anticancer therapy (1) - univerzita karlova · vinca-alkaloids – mitosis hydroxyurea, mtx, ara-c...
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Anticancer
therapy (1)
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Tumor epidemiology
Major death cases:
year 2001 ÚZIS
1. Cardiovascular diseases 53%
2. Cancer 26%
3. Injuries, intoxication 6%
4. Respiratory diseases 4%
5. GI diseases 4%
6. others
Oncology reporting is mandatory
Death according to cancer:
year 2001 ÚZIS
1. Lung cancer 33,8%
2. Colorectal cancer 23,7%
3. Brest cancer 11,0%
4. Gastric cancer 8,3%
5. Pancreas 8,1%
6. Kidney 6,3%
7. Prostate 6,2%
8. Ovarian 4,1%
9. Uterus 2,4%
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Cell cycle
19%
39%
40%
2%
mitosis
differentiation
Synthesis of cell components
essential for DNA synthesis replication
DNA (synthesis)
Synthesis of cell
components
essential for
mitosis
G1 S
G2
M
Cell cycle regulation:
Positive – cyclines, CDK a growth factors, negative – pRb, p53
G0
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Cell cycle and role of cyclines and CDK
M
G1S
G2
G0
differentiation
Cyclin D1 – 3
+
CDK 2 – 6
Dephosphorylation
pRb, p53
Cycline B
+
CDK 1
Cycline A
+
CDK 2
Cycline E
+
CDK 2
Stimulation by
means of
growth factors
Phosphorylation
pRb
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Tumor growth(I) • Tumor growth is cell proliferation out of growth
control, in comparison with healthy tissues:
– Uncontrolled proliferation
– Dedifferentiation and loss of function
– Invasivity
– Metastases
• Tumor growth as an alteration of:
– Growth factors function
– Cyclines and CDK function
– DNA synthesis and increase of oncogen expression
– Influence of negative regulation in relation to mutations and
suppressor gens
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Tumor growth (II) • Mechanism of uncontrolled proliferation
– Extracellular signals (oncogens) e.g. growth factors
• Platelet derived growth factor – PDGF
• Vascular endothelial growth factor – VEGF
• Epidermal growth factor – EGF
– Receptors (cell membrane) e.g. • c-erb – epidermal growth factor EGF/EGFR
– Intracellular signal transduction e.g. • Cytosolic – proto-oncogene ras
• Nuclear – proto-oncogene c-myc transduction = stimulation of multiple cell division.
– Cell cycle • Cycline and CDK production
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TK receptor family and their activation
IGF-1R
P
P
P
P
HER2 HER3 HER4 EGFR
TGF-a
EGF
Heregulin
Epiregulin
Heregulin
Epiregulin None
HER (erbB) Family
VEGFR-2 VEGFR-3 VEGFR-1
VEGF-A
VEGF-B VEGF-C
VEGF-D
VEGFR Family
Flt-3 PDGFR KIT
FL PDGF SCF
PDGFR Family
P
P
P
P
VEGFRs, PDGFR,
KIT, Flt-3
Mutant Flt-3
P
P
P
P
EGFR/HER2
P
P
P
P
Receptor Dimerization and Activation
VEGF-A
VEGF-C
VEGF-D
IGF-1 IGF-2
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Tumor growth vs. number of duplication
0
10
20
30
40
50
60
70
80
90
100
počet buněk 106 109 1012
Duplication 10 20 27 30 40
Cell count 103 106 108 109 1012
Tumour mass 1mg 1mg 1g 1kg
neovascularisation, first metastase
Clinical manifestation X-ray manifestation
Lethal borderline
Slow growth
Tu
mo
r g
row
th
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• Cytostatics
• Hormones a antihormones
• Retinoids and other inducers of
differentiation
• Bio therapeutics
• Inhibitors osteolysis
• Antidotes a protectives
• Supportive therapy
Antitumor therapy
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Category
Antimetabolites
Alkylating agents
Antitumor antibiotics
Others
Alkaloids of plant origin
Classification of cytostatics
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According to
Cell cycle alteration
Phase specific
Vinca-alkaloids – mitosis
Hydroxyurea, MTX, Ara-c – S-phase
5-FU – G1 a S-phase
Cycle specific
Alkylating agents, doxorubicin, DDP – all cycle around
Cycle non-specific
Bleomycin, nitrosoureas – cycle independent
Classification of cytostatics
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Cytostatics and cell cycle
M
G1S
G2
G0
diferenciation
Vincristine (HD)
Prednizon
Actinomycin D
(carmustine) BCNU
Alkylating agents
Antitumor antibiotics
Tenopozide
Vincristine
Vinblastine
Colchicine
Ara-C
Bleomycin
Alkylating agents
Hydroxyurea
Mitomycin C
Cytarabine (Ara-C)
Alkylating agents
6-Mercaptopurine
Methotrexate
5-Fluorouracil
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Mode of action of cytostatics
• Inhibition of nucleic acid synthesis
• Damage of nucleic acid
• Alteration microtubular protein (spindle
poisons)
• Proteosynthethic inhibitors
• Cell membrane damage
• Combined effects
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• Inhibition of nucleic acid synthesis
– Direct inhibition (level of intermediary metabolism)
– Incorporation of antimetabolites (false NA chains)
Inhibition of metabolism (feed back mechanism)
– Classification of antimetabolites according to
substrates
Antimetabolites
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Antimetabolites
• Antifolates (dihydrofolate reductase inhibition)
• Antipyrimidines
– Uracil – fluorinated pyrimdines (5-Fluorouracil)
• Antipurines
– Guanin – hypoxantin
– Adenin – adenosin
• Ribonucleosid reductase inhibitors
– hydroxyurea
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Antimetabolites - Antifolates
• Methotrexate (MTX)
• Trimethotrexate
– Dihydrofolate reductase inhibition = dihyhrofolic acid can not be reduced to tetrahydrofolic acid.
