Lecture 10.1 - Neoplasia 3

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