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Part 1:
Tumor Biology and KineticsIntroduction of Cytotoxic Agents
Pharmacologic Anti-Cancer Treatments Seminars 2007:
Carlos Linn, M.D. 林錦洲 醫師Clinical Research Physician, Oncology
Lilly Oncology
Board Certified Gynecologic Oncologist
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Cellular Kinetics
• Human body contains 5x1013 cells
• Cells can either be - non dividing and terminally
differentiated - continually proliferating- rest but may be
recruited into cell cycle
• Tumour becomes clinically detectable when there is a mass of 109 cells (1g)
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DEATHDEATH
DIFFERENTIATIONDIFFERENTIATION
DNA content = 2nDNA content = 2n
MitosisMitosis
MM
SSDNA synthesisDNA synthesis
GG22
GG11
GG00
DNA content = 4nDNA content = 4n
The Cell Cycle
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The Cell Cycle
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CANCER CELLS NORMAL CELLS
Loss of contact inhibition
Increase in growth factor secretion
Increase in oncogene expression
Loss of tumor suppressor genes
Oncogene expression is rare
Intermittent or coordinatedgrowth factor secretion
Presence of tumor suppressorgenes
FrequentFrequentmitosesmitoses
NucleusNucleus
Blood vesselBlood vessel
AbnormalAbnormalheterogeneous cellsheterogeneous cells
NormalNormalcellcell
FewFewmitosesmitoses
Cancer Cells and Normal Cells
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GrowthFactor
Growth FactorReceptor
Paracrine (Adjacent cells)
Growth Factor and Receptor Synthesis
PostPostreceptor signalreceptor signaltransductiontransductionpathwayspathways
Gene Activation
Oncogenes
Autocrine stimulation
Growth Factors and Oncogenes
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NORMAL GROWTH ANDNORMAL GROWTH ANDDEVELOPMENTDEVELOPMENT
NORMAL EXPRESSION & NORMAL EXPRESSION & RESPONSIVE ONCO SUPPRESSION GENERESPONSIVE ONCO SUPPRESSION GENE
MUTAGENIC orMUTAGENIC orCARCINOGENIC AGENTSCARCINOGENIC AGENTS
VIRAL ONCOGENEVIRAL ONCOGENE
Oncogenesis
CELLULARCELLULARONCOGENEONCOGENE
INCREASED OR ABNORMALEXPRESSION
CANCERGROWTH
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Example: Oncogenesis Integrated by HPV
Beutner, KR et al, "Human Papillomavirus and Human Disease." Am J Med 1997; 102(5A):9-15.
Complete viral Complete viral life cycle with life cycle with KoliocytosisKoliocytosis Virus Virus duplicationduplication
Integration of Integration of HPV DNA HPV DNA genome E6, E7 genome E6, E7 into Host-cell into Host-cell Immortally Immortally malignantmalignantNO more NO more KoliocytosisKoliocytosis Virus stops Virus stops duplicationduplication
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E6, E7 Protein involvement in cell cycle
regulation
Cell cycle proteins, influenced by E6, E7 proteins
E6 Bind and Degrade p53:
Loss of p53-induced apoptosis/G1 arrest of the cell cycle; reduces p53 protein via degradation.
E7 releases the E2F transcription factor by binding Rb (retinoblastoma protein), promoting cell cycle progression
transcriptional deregulation of cell cycle control, uncontrolled cell proliferation
intracellular control - cyclin-intracellular control - cyclin-dependent kinase inhibitors (CKI) dependent kinase inhibitors (CKI)
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CYCLIN DEPENDENT KINASES
tyr15-P
P-thr161
thr14-P
e.g. cdk1 (= cdc2)
- protein kinase- binds to cyclin- kinase domain- regulatory domain- present throughout cell cycle
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CYCLINS
- No intrinsic enzymatic activity- Binds cdk- Synthesized and degraded each cycle- Essential component for cdk activity
e.g. Cyclin Be.g. Cyclin B
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CYCLIN / CDK
tyr15-P
P-thr161
thr14-P
cdk1cdk1(cdc2)(cdc2)
cyclin Bcyclin B
• Regulated by:• - tyr15 phosphorylation
• inhibitory kinases• activating phosphatases
• - Direct interaction• inhibitory proteins
• p21, p27, p57• p16, p15, p18,p19
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CELL CYCLE CHECKPOINTS
G2
G1
S
M
CYCLIN E / cdk 2CYCLIN E / cdk 2
CYCLIN D / cdk 4,5,6CYCLIN D / cdk 4,5,6
CYCLIN A / cdk 2
CYCLIN B / cdk 1CYCLIN B / cdk 1
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Variation in Cell Cycle Cyclins
M G1 G2S M G1
Start
Cell cycle phases
Cyclin-dependent kinases (CDK)
D E A B(A)CyclinsCyclins
CDK 4 CDK 2 CDK 1
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G1
Cell Cycle
G0
6-8 h
DNA, RNA, Protein
3-4 h
RNA, Protein
1 h
Mitosis, Cytokinesis
S
G2 Cyclin D’s
CDK4,6Cyclin B/A
CDK1
Cyclin A
CDK2
M
Cyclin E
CDK2
6-12 h RNA, Protein
p53pRb
LaminH1Abl
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E6, E7 involvement in cell cycle regulation DNA damageDNA damage
Phosphorylation
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DNA Damage - Cell Cycle ArrestDamage Dependent Checkpoints
CELL No.