– Active transport into the cells
– Tumor cells with altered transport mechanism are resistant
– HD MTX – passive transport (overcome the resistance)
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Antimetabolites - Antipyrimidines
• 5-fluorouracil (5-FU) – Regimes (examples):
• FOLFIRI – 5-FU + Folic acid + Irinotecan (breast)
• FOLFOX – 5-FU + Folic acid + Oxaliplatin (breast)
• IFL – 5-FU + Irinotecan (solid tumors)
• Cytarabine (Ara-C)
• Gemcitabine
• Capecitabine
5-FU g5-FUMP gFUTP and/or FdUMP
1. FUTP – incorporation into DNA = alteration
2. FdUMP (fluorodeoxyuridin monophosphate) thymidylate synthethase inhibition = disruption of DNA synthesis
– MTX potentiates effect of antipyrimidines
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Antimetabolites - Antipurines
• 6-Mercaptopurine
• Thioguanine
• Azathioprine
1. De novo purine synthesis inhibition
2. False precursor – nukleotidtriphosphate
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Antimetabolites - Antipurines
• Adenosine analogue
– Fludarabine
– Cladribine
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Antimetabolites - ribonucleotid reductase inhibitors
• Hydroxyurea
• Diarylsulfonylurea
– Structurally not related to nucleotide precursors
1. Ribonucleotid reductase inhibition = disruption in
DNA synthesis
2. Disruption of reparation altered DNA
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Alkylating agents
• Mechlorethamine – Regime MOPP: Non-Hodgkin s lymphoma
(mechlorethamine – vincristine/oncovine – prednisone – procarbazine)
• Chlorambucil
• Melphalan
• Oxaphosphorines
• Nitrosoureas
• Busulfan
• Estramustine
• Tetrazines
• Non-classified
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• Alteration of structure and function of nucleic acid –
inhibition of replication, transcription, translation
– Alkylation
• Simple substitution (substitution of base e.g. N7 guanine or
phosphate esterification)
• Bi-functional substitution – necessity of 2 radicals (groups) capable
to react between neighboring guanines of the same or parallel
(neighboring) chains
• Other mode of action – depurination and split of the DNA
(radiomimetic effect)
• Resistance mechanisms
– Increased endonuclease production (reparation of altered DNA)
– Increased contents of proteins with SH groups binding alkylation
agents
– Differences in transport mechanisms and properties functional group
Alkylating agents
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Alkylating agents - Oxaphosphorines
• Cyclophosphamide
– Regimen CHOP (cyclophosphamide +
doxorubicine + vincristine/o + prednisone –
NHL, B-CLL)
• Iphosphamide
• Maphosphamid
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• Carmustine (BCNU)
• Lomustine (CCNU)
• Streptozocine
Alkylating agents - nitrosoureas
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• Dacarbazine (DTIC)
– Combined mode of action (alkylation agent +
purine antimetabolite)
• Temozolomide
Alkylating agents - Tetrazines
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• Procarbazine
– Atypical alkylating agent
Alkylating agents – non-classified
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Antitumor antibiotics
• Antracyclines
• Drugs related to antracyclines
• Bleomycin
• Mitomycin C
• Dactinomycin
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• Alteration of structure and function of nucleic acid – inhibition of replication, transcription, translation
– Intercalation (vmezeření, vsuvka in Czech) • No covalent link (cytostatic – DNA)
– Topoizomerase II inhibition
– Cell membrane alteration
– Formation of oxygen radicals (superoxides and peroxides)
• Outcome – antracycline cardio toxicity
Antracyclines – Antitumor antibiotics
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Antracyclines – Antitumor antibiotics
• Doxorubicine
– Pegylated liposomal doxorubicine (CAELYX)
• Daunorubicin
• Idarubicine
• Epirubicine
• Related compounds - Mitoxantrone
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• Alteration of structure and function of nucleic
acid – inhibition of replication, transcription,
translation
– Split of DNA molecule (radiomimetic effect)
• Disruption on one or both DNA chains
• Formation of oxygen radicals (superoxides and peroxides)
• Ligase inhibition disable reparation of altered chains
– Decreased amino peptidase concentration results in lung and
skin alteration
Bleomycin - Antitumor antibiotics
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Alkaloids of plant origin
• Vinca-alkaloids
• Taxanes
• Camptotecine analogues
• Podophylotoxine alkaloids
