosphamide,
  bleokycin,etc.)
• 2.Inhibitors of nucleotide metabolism
  (Antimetabolites),
• ( 5-fluoruracil, methotrexate,
  etc)
• 3. Topoizomerase inhibitors
• (irinotecans, anthracyclins)
• 4. Inhibitors of mitotic spindle
• ( vinca
  alkaloids, taxanes)

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ANTITUMOR POTENCY OF
CYTOTOXIC AGENTS Inhibition of cell
proliferation Selectivity depends on 1.
difference in drug metabolism, 2. repair
mechanism, 3.apoptotic mechanism 4. Cellular
transport 5. Metabolic response
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Clinical application

• TREATMENT .maximal tolerated doses,
• . intermittent schedule ,
• Sdjuvant or single, or combined application
• EVALUATION complete/partial remmission
• OUTCOME
• Modest antitumor efficacy, Resistancy
• .Toxicity severe
• Prolonged survival ,,
• Cure in certain malignancies

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Macrophages Fibroblast Endothel
Fragments TIMP MMPs
Tumour cell
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Laminin Perlecan Fibronectin Collagen IV
BM180
Invasive tumour cell
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PLASTICITY of TUMOUR INVASION MECHANISMS
modified after Friedel
and Wolf in Nature Reviews Cancer 3 362..2003
CANCER-CELL
COLLECTIVES
(epithelial sheets or strands)
c ell-cell interaction lost
integrins
blocked
EMT
CAT



MAT Type of
migration MESENCHYMAL
AMOEBOID

proteases inhibited CAT
Collective-amoeboid transition

EMT Epithelial-mesenchymal
transition MAT Mesenchymal-amoeboid Transition

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Molecular aspect of malignant cells
1.Activation of oncogenes and inactivation of
tumor suppressor genes elicit alterations in
cellular regulation . 2. Abnormalities in gene
regulation 3. Tumor cells show insensitivity
to antigrowth signals, but self-sufficiency in
growth signals 4. Signal transductions are
operated through phosphorylation of proteins
5.Generation of biologically active substances
( cytokines, hormones etc.) causing changes in
homeostasis of the host organism.
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DRUGS ACTING ON MOLECULES CONTRIBUTING TO
MALIGNANCY
TYROSINE-KINASE INHIBITORS ANTIANGIOGENIC
AGENTS ANTIMETASTATIC AGENTS BIOLOGICAL
AGENTS INHIBITOTRS OF ENDOCRIN
REGULATION CYTOKINES MONOCLONAL ANTIBODIES
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Categories of cytostatic drugs Tyrosine
kinase inhibitors ( imatinib,tarceva m
sunitinib, lapatinib etc) Monoclonal antibodies
9nactivate molecules participating in
malignancy Carriers of cytotoxic agent generate
antibody dependent cell cytotoxicity
(trastuzumab( rituximab etc.) Inhibitors of cell
cycle (flavopiridol)
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PREDICTIVE TEST before TREATMENT with HERCEPTIN
First step IHC
-test 1positivity 2 positivity
3 positivity 76 - 82
8-11 10-13 Second
step No FISH test FISH test
FISH-test none negative
positive negative positive
75-85 15-25
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Herceptin treatment NO
NO YES
NO YES
10-15 of breast cancer patients
will receive Herceptin.
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Hormone analogs Tumors of the endocrine organs
are hormone dependent Mechanism of hormone
actions on endocrine responsive tumours ( in
breast, prostata) must be controled Levels of
interferences receptors,

enzymes involved in hormone
productions. Cytokines Tumors show abberant
cell regulation Produce their own regulatory
factors which must be counteracted Interferons,
Interleukines)
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Antimetastatic agents Tumor cells migrate and
settle down in remote organs Represent novel
family of antitumour drugs. Bisphosphonates
inhibit osteoclasts . Antiangiogenetic drugs
Tumor growth require nutrients
Bevacizumab inactivates VEGF receptor
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• COMBINED DRUG THERAPY
• CYTOTOXIC CYTOSTATIC DRUGS
• CYTOSTATIC CYTOSTATIC DRUGS
• VERY PROMISING BUT MAY WORK IN OPPOSITE
  DIRECTION AS WELL
• MODE OF ACTION MUST BE CONSIDERED

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MOLECULAR TARGETS FOR ANTITUMOR DRUGS
EGFR, PDGFR,c-KIT
Herceptin Iressa
ECM Integrins
Endostatin
Glivec
RHO/ROCK
RAS
Alendronat
MKK4 p38
PI3-K AKT
RAF
NSAID
PD980059
SB203580
apoptosome
MEK1/2
API-1 NF?B
ETS-1
PS-341
Rapamycin
DNA
Batimostat
mRNA Protein
synthesis
MMPs
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MOLECULAR ONCOPHARMACOLOGY
TARGETTED THERAPY Drug action aimed at
molecules associated to malignant phenotype
High antitumor efficacy with modest
toxicity Clinical response in a significant
proportion of patients, but minimal responses
in patients whose tumors do not express the
target Predictive test available