DNA content DNA content
AsynchronousX-ray treatedX-ray treatedG1/S blockG1/S blockG2/M blockG2/M block(6-9 hours)(6-9 hours)
G1 - S - G2
wild-type
Loss of G1/S in p53 deficientcells
G1 - S - G2
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G1/S CHECKPOINTIN RESPONSE TO DAMAGE
strandbreak
p53 p21
P-tyr15
cdk2
cyclin Ecyclin E
p21 = CKI class (cyclin dependent kinase inhibitors)N-terminal of p21 forms complex with cyclin / cdk - inhibit kinase
X-rays
ATM
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pRbpRb
Cell Cycle Regulation
CDK2CDK2
CECE
E2FE2FEnzymes for DNA synthesis
Passage from G1 to S
DNA damage1. CDK phosphorylation
2. C degradation
3. C & CDK synthesis
4. CDK inhibition
pRbpRb
P
Active p53
p21p21
pRbpRb
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Gene Transcription
G0G1
Priming
S
G2
M
Cell CycleCell Cycle
Growth Factors
++
Growth Factors & Cell Cycle
Receptors
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Retinoblastoma protein (pRb) & CDK inhibitors: p21, p27, p16
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The Normal Cell Cycle &“Cyclins” of the cell cycle
Normal cell cycle (with tumor suppression and apoptosis)
Neoplastic cells (immortal)
E5 protein
E6, E7: immortalize E6, E7: immortalize human keratinocytehuman keratinocyte
G1 arrest
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Common Chemotherapeutic Agents
• Alkylating agents
• Antimetabolites
• Antitumor Antibiotics
• Alkaloids
• Taxanes
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Classes of antineoplastic drugs
• Alkylating agents• Interact directly with cellular DNA
• Antimetabolites• Resemble cellular metabolites (folic acid, purine, pyrimidine)• Interfere with DNA precursors & cellular metabolism
• Antitumor antibiotics• Derived from soil fungus, some antiinfective activity• Interfere with DNA activity
• Mitotic Inhibitors• Derived from plant extracts• Interfere with formation of mitotic spindle, arresting mitosis
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Alkylating agentsAlkylating agents Carboplatin, cyclophosmamide, melphalan, thiotepa
AntimetabolitesAntimetabolites Methotrexate, fluorouracil, gemcitabine
Natural ProductsNatural Products doxorubicin, docetaxel, vinolbine, topotecan
Endocrine agentsEndocrine agents Anastrozole, tamoxifen, prednisolone, goserelin
Molecularly targeted agentsMolecularly targeted agents Retinoids, trastuzumab, gefitinib
Biologic response modifiersBiologic response modifiers Interferon, thalidomide, filgrastim
(Form bonds with nucelic acids and proteins)
(similar to metabolites involved in nucelic acid synthesis)
(anti tumour antibiotics,mictotubule stabilizer, mitotic inhibitor, topoisomerase inhibiotor)
(Aromatase inhibitors, oestrogen antagonist, corticosteroids, LHRH agonist)
(gene expression, monoclonal antibody, tyrosine kinase inhibitor)
Antineoplastic Agents
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Alkylating Agents
• Interact with DNA causing substitution reactions, cross-linking reactions or strand breaks
• Example: cisplatin
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Antimetabolites
• Cytotoxic effects via similarity in structure or function to naturally occurring metabolites involved in nucleic acid synthesis—either inhibit enzymes involved in nucleic acid synthesis or produce incorrect codes