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Alkaloids of plant origin
• Alteration of microtubular protein (spindle poison)
– Inhibition of polymeration (colchicin, vinca- alkaloids) disruption of mitosis in metaphase
– Inhibition of depolymeration (taxanes) accelerates formation of microtubues
– Outcome of both mechanisms same – alteration of mitosis
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Microtubules
Microtubule
Dynamics
G2
Mitosis
G1
S
Cell Death
Microtubule
Stabilizer
Depolymerization
Polymerization
Microtubules – outcome of targeted antitumor therapy
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Alkaloids of plant origin – Vinca-alkaloids
• Vincristine
• Vinblastine
• Vindesin
• Vinorelbine (i.v./oral)
– Outcome of inhibition – irregular distribution of
chromosomes (explosive metaphasis)
– Vinca-alkaloids reveal as well antimetabolic
effect and RNA-polymerase inhibition
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• Paclitaxel
• Docetaxcel (higher affinity to microtubules)
– Altered microtubules bundles and/or non-functional
formations (pseudo asters) – mitosis is extended from 30
min to 15 hrs.
– Taxanes disrupt transition from G2 to M phase –
radiopotentiation effect on cells in most sensitive phase
– Apoptotic inducer
Alkaloids of plant origin - Taxanes
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• Alteration of structure and function of nucleic
acid – inhibition of replication, transcription,
translation
– Topoizomerase I, inhibition – single strand
breaks in DNA
– Topoizomerases - enzymes, supporting changes
in sterical configuration during DNA replication
Topoizomerase I inhibitors do not reveal MDR
(multidrug resistance)
Alkaloids of plant origin - Camptotecin
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Topoisomerase I
Replication
DNA Ligase
DNA Polymerase
TOPO I
Replication Fork
3' 5' 5'
3'
Topoisomerase I Inhibitor
Replication Fork
3' 5'
3'
5'
TOPO I
Replication Fork
Replication
3' 5'
3'
5'
TOPO I
• Replication fork
encounters stabilized
Topo I DNA complex
• Replication stops
• DNA single-strand breaks
• Cell death
3' 5'
3'
5'
TOPO I
Topoisomerase I inhibition induces DNA breaks and cell death
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• Irinotecan – regime: IROX, IFL (solid tumors)
• Topotecan
Alkaloids of plant origin - Camptotecin
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Alkaloids of plant origin - Podofylotoxin
Alteration of structure and function of nucleic
acid – inhibition of replication, transcription,
translation
– Topoizomerase II inhibition
– Antitumor effect only in sufficient dose –
repeated dosage needed
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• Etoposide
• Tenoposide
Alkaloids of plant origin - Podofylotoxin
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Non-classified cytostatics
• Platinum cytostatics
– Mode of action similar to alkylating agents
alteration and inhibition of DNA synthesis
– Initiate intercalation bonds between DNA chains
• Non-essential amino acids
– L-asparginase – proteosynthetic inhibitor results
L-asparagine depletion. Resistance based on L-
asparaginsynthethase excessive production
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Platinum cytostatics
• Cisplatin (DDP)
• Carboplatin
• Oxaliplatin – regimes: FOLFOX, IROX (solid
tumors)
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Adverse effects o cytostatics
• Immediate – hrs-days
– Nausea, vomitus, renal insufficiency, rash, local reactions
• Early – days-weeks
– Leucopenia, thrombocytopenia, alopecia, stomatitis
• Delayed – weeks-months
– Anemia, pulmonary fibrosis, hyper pigmentation
• Late – months-years
– Sterility, hypogonadism, secondary malignancies
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Evaluation of toxicity according to WHO a CTC NCI
• Toxicity grades 0 – 4
0 – None / normal status
1 – Mild
2 – moderate
3 – Pronounced
4 – Severe / irreversible /life threatening
CTC = Common Toxicity Criteria
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Frequency of AE
• 1/10 Very frequent
– neutropenia, thrombocytopenia, anemia,
alopecia, vomitus
• 1/100 Frequent
• 1/1 000 Less frequent
• 1/10 000 Rare
• 1/100 000 Very rare
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Adverse effects o cytostatics
• Hemopoesis – Myelosupression, granulocytopenia, thrombocytopenia,
anemia – majority of cytostatics
• GI – Malabsorption, diarrhea
– Nausea and vomitus
• Very strong emetogen: cisplatin, cyclophosphamid
• Strong emetogen: carboplatin, doxorubicin
• Moderate emetogen: etoposid, methothreat
• Mild emetogen: busulfan, cyclophosphamid
p.o.
