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QSAR in CANCER ASSESSMENT
PURPOSE and AGENDA
Gilman VeithDuluth MN
May 19-21, 2010
Lethality
Sensitization
Birth Defect
Reproductive Impairment
Cancer
AlteredFunction
Altered Development
Gene Activation
Protein Production
Signal Alteration
Chemical Reactivity
Profiles
Receptor, DNA,
ProteinInteraction
s
Structure
Extinction
Cellular Organ
Mechanistic Profiling
In VivoTesting
Biological Responses
ITS and Adverse Outcome Pathway
Toxicant OrganismMacro
-Molecular Interactions
Molecular
Initiating
EventPopulation
Cellular & In Vitro Testing
PATHWAYS IN REACTIVE CHEMICALS
MichaelAddition
Schiff baseFormation
SN2
Acylation
MichaelAddition
Schiff baseFormation
SN2
Acylation
AtomCentered
Irreversible(Covalent)Binding
AtomCentered
Irreversible(Covalent)Binding
InteractionMechanisms
MolecularInitiatingEvents
In vivoEndpoints
Pr-S AdductsGSH OxidationGSH DepletionNH2 AdductsRN AdductsDNA Adducts
Pr-S AdductsGSH OxidationGSH DepletionNH2 AdductsRN AdductsDNA Adducts
In vitroEndpoints
Death
ImpairedGrowth
Impaired Development
Impaired Reproduction
Cancer
Membrane Alteration
___
Oxidative Stress
___
Genotoxicity
OXIDATIVE STRESS from GSH DEPLETION
Pr-S Adducts
GSH Oxidation
GSH Depletion
NH2 Adducts
RN Adducts
DNA Adducts
Oxidative
Stress
Cell toxicit
y
Other Effects
DirectGSH
Reactions
AlteredSynthes
is
Oxidation
How Many Ways to Deplete GSH? How Many Downstream Effects?
Karlberg et al. Chem. Res. Toxicol. 2008, 21,
53-69.
1. Haptenation; 2. Epidermal inflammation & LC activation; 3. LC migration; 4. DC: T cell interaction; 5. T cell proliferation; 6. Increase in hapten-specific T cells; 7. Hapten re-exposure; 8. Acute inflammation; 9. T cell-mediated inflammation
GROUPING BY CANCER PATHWAYS
Genotoxic Carcinogenesis Direct DNA damage through abiotic chemical “binding” Most electrophiles bind to many DNA/protein sites Metabolic differences impact cell, organ, species
sensitivity
Epigenetic Carcinogenesis Cytoxicity-induced cell proliferation Receptor-mediated pathways Disturbance of homeostatic control Loss of immune surveillance Oxidative Stress- Indirect DNA damage Loss of intercellular communication
Mode of Action
Receptor-mediated pathways
Disturbance of homeostaticcontrol
Loss of immune surveillance
Oxidative Stress- Indirect DNA damage
Loss of intercellular communication
Cytotoxicity-induced cell proliferation
GENOTOXICITY
Direct DNA Damage
Indirect DNA Damage
NON-GENOTOXICITY
Receptor-mediated pathways
Disturbance of homeostaticcontrol
Loss of immune surveillance
Oxidative Stress- Indirect DNA damage
Loss of intercellular communication
Cytotoxicity-induced cell proliferation
GENOTOXICITY
Direct DNA Damage
Indirect DNA Damage
NON-GENOTOXICITY
DNA Mechanism #1DNA Mechanism #2DNA Mechanism #3
DNA Mechanism #n……………………………
Prot Mechanism #1Prot Mechanism #2Prot Mechanism #3……………………………Prot Mechanism #n
AR BindingER BindingAromatase Inh.Thyroid Disturbance
Mechanism/AlertMode of action
Receptor-mediated pathways
Disturbance of homeostaticcontrol
Loss of immune surveillance
Oxidative Stress- Indirect DNA damage
Loss of intercellular communication
Cytotoxicity-induced cell proliferation
GENOTOXICITY
Direct DNA Damage
Indirect DNA Damage
NON-GENOTOXICITY
Mechanism/Alert
DNA #1DNA #2DNA #3
DNA #n………….