• Example: methotrexate, pemetrexed, gemcitabine, 5-FU
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Antitumor Antibiotics
• Group of related antimicrobial compounds produced by Streptomyces species in culture
• Affect structure and function of nucleic acids by:– Intercalation between base pairs (doxorubicin),
– DNA strand fragmentation (bleomycin),
– Cross-linking DNA (mitomycin)
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Alkaloids
• Bind free tubulin dimers
• Disrupting balance between microtubule polymerization and depolymerization
• Arrest of cells in metaphase
• Examples: vincristine, vinblastine, vinorelbine
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Taxanes
• Disrupt equilibrium between free tubulin and microtubules
• Stabilization of cytoplasmic microtubules
• Formation of abnormal bundles of microtubules
• Examples: paclitaxel and docetaxel
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Paclitaxel & Docetaxel
1971
1986
OH
European Yew: Taxus baccata
Pacific Yew: Taxus brevifolia
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BUSULFAN CYTOSINE ETOPOSIDE BLEOMYCIN L-ASPARAGINASE
CARMUSTINE ARABINOSIDE TENIPOSIDE DACTINOMYCIN HYDROXYUREA
CHLORAMBUCIL FLOXURIDINE VINBLASTINE DAUNORUBICIN PROCARBAZINE
CISPLATIN FLUOROURACIL VINCRISTINE DOXORUBICIN
CYCLOPHOSPHAMIDE MERCAPTOPURINE VINDESINE MITOMYCIN-C
IFOSFAMIDE METHOTREXATE TAXOIDS MITOXANTRONE
MELPHALAN GEMCITABINE TAXANES PLICAMYCIN
PEMETREXED ANTHRACYCLINES
EPOTHILONES
ALKYLATING
AGENTS
ANTI-
METABOLITES
MITOTIC
INHIBITORSANTIBIOTICS OTHERS
Classification of Cytotoxic Agents
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Antibiotics
Antimetabolites
S(2-6h)
G2
(2-32h)
M(0.5-2h)
Alkylating agents
G1
(2-h)
G0
Vinca alkaloids
Mitotic inhibitors
Taxoids
Sites of Action of Cytotoxic Agents – Cell Cycle Level
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Types of chemotherapy
• Cell cycle dependent – Cell cycle phase specific
• Cell cycle independent – Cell cycle phase non-specific
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Cycle-Specific Agents
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DNA synthesis
AntimetabolitesAntimetabolites
DNA
DNA transcription DNA duplication
Mitosis
Alkylating agentsAlkylating agents
Spindle poisons & Spindle poisons &
Microtuble StablizersMicrotuble Stablizers
Intercalating agentsIntercalating agents
Sites of Action of Cytotoxic Agents – Cellular Level
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6-MERCAPTOPURINE6-THIOGUANINE
METHOTREXATE5-FLUOROURACIL
HYDROXYUREAPEMETREXED
CYTARABINEGEMCITABINE
PURINE SYNTHESIS PYRIMIDINE SYNTHESIS
RIBONUCLEOTIDES
DEOXYRIBONUCLEOTIDES
DNA
RNA
PROTEINS
MICROTUBULESENZYMES
L-ASPARAGINASE
VINCA ALKALOIDS
TAXOIDS
ALKYLATING AGENTS
AKYLATING LIKE
(INTERCALATING)
ANTIBIOTICS
ETOPOSIDE
Sites of Action of Cytotoxic Agents
TOPOISOMER
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EXTRACELLULAR INTRACELLULAR
ATPATP
PGPPGP170170 ATPATP
DrugDrug
DrugDrug
PlasmaPlasmaMembraneMembrane
Drug Resistance
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Effect of tumorgrowth kinetics
Tubulin binding sitemutations
P-gp = P-glycoprotein.Dumontet and Sikic. J Clin Oncol. 1999;17:1061.