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Adverse effects o cytostatics • Skin and soft tissues
– Pigmentation, cellulites, alopecia, palmo-plantar erytema
– Alopecia
• Cardiotoxicity
– Arrhythmias, bradycardia – antracyclines, paclitaxel
• Lung toxicity
– Interstitial lung fibrosis – bleomycin
• Nefrotoxicity
– cisplatin
• Neurotoxicity
• Reproductive organ toxicity
• Ocular toxicity – cataracta (busulfan)
• Teratogenity
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Cumulative toxicity limiting therapy
Carboplatin trombocytopenia
Cisplatin peripheral neuropathy, nefrotoxicity
Paclitaxel peripheral neuropathy
Etoposid p.o. secondary leukemia, myelosupression
Vinorelbin leucopenia
Taxotere liquid retention
Ifosfamid leucopenia, anemia, nefrotoxicity
Doxorubicin hand-foot syndrome
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Mechanisms of resistance to cytostatics
Increased efflux
Cytostatics (MDR)
Transmembrane
P-glykoprotein
(doxorubicin, vinblastine…)
Decreased penetration
of cytostatic
(MTX) Increased intracellular
link of cytostatic
(glutathionový systém)
Change in intracellular
distribution of cytostatic
(e.g. to lysozomes)
Alteration of specific target
enzymes (e.g. DHFR u
rezistance to MTX)
Increased intensity
of reparation DNA
(alkylating agents)
Increased metabolic
turnover of cytostatic
to inactive metabolite
(ara-C)
Decreased metabolic
turnover inactive to
active compound
(5-FU, ara-c)
• Primary rezistance – tumor a priori resistant
• Secondary rezistance – acquired
Alteration of specific target
enzymes (topoizomerse II –
doxorubicin)
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Handling of cytostatics
• Cytotoxic, mutagenic and cancerogenic
substances – special hygienic regulations
• SOPs for handling with cytostatics
• Special working compartment
• Prevention of contamination and rules of
decontamination
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General rules of rational chemotherapy
Cyclic application and intervals
Specific rules for different cytostatics and tumors
• Initiate treatment asap.
• Combine more drugs to increase outcome
• Sufficient high doses
• Optimum application intervals
• Optimum intervals between cycles
• Fight residual disease after clinical remission
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General rules of rational chemotherapy
First choice Second choice
Broad spectrum
cytostatics
Low toxicity
cytostatics
Narrow spectrum
cytostatics
Cytostatics with
narrow
therapeutic index
Antracyklines
Cyclophosphamide
Nitrosourea
Cisplatin
Etopozide
Vinca-
alkaloids
Bleomycin
Dacarbazine
Hydroxyurea
Cytarabine
Mercaptopurin
Novel compounds
Mitomycin C
Novel compounds
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Treatment of progressive disease
0 m 6 m 12 m 18 m 24 m 30 m 36 m
Pretreatment
e.g. platinum
1st line
2nd line chemotherapy Remision Remision
3rd line chemoterapie
R E L A P S
R E L A P S
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• Induction th: – first aggressive therapy – outcome = remission (HD therapy, several cycles, AEs)
• Consolidation th: new combination to fight with resistant cells
• Re-induction th: residual disease management
• Maintenance th: dubious (small doses to prevent relapse)
Application of cytostatics (I)
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• Neoadjuvant – prior surgery or irradiation
– To reduce tumor mass
• Adjuvant – complementary to basic therapy
e.g. surgery
– Cure residual disease
Application of cytostatics(II)
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Influence of chemotherapy on tumor cell population
0
2
4
6
8
10
12
CH
CH
CH
CH
CH
CH
a b
imunotherapy
c
rela
ps
lethal borderline
cured
Nu
mb
er
of
tum
or
cell
s 1
0n
rem
isio
n
time
a = relaps after treatment
b = treatment delayed relaps
c = cured
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Therapy in oncology (I)
• Complex approach – palliative/curative
• Surgery
• Radiotherapy – External irradiation
– Internal irradiation
– Intraperitoneal (cave irregular distribution!)