Prot #1Prot #2Prot #3…………..Prot #n
AR BindingER BindingAromatase Inh.Thyroid Disturbance
Mechanism/Metabolites
DNA Mechanism #1-Met 1…mDNA Mechanism #2-Met 1…mDNA Mechanism #3-Met 1…m
……………………………DNA Mechanism #3-Met 1…m
Prot Mechanism #1 - Met 1..mProt Mechanism #2 - Met 1..mProt Mechanism #3 - Met 1..m
……………………………Prot Mechanism #n - Met 1..m
Receptor-mediated pathways -Met 1…m
Disturbance of homeostatic control -Met 1…m
Loss of immune surveillance-Met 1…m
Oxidative Stress- Indirect DNA damage -Met 1…m
Loss of intercellular comm.-Met 1…m
Cytotoxicity-induced cell proliferation-Met 1…m
Mode of action
Receptor-mediated pathways
Disturbance of homeostaticcontrol
Loss of immune surveillance
Oxidative Stress- Indirect DNA damage
Loss of intercellular communication
Cytotoxicity-induced cell proliferation
GENOTOXICITY
Direct DNA Damage
Indirect DNA Damage
NON-GENOTOXICITY
Mechanism/Alert
DNA #1DNA #2DNA #3
DNA #n………….
Prot #1Prot #2Prot #3…………..Prot #n
AR BindingER BindingAromatase Inh.Thyroid Disturbance
Mechanism/Metabolites
Receptor-mediated pathways -Met 1…m
Disturbance of homeostatic control -Met 1…m
Loss of immune surveillance-Met 1…m
Oxidative Stress- Indirect DNA damage -Met 1…m
Loss of intercellular comm.-Met 1…m
Cytotoxicity-induced cell proliferation-Met 1…m
DNA #1-Met 1…mDNA #2-Met 1…m
……………………………DNA #3-Met 1…m
Prot #1 - Met 1..mProt #2 - Met 1..mProt #3 - Met 1..m……………………………Prot #n - Met 1..m
DNA #3-Met 1…m
In vitro data
Ames Ames+S9 CA CA+S9 MLA MLA+S9 CTA
Mode of action
Receptor-mediated pathways
Disturbance of homeostaticcontrol
Loss of immune surveillance
Oxidative Stress- Indirect DNA damage
Loss of intercellular communication
Cytotoxicity-induced cell proliferation
GENOTOXICITY
Direct DNA Damage
Indirect DNA Damage
NON-GENOTOXICITY
Mechanism/Alert
DNA #1DNA #2DNA #3
DNA #n………….
Prot #1Prot #2Prot #3…………..Prot #n
AR BindingER BindingAromatase Inh.Thyroid Disturbance
Mechanism/Metabolites
Receptor-mediated pathways -Met 1…m
Disturbance of homeostatic control -Met 1…m
Loss of immune surveillance-Met 1…m
Oxidative Stress- Indirect DNA damage -Met 1…m
Loss of intercellular comm.-Met 1…m
Cytotoxicity-induced cell proliferation-Met 1…m
DNA #1-Met 1…mDNA #2-Met 1…m
……………………………DNA #3-Met 1…m
Prot #1 - Met 1..mProt #2 - Met 1..mProt #3 - Met 1..m……………………………Prot #n - Met 1..m
DNA #3-Met 1…m
In vitro data
Ames
Ames+S9
CA
CA+S9
MLA
MLA+S9
CTA
In vivo data
COMET UDS CA MN(BN) CTA RCA
Mode of action
SCREENING LEVEL HAZARD ID
Direct DNA
Binding
Nongenotoxic
Mechanisms
ActivatedMetabolites
Indirect DNA
Damage
ParentChemica
l Individual
Initiating Events/Structur
al Alerts
Grouping Data for Interacti
onCategori
es
StructuralEvidence
of Cancer
Potential
Category with
Data for Cancer Potential
No EvidenceOf Cancer Potential