QSAR in CANCER ASSESSMENT PURPOSE and AGENDA Gilman Veith Duluth MN May 19-21, 2010.

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







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







GENOTOXICITY

Direct DNA Damage

Indirect DNA Damage

NON-GENOTOXICITY

Mechanism/Alert

DNA #1DNA #2DNA #3

DNA #n………….

Prot #1Prot #2Prot #3…………..Prot #n


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







GENOTOXICITY

Direct DNA Damage

Indirect DNA Damage

NON-GENOTOXICITY

Mechanism/Alert

DNA #1DNA #2DNA #3

DNA #n………….










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







GENOTOXICITY

Direct DNA Damage

Indirect DNA Damage

NON-GENOTOXICITY

Mechanism/Alert

DNA #1DNA #2DNA #3

DNA #n………….










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

QSAR in CANCER ASSESSMENT PURPOSE and AGENDA Gilman Veith Duluth MN May 19-21, 2010.

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