• Cytostatics
• Immunotherapy, cytokines, imunotoxins, monoclonal antibodies
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Therapy in oncology (II)
• Systemic therapy:
– cytostatics - chemotherapy - cytotoxic nonselective effect
– hormonal - breast, endometrial and prostate carcinomas -
antiestrogen-tamoxifen
• Pain management, symptomatic therapy
Survival length and QoL
KPI (Karnofsky Performance Index 100 – 0) and WHO
scale 0 – 4
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Evaluation of therapeutic effect
• Extend of tumor reduction
• Duration of response
• Survival rate
• Toxicity
• Objective response (OR) – Measurable disease (WHO) – Change in sum of 2 largest
rectangular diameters
– Target lesions (NCI – RECIST) – Change in sum of largest diameter 5/organ 10/total
– Non-measurable lesions
• Intraabdominal, spinal, bone or diffuse brain metastatic lesions
WHO RECIST
RECIST = Response Evaluation Criteria in Solid Tumors
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Objective response (OR) evaluation (RECIST/WHO)
• Complete Response CR – Disappearance of measurable signs of disease documented during control as minimum after 4 weeks
• Partial Response PR – Decrease of measurable signs 30% and more documented during control as minimum after 4 weeks
• (WHO dtto, but 50%)
• Stable Disease SD – Does not fit into criteria for PR or PD. (WHO – no change NC)
• Progressive Disease PD – tumor growth or increase of measurable changes 20% more vs. least sum or new lesion (WHO 25% in 1 or more lesions or new lesion)
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• Disease free interval DFI – From complete remission first signs of relapse (patients in
complete remission)
• Time to progression TTP – From initiation of the therapy to the progression (patients
in PR, CR, NC)
• Overall survival OS – From first therapy (resp. first diagnosis) and death –
surviving patients are censored to the date of last visit
• Event = událost (úmrtí, relaps, progrese…)
• Time to event
• Follow up (další sledování)
Evaluation of duration of response
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Hormones a antihormones
• Estrogens
• Antiestrogens
• Progesterone
• Aromatase inhibitors
• Androgens
• Antiandrogens
• Corticosteroids
• Gonadorelin antagonists
• Others
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Mode of action od steroid hormones
S
SBG
S S
SR
S
SR x2
A
S
SR
A DNA
transcription mRNA
translation tRNA
proteosynthesis
polysomes
*SRE *GRE is encoded:
GGTACA nnn TGTTCT
1. Change
in cell
function
2. New
receptor
protein
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Estrogens – Antiestrogens – Progesterons
• Estrogens – Polyestradiol
– Estramustine
• Ca prostate
• Antiestrogens – (Selective Estrogen Receptor Modulator – SERM) – Tamoxifen
– Fulvestrant
– Raloxifen
• Disrupt link if estrogen on the level of ERE (estrogen response element)
• Proteinkinase C inhibitors
• Progesterons – Megestrol
– Medroxyprogesteron acetat
• Endometrial Ca, Progesterond decrease number of estrogen receptors
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Aromatase inhibitors
• Steroid
– Exemestan
• Non-steroid
– Aminoglutetimide
– Formestan
– Anastrozol
– Letrozol
• Aromatases convert androstendione and testosterone to
estrone and estradiol in suprarenal gland
• Inhibition = medicamentous adrenalectomy
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Androgens - Antiandrogens
• Androgens
– Testosterone propionate
• Breast cancer
• Antiandrogens
– Cyproteron acetat
– Nilutamid
– Bikalutamid
– Flutamid
• Prevent by competitive inhibition to link testosterone
and dihydrotestosterone on cellular receptors
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Glucocorticoids
• Prednisone
• Dexamethasone
– Inhibition of uridine entry into NA by decreasing
of RNA-polymerase activity
– Induce apoptosis in lymphocytes
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Gonadoliberin agonists
• Gosrelin
• Leuprolin
• Triptorelin
Gonadoliberins (LH a FSH)
– In physiological dose control gonad function
– In pharmacological dose suppress gonadotrophin release = pharmacological castration
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Retinoids and other differentiation inducers
• Tretinoin
• Izotretinoin
• Etretinate
• Vitamin D3
• Selective agonists of retinoid receptors
• Deltanoids
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Anticancer
therapy (2)
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Biological therapy and regulatory peptides
• Interleukins
• Hemopoetic growth factor
• Interferons
• Monoclonal antibodies
• Small molecules interfering with
intracellular signal transduction
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Interleukines – Imunomodulation cytokines
• IL-1 – ...
