Toxicology - Chemical carcinogenesis

What is cancer?

groups of cells:

• uncontrolled growth (a lot of cell divisions)

• invasion (intrusion on and destruction of adjacent tissues)

• Metastasis (spread to other locations in the body via lymph or blood)

• there are benign (friendly) and malignant tumors

What are characteristics of the two different types of tumors?

Benign:

• well differentiated

• there is no infiltration (capsule)

• it has slow growth

• there is no necrosis

Malignant:

• is poorly differentiated

• there is infiltration

• no capsule

• fast growth

• necrotic tissue

What is the leading cause of death?

cancer —> 8.2 million cases world wide

1. lung cancer

2. liver cancer

3. stomach cancer

4. colorectal cancer

5. breast cancer

6. oesophagus cancer

Different which cancer based on gender

What are the main cancer risk factors?

1. diet

2. tobacco

3. infection

4. reproductive and sexual behavior

How is cancer induced chemically?

Mutations —> regulations of cell divisions —> cancer

• multistep process

How do you go from a mutation to cancer?

The regulation of the cell cycle:

• mutations of two types of cell cycle regulators may promote cancer development

  • overactivation of positive regulators (oncogenic)

  • inactivation of negative regulators (inhibition of tumour supressors)

What does oncogenic mean?

overactivation of positive regulator

What are proto-oncogenes?

genes with a normal function in regulating cell division

what are the mutations caused by proto-oncogenes?

• “always on” protein

• Amplification (more protein)

• “combo” unregulated

What do proto-oncogenes turn into?

Oncogenes —> transformed genes causing uncontrolled cell division

How does tumour suppression work?

This is a gene that normally blocks cell cycle progression (in response to DNA damage)

1. active tumour suppression gene is inactivated

2. inactive tumour suppressor genes —> no control of cell division of cells (with damage to DNA)

What is cancer?

the loss of control over cell division

• changes in genes involved in the cell cycle

no single event is enough to turn a cell into a cancerous cell (multi-step)

Accumulation of damage to a number of genes (multiple hits) across time leads to cancer

What is the difference between genotoxic and non-genotoxic carcinogens?

Genotoxic carcinogens —> every molecule increases cancer risk

Non-genotoxic carcinogens —> a threshold/safe level of exposure can be defined

What is an example of chemical carcinogenesis?

• PAHs

  • Benzo[a]pyrene (cigarette smoke, charbroiled food [is a PAH]) —> need metabolic activation

• genotoxic carcinogens

  • Aflatoxin B1 (mycotoxin on rice, cereals, peanuts) —> need metabolic activation

Explain the P53 tumor protein?

normal —> can bind to damaged DNA

• stops cell division

non functional —> cannot bind to damaged DNA

• cell cycle progresses

What are non-genotoxic chemicals?

They:

• have no direct binding of chemical to DNA

• no direct damage

• no interaction of chemical or metabolite with DNA

Are chemicals that:

cause cell death and aberrant repair (usually at high

concentrations only)

Affect metabolism of chemicals (P450 enzymes)

Affect cell growth (up)

● Induce DNA synthesis (up) -> gene expression (up)

● Affect hormonal system

● Induce production of reactive oxygen species

What is an example of a indirect genotoxic chemical?

• Reactive oxygen species (ROS) —> effects: gene transcription and cell proliferation

• Dioxins (TCDD) —> activate aryl hydrocarbon receptors

• Asbestos fibers —> frustrated phagocytosis: activates macrophages —> inflammation & ROS production —> followed by fibrosis (increased collagen deposition) —> asbestosis (lung fibrosis) —> lung cancer —> malignant mesothelioma

How are carcinogens classified?

• G1 —> carcinogenic

• G2 —> probably carcinogenic

• G 2B —> possibly carcinogenic (no longer needs to be forbidden)

• G3 —> cannot be classified (lack of data)

• G4 —> proven to be non-carcinogenic

What are limitations of carcinogenic studies?

• high doses needed to find effects

• difficult to extrapolate to low doses (real-life exposure)

• considered unethical

• predictive

• rats or mice arent humans