Lecture 10.1 - Neoplasia 3

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Questions and Answers

What is the primary reason for incubating bacteria with a rat liver S9 fraction in the Ames test for mutagenicity?

To provide a source of histidine for bacterial growth

To facilitate the metabolic activation of carcinogens (correct)

To simulate the human liver's detoxification mechanisms

To inhibit the growth of non-mutagenic bacteria

What is the correlation between mutagenic and carcinogenic activity observed in some studies?

75%

100%

90% (correct)

50%

What is the suspected outcome of exposing humans to most known carcinogens in experimental animals?

They may be carcinogenic in some humans, but not others

They are always non-carcinogenic in humans

They are potentially carcinogenic in humans, but documentation is lacking (correct)

They are likely to be non-carcinogenic in humans

What is the characteristic of many carcinogens that must be metabolized to form reactive species?

They are electron acceptors Signup and view all the answers

What is the result of a reversion to the wild type phenotype in the Ames test?

The bacteria are able to grow in the absence of histidine Signup and view all the answers

What is the primary mechanism of chemical carcinogenesis?

Reaction with cellular nucleophiles Signup and view all the answers

What is the primary reason for the decreased incidence of cancer of infectious origin in immigrants to the United States?

Reduced exposure to infectious agents in the host country Signup and view all the answers

What is the name of the first pure carcinogen synthesized in 1929?

1,2,5,6-dibenzanthracene Signup and view all the answers

What is the primary mechanism of action of the Ames test?

Measuring mutagenicity in Salmonella strain Signup and view all the answers

What is the primary criterion for selecting compounds for testing as potential carcinogens?

Compounds related to known carcinogens Signup and view all the answers

What is the name of the scientist who proposed a mutation theory of carcinogenesis in the early 1900s?

Boveri Signup and view all the answers

What is the primary advantage of in vitro testing of chemical carcinogens?

Reduced cost Signup and view all the answers

What type of cancer has been linked to infection with Helioobacter pylori?

Stomach cancer Signup and view all the answers

What is the name of the virus that causes cervix cancer?

Human papilloma virus Signup and view all the answers

What is the result of the reaction between carbonium ions and guanine in the metabolism of nitrosamines?

Formation of an O6-methyl derivative Signup and view all the answers

What is the mechanism of benzo(a)pyrene activation?

Formation of epoxides Signup and view all the answers

What is the role of initiation in the process of carcinogenesis?

Induction of a mutation in a critical gene involved in the control of cell proliferation and/or apoptosis Signup and view all the answers

What is the result of the promotion stage of carcinogenesis?

Selective growth enhancement of initiated cells Signup and view all the answers

What is the target of mutational activation in the initiation of carcinogenesis?

Growth factor receptors and downstream signalling proteins Signup and view all the answers

What is the result of mutational inactivation of DNA repair mechanisms during initiation?

Decreased efficiency of DNA repair Signup and view all the answers

What is the role of cell division in the initiation of carcinogenesis?

One or more rounds of cell division are required for the fixation of the process Signup and view all the answers

What is the characteristic of the initiation stage of carcinogenesis?

Irreversible Signup and view all the answers

Study Notes

Mutation and Carcinogenesis

Mutation can result in a reversion to the wild type phenotype, permitting growth in the absence of histidine.
The Ames test is used to measure mutagenicity in a Salmonella strain that requires histidine for growth.

Theoretical Basis of Mutagenicity Tests

There is a good but not perfect correlation between mutagenic and carcinogenic activity, with a correlation of around 90% for large numbers of compounds.

Chemical Carcinogens

Many carcinogens require metabolic activation, and the bacteria are incubated with a rat liver S9 fraction to test for this.
The number of known carcinogens in experimental animals is large, and it is suspected that most of these are potentially carcinogenic in humans.
Good evidence of carcinogenicity in humans exists for certain substances, including those linked to infectious diseases such as hepatitis B and human papilloma virus.

Carcinogen Metabolism and Activation

Chemical carcinogenesis is associated with reaction with cellular nucleophiles (electron donors).
Many carcinogens must be metabolized to form electrophilic species (electron acceptors).
Organic compounds with double bonds may be metabolized to form reactive epoxides.

History of Carcinogenesis Research

The first chemical induction of cancer in laboratory animals was achieved by Yamagiwa and Ichikawa in 1915.
The first pure carcinogen, 1,2,5,6-dibenzanthracene, was synthesized in 1929.
In the early 1900s, Boveri proposed a mutation theory of carcinogenesis.

Testing of Chemical Carcinogens

Criteria for selecting compounds to test include those related to known carcinogens, new compounds to be placed in the environment, and compounds associated with an increased incidence of cancer.
In vitro testing, such as the Ames test, is used to screen for mutagenicity due to the high cost of animal screening.

In vitro Testing of Chemical Carcinogens

The Ames test measures mutagenicity in a Salmonella strain that requires histidine for growth.
Nitrosamines can be metabolized to form carbonium ions that react with guanine to give an O6-methyl derivative.

Carcinogenesis Process

Initiation involves a mutation in one or more cellular genes controlling key regulatory pathways of the cell.
Promotion involves selective growth enhancement induced in the initiated cell and its progeny by the continuous exposure to a promoting agent.
Progression results from continuing evolution of unstable chromosomes, leading to further degrees of independence, invasiveness, and metastasis.

Initiation

Initiation is the induction of a mutation in a critical gene involved in the control of cell proliferation and/or apoptosis.
Initiation requires one or more rounds of cell division for the "fixation" of the process.
The metabolism of initiating agents to non-reactive forms and the high efficiency of DNA repair of the tissue can alter the process of initiation.

Mutational Targets of Initiation

Chemical and physical carcinogens initiate cells via:
- Mutational activation of oncogenic pathways
- Mutational inactivation of apoptotic pathways
- Mutational inactivation of DNA repair mechanisms
- Mutational inactivation of antioxidant response

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Description

Test your understanding of mutation, carcinogenesis, and the Ames test, with a focus on the correlation between mutagenic and carcinogenic activity.