• IL-2 – T-cell growth factor (Aldesleukin -
Proleukin) Receptor IL-2R transduce signal
trigger by means of activation pathways:
– A. Mitogen Activated Protein Kinase cascade
(MAPK): outcome = cell proliferation
– B. fosfatidil-inositol-3 kinase pathway influencing
changes in cytoskeleton
– C. activation of Janus kinase (JAK1 a JAK3)
• …IL-18…
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Interleukin 2 (Aldesleukin)
• Indication
– in combination: 5-FU + IFNa + IL-2 (RCC) - 1. line
– Melanoblastoma
• Adverse events
– Capillary leak syndrome – hypotension, edema
intravascular hypovolemia
– Nefrotoxicity
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Grb2 Sos
Shc Grb2
Sos
PI3K Akt
Ras
Raf
MEK1/2
MAPK BAD
Survival Proliferation
PTEN
mTOR
Cell cycle - progression
FKHR GSK3 p27
Cyclin D1, E
Interleukin 2 (Aldesleukin) and signal transduction
IL-2
(Mitogen Activated Protein Kinase)
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Hemopoetic growth factors (I)
• Leukocyte growth factors
– Filgrastim (rHuG-CSF) – Neupogen,
• pegfilgrastim – Neulasta, Neupeg
– Lenograstim (G-CSF) – glykosilated
– Molgramostim (rHuGM-CSF)
– Sargramostim (rHuGM-CSF) – glycosilated
– Interleukin 3 (rHu-IL-3) Multi-CSF)
• Indication
– Neutropenia
– Shorten of neutropenic period in cytostatic therapy
– Prevention of febrile neutropenia
• Adverse events
– Musculoskeletal pain
– Dysuria
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Hemopoetic growth factors(II)
• Erythropoietin – glycoprotein – released by peritubular cells in the kidney – Epoetin a – Eprex, Epogen, Procrit
– Epoetin b – Neorecromon, CERA (PEG-Epo b)
– Epoetin d – Dynepo
– Epoetiny: g, e, z, o
– Darbepoetin a - Aranesp, Nespo • Indication
– Anemia Hb below 9-11 g/dl
» Renal origin
» CHRI
» Chemotherapy induced anemia (CIA)
» In malignant lymphomas, myelomas, MDS
• Adverse events
– Flu like syndrome
– Thrombotic vascular complication
– Increase of BP
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Interferones – Imunomodulation cytokines (I)
• Interferon alpha (IFN a) – leukocyte –
Roferon (2a), Introna, Viraferon (2b),
Infergen (akon-1)
– Indication – Oncology, infection diseases
• Interferon beta (IFN b) – fibroblastic –Avonex,
Rebif (1a), Betaferon (1b)
– Indication – Sclerosis multiplex
• Interferon gamma (IFN g) – T-lymphocyte –
Imukin
– Indication – Infection complications in chronic
granulomatosis
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• Mode of action of IFN a
– Antiproliferative – delays transit from G1 to S phase
– Imunomodulation – promote expression of cytotoxic
lymphocytes, macrophages and NK-cells participate on
induction of cytotoxc reaction
– Inhibition of viral replication
– Antitumor activity– suppresses expression of oncogens c-
myc, v-myc…
• Adverse events IFN a
– Thrombocytopenia is limiting factor for application of IFN a
– Flu-like syndrome (2 – 4 hr after application, last 4 – 8 hr)
Interferons – Imunomodulation cytokines (II)
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Murine MAb
100% murine
•Hypersensitivity
(not in use)
Chimeric MAb
34% murine
• Hypersensitivity
(rituximab)
Humanized MAb
5-10% murine
• Hypersensitivity
(trastuzumab)
Human MAb
100% human
• Hypersensitivity
(panitumumab)
Monoclonal antibodies
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Monoclonal antibodies in oncology
• Non-conjugated MAb
– Direct antitumor activity
• Induction of apoptosis
• Interference with receptor and ligand
• Influence of cytostatics (chemo + MAb – breast cancer)
• Conjugated MAb
– Toxins (pseudomonad, diphteric, ricin)
– Cytokines
– Radionuclides
– Cytostatics
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INN Brand Target structure Indication
trastuzumab Herceptin HER-2-neu Breast Ca
cetuximab Erbitux EGFr NSCLC, ORL
bevacizumab Avastin VEGF Various tumors
rituximab Mabthera CD-20 NHL, B-CLL
ibritumomab Zevalin (90Yt) CD-20 NHL
tositumomab Bexxar (131I) (131I) CD-20 NHL
epratuzumab CD-22 human. NHL
apolizumab HLA-DR NHL
alemtuzumab MabCampath CD-52 B-CLL
gemtuzumab Mylotarg CD-33 AML
oregovomab Ovarex CA-125 Ca ovaria
edrecolomab
panitumomab
Panorex CO-17-1A
EGFr
Ca kolorekta
Renal Ca (RCC)
Monoclonal antibodies in oncology
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INN Brand Indication
Thyrosinkinase inhibition
imatinib
dasatinib
Glivec
Sprycel
CML, GIST
CML
gefitinib Iressa NSCLC, ORL
erlotinib Tarceva NSCLC
semaxanib
lapatinib
sorafenib