P-gp mediated drug efflux
Taxanes
Mechanisms of Taxane Resistance
Inhibition of apoptotic signaling
Altered metabolism by host
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Taxane Resistance Mediated through
Multidrug Resistance (MDR)
• MDR is mediated by mdr1 gene amplification encoding P-gp
• P-gp is a cell membrane protein
• Overexpressed in some chemoresistant tumors
• In chemosensitive tumours, can be upregulated after therapy
• Anthracyclines, taxanes, vinca alkaloids are P-gp substrates
NBF = nucleotide binding factor
2 3 4 5 6 7 8 9 10 11 12
Extracellular
Intracellular
NH2
NBF1 NBF2 COOH
1
me
mbra
ne
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Anti-Folate Transporters
Reduced Folate Carrier (RFC) THFs
Methotrexate, 5-FU,
Raltitrexed (Tomudex)
Pemetrexed (ALIMTA®)
Folate Receptor (FR-α)
Rothberg KG et al., J Cell Biol. 110: 637-649, 1990.Folic Acid, THFs
CB 3717l
Pemetrexed (ALIMTA®)
Efflux by MRP
Westerhof GR et al., Mol. Pharmacol 48: 459-471, 1995Zhao R et al., Clin Cancer Res 6: 3687-3695, 2000Pratt SE et al., Proc. Am. Assoc. Cancer Res 43: 782, 2002
MethotrexatePemetrexed (ALIMTA®)
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ADP
ATP
ALIMTA
MRPs
Multiple Drug Resistance Proteins &
Anti-Folate Drug Resistance
Reduced Folate CarrierReduced Folate Carrier
Low affinity for folic acid
High affinity for antifolates
High activity in malignant tissue
Membrane Folate ReceptorMembrane Folate Receptor
High affinity for folic acid
Low affinity for antifolates
High expression in certain malignancies (mesothelioma, ovary)
MDRs: Multiple Drug MDRs: Multiple Drug Resistance Resistance ProteinsProteins
RFC
Folate receptor
(cell membrane)
MFR
Anti-folate
Anti-folateAnti-folate
Anti-folate
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Tumour kinetic
Growth rate depends on:
growth fraction
-percent of proliferating cells within a given system
-human malignacy ranges from 20-70%
-bone marrow 30 %
cell cycle time
-time required for tumour to double in size
rate of cell loss
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Doubling times of some human tumours
Burkitt’s lymphoma 1.0
Choriocarcinoma 1.5
Hodgkin’s disease 3-4
Testicular embryonal carcinoma 5-6
Colon 80
Lung 90
Tumour Doubling times (days)
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Tumor Kinetics – Original Hypothesis
• Conventional views in the field of oncology support the notion that:
– tumor growth is exponential
– chemotherapy treatment is designed to kill in log intervals (kills constant fractions of tumor)
• Currently, chemotherapy for ovarian cancer is administered in 3-week intervals.
• Combination therapy and increased drug dose levels aim at improving ovarian cancer chemotherapy.
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Gompertzian Growth
• Growth rates are exponential at early stages of development and slower at later stages of development.
- Biological growth follows this characteristic curve.- Biological growth follows this characteristic curve.
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Gompertzian growth model
Initial tumour growth is first order, with later growth
being much slower
Smaller tumour grows slowly but large % of cell dividing
Medium size tumour grows more quickly but with
smaller growth fraction
Large tumour has small growth rate and growth fraction
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number of number of cancer cellscancer cells
diagnosticdiagnosticthresholdthreshold
(1cm)(1cm)
timetime
undetectable undetectable cancercancer
detectable detectable cancercancer
limit ofclinical
detection
hostdeath
10 10 1212
10 10 99
Tumor Growth
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Rationales in Human Cancers
• Small tumors grow faster than larger tumors
• Human cancers grow by non-exponential Gompertzian kinetics
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Principle of chemotherapy
First order cell kill theory
- a given dose of drug kills a constant percentage of tumour cells rather than an absolute number
Maximum kill
Broad coverage of cell resistance
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Theoretical Tumor Kinetics
Tumour Surviving cells Viable mass Recovery of tumour kill (%) (doubling time)
untreated 109 1g -90 (1-log) 108 100mg 3.33 days99 (2-log) 107 10mg 6.66 days99.9 (3-log) 106 1mg 9.99 days99.99 (4-log) 105 100μg 13.3 days
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3 LOG KILL, 1 LOG REGROWTH
Time
TU
MO
R C
EL
L N
UM
BE
R
Chemotherapy
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The rate of tumor volume regression is proportional to the rate of growth.
Tumor cell regrowth can be prevented if tumor cells
are eradicated using a denser dose rate of cytotoxic therapy.
Tumors given less time to grow in between treatments are more likely to be destroyed.
Hypothesis of Alternative Intervals
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Principle of chemotherapy
Rationale for combination chemotherapy
Different drugs exert their effect through different mechanisms and at different stages of the cell cycle, thus maximize cell kill
Decease the chance of drug resistance
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Thanks for Your Attention
To Be Continued…..
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CYCLOPHOSPHAMIDE
4-OH CYCLOPHOSPHAMIDE
ALDOPHOSPHAMIDE
PHOSPHORAMIDE
MUSTARD
4-KETOCYCLOPHOSPHAMIDE
CARBOXYPHOSPHAMIDE
ACROLEIN
HEPATICCYTOCHROMES
P 450ACTIVATION
CYTOTOXICITYTOXICITY
INACTIVATION
ALDEHYDE
DEHYDROGENASE
Example: Metabolism of Cyclophosphamide