Sugen – withdrawn
Tykerb
Nexavar
Colorectal Ca
RCC, Breast Ca, H + N
Liver Ca
Proteasom inhibition (multikatalytic protease complex)
bortezomib Velcade Multiple myeloma, NHL
Inhibition of signal transduction and proteasom
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Targeted antitumor therapy
• Small molecules interfering with intracellular
signal transduction
– EGFR (epidermal)
• Erlotinib
• Lapatinib (dual)
• Gefitinib
– VEGFR (vascular)
• Sorafenib
– PDGFR (thrombocytar)
• Imatinib
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ErbB receptor
• ErbB are tyrosine kinase receptors
• Receptor consist of 4 transmembrane
glycoproteins
ErbB1 - ErbB4
(HER1 - HER4)
• Structure of ErbB receptor - 3 domaines
– Extracellular (1)
– Tran membrane (2)
– Cytoplasmatic with TK activity (3)
– Similar structure in other TK receptors (VEGFR
a PDGFR)
(2)
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Dimerization of ErbB receptor
• 2 molecules of ErbB receptor
conjugates = (homo/hetero forma)
• This active form is capable to transduce
external stimuli into the cell
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Dimerization of ErbB receptor
ErbB1-1 ErbB2-2 ErbB2-3 ErbB1-2 ErbB2-4
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Increased expression
ErbB1 or ErbB2 Mutation
on ErbB1 Autocrine
loop
ErbB and tumors
All are potentially malignant
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Strategy of targeted therapy
Receptor
antagonists MAb TK inhibitors
Ligand-toxin conjugates
Antisense oligonukleotides
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Target of action of small molecules
MAb bind to
extracelular
epitopes may not
recognize mutations
Small molecules are active in mutations due to different binding site
Proteolytic cleavage
Mutation
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VEGF-A, -C, -D, -E
Angiogenesis
RAF
MEK
ERK
Sck
Migration
Paxillin
FAK
PLCg PKC
P
P
P
P
PI(4,5)P2 PI(3,4,5)P3
PTEN
PlGF
VEGF-A, -B
VEGFR-1 / Flt-1
VEGF-C, -D
VEGFR-3
Lymphangiogenesis
VEGFR-2 / KDR
Survival Permeability
Akt/PKB
PDK1,2
RAC
RAS
PI(4,5)P2 DAG
IP3 +
Ca++
TKI
PI3-K
VEGF receptors in angiogenesis
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Angiogenesis
• Solid tumors above 1-2 mm3 need oxygen and nutrition
• Angiogenesis is the only way
1-2 mm3
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Angiogenesis
• Tumor angioneogenesis is an answer to hypoxia
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Angiogenesis
• VEGF are angiogenic factors released by tumor
VEGF family:
• VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E
VEGF-B
VEGF-A
VEGF-E
VEGF-C
VEGF-D
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Angiogenesis
• VEGFs link to VEGFR receptors of endothelial cell
• 3 VEGF receptors exist: VEGFR-1, VEGFR-2, a VEGFR-3
• VEGFR-1 a VEGFR-2 stimulate angiogensis, VEGFR-3
stimulates both angiogenesis and lymphangiogenesis
VEGFR-1 VEGFR-2 VEGFR-3
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Angiogenesis
• Angiogenesis support tumor and metastatic growth
• Inhibition may influence tumor growth
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Methods to suppress angiogenesis
Control of angiogenc factors
suramin
antibidies anti VEGF (bevacizumab)
antibodies anti VEGF receptor
Proteinkinase inhibitors of VEGF receptor
(sorafenib, semaxanib, pazopanib, SU6668, ZD4190)
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Supportive
therapy
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Antiemetics in oncology
5-HT3 antagonists setrons
ondansetron, dolasetron, granisetron, tropisetron, palonosetron
D2/5-HT3 antagonists substituted benzamides
metoclopramid alizaprid
D2 antagonists butyrophenons
haloperidol droperidol
D2 antagonists substituted butyrophenons
domperidon
D2 antagonists fenothiazins
prochlorperazin chlorpromazin
Glucocorticoids dexamethason methylprednisolon
GABA Benzodiazepins
lorazepam alprazolam
Substance P/NK1 antagonists
aprepitant (EMEND)
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League of emetogenic potential
>90 % 1. Cisplatin 2. Dacarbazin 3. Dactinomycin 4. Cyclophosphamid 5. Carmustin 60-90 % 6. Prokarbazin 7. Doxorubicin 8. Cytarabin 30-60 % 9. Epirubicin 10. Ifosfamid 11. Methotrexat 10-30 % 12. 5-fluorouracil 13. Taxans <10 % 14. Bleomycin 15. Vinblastin 16. Vincristin 17. Chlorambucil
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AnticipationPsychical
influence
EarlyWithin first 24 h
DelayedAfter 24 h
Several days
Emesis in oncology
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Early and a delayed emesis after platinum therapy
0
10
20
30
40
50
60
70
80
90
100
0 12 24 36 48 60 72 84 96 108 120
(Intensity %)
(h)
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Setrons and emetic reflex
CNS
GIT periphery 5- HT3
receptors central 5- HT3
receptors
Afferent n. Vagus
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Structural formulae of serotonin and some setrons
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Mode of action of setrons
• Activation of 5 - HT3 receptor
fast depolarization
• Opening of ion channel
Transport of Ca++ into the cells
• Increased concentration of Ca++
Neurotransmitter release from n. ending
• Increase of c - GMP
Biological answer
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HT/JP 04/24/98
Pharmacokinetics of setrons*
tmax (h) CL (ml/h) t0,5 (h)
ondansetron 0,8 - 2,0 34 - 36 2,4 - 5,8
tropisetron 2,0 - 3,0 60**/100 7 - 8**/30 - 40
granisetron 1,5 - 3,5 15 - 50 3,0 - 10,0
dolasetron*** 0,8 - 1,0 35 - 63 4,0 - 9,0
palonosetron - 160t/66r +/- 40
**) fast metabolization, ***) resp. Hydrodolasetron
t = total, r = renal clearance
*) Bioavailability 50 - 80 %, protein binding 65 - 70 %
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Vomiting centre and connection
It is not anatomic structure it is function
determined part of Area postrema in IV.
chamber
Afferent impulses
– Not only from GIT, also from peritoneum,
gall bladder and liver
– CNS - intracranial hypertension,
psychogenic impulses, vestibule trigger
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Area postrema and vomiting center
IV. chamber
Vomiting
center
Nucleus tractus
solitarii
CTZ (central
trigger zone) is
located in Area
postrema
Direction of
CSF flow
Area
postrema
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Vomiting reflex
Process of emesis is in general
physiological response activated by
certain impulses
Participating
– Feeling of emesis, gastric stasis, rhythmical
contraction of respiratory and abdominal
muscles
– Increased salivation, paleness, sweating
Vomiting does not replace toxins from
organism
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Mediators of vomiting reflex
Serotonin - 5-HT3, antagonists (setrons)
Dopamine - D2, antagonists
(metoclopramide)
Histamin - H1, antihistamines (difenhydramine)
Acetylcholine- M, anticholinergics (scopolamine)
Other mediators - e.g. somatostatin,
g-amino-butyric acid
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Classification of 5-HT receptors
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Vomiting centre
5- HT3, NK1
D2, 5- HT3, NK1 Pain, smell
anticipation
Higher ctrs.
NTS
Cerebellum
Vestibule
nuclei
Vestibule
system Movement
AP
CTZ
Apomorfin, CuSO4,
Cytotoxic subst., morphin
5- HT3, 5- HT4 , NK1
Irradiation,
Cytotoxic subst.
Toxins
Abdominal visceral afferent nerves
n. Vagus M, H1
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AE of setrons a metoclopramide in %
headache obstipation diarrhoea fatigue
ondansetron 11 4 2 8
tropisetron 26 14 7 8
granisetron 18 3 5 9
dolasetron 22 2 8 10
metoclopramide 13 3 19 14
placebo 6 4 n 4
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Substance P/NK1 Antagonists
• Mode of action – Selective antagonist substance P/NK1 receptors
– No activity against 5-HT3, dopaminergic a steroid receptors (= different MoA)
– Additive effect to above mentioned receptors
• Pharmacokinetics and interactions – Bioavailability 65%
– Metabolism - P-450!!! (CYP 3A4, CYP 1A2, CYP 2C19)
– Elimination half live 9 – 13h (55% urine, 45% stool)
• AE – No significant AEs in comparison with standard therapy
setrons and dexamethasone
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Outcome of prevention of nausea and
vomiting in oncology
Progress in supportive therapy in
oncology
Intensifying of highly emetogenic
chemotherapy
Increase of QoL
Improvement of prognosis
Economic
consequences ?
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Economic consequences of the entry of
new therapies (example antiemetics)
Costs of new antiemetics with their
economic consequences negligible
Higher doses of cytostatics and further
intensifying of therapy increase direct costs
Improvement of prognosis related to further
survival, longer and more effective therapy
i.e.. increase of direct and indirect costs