In: Biology
You have isolated two novel compounds, Compound X and Compound Y, which you suspect might be carcinogenic in some way. Based on their chemical characteristics, you hypothesize that Compound X is a cancer initiator and Compound Y is a cancer promoter. Design an experiment to test your hypothesis.
The initial experimental studies of carcinogenesis were conducted in animals. Chemicals able to react with DNA and non-reactive compounds were both tested for their ability to cause cancer. The model used was mouse skin carcinogenesis. In this system researchers painted test chemicals on the skin and observed the growth of tumors. Researchers found that application of a DNA reactive substance only resulted in tumor formation when the animals were further treated with another non-reactive substance. A compound that reacts with DNA and somehow changes the genetic makeup of the cell is called a mutagen. The mutagens that predispose cells to develop tumors are called initiators and the non-reactive compounds that stimulate tumor development are called promoters. Approximately 70% of known mutagens are also carcinogens--cancer-causing compounds. 3A compound that acts as both an initiator and a promoter is referred to as a 'complete carcinogen' because tumor development can occur without the application of another compound. 4
Initiation
Initiation is the first step in the two-stage model of cancer
development. Initiators, if not already reactive with DNA, are
altered (frequently they are made electrophilic) via
drug-metabolizing enzymes in the body and are then able to cause
changes in DNA (mutations). 4Since many initiators must be
metabolized before becoming active, initiators are often specific
to particular tissue types or species. 5The effects of initiators
are irreversible; once a particular cell has been affected by an
initiator it is susceptible to promotion until its death. Since
initiation is the result of permanent genetic change, any daughter
cells produced from the division of the mutated cell will also
carry the mutation. 4In studies of mouse skin carcinogenesis, a
linear relationship has been observed between the dose of initiator
and the quantity of tumors that can be produced, thus any exposure
to the initiator increases risk and this risk increases
indefinitely with higher levels of exposure. 5
Promotion
Once a cell has been mutated by an initiator, it is susceptible to
the effects of promoters. These compounds promote the proliferation
of the cell, giving rise to a large number of daughter cells
containing the mutation created by the initiator. 6Promoters have
no effect when the organism in question has not been previously
treated with an initiator. 5
Unlike initiators, promoters do not covalently bind to DNA or macromolecules within the cell. Many bind to receptors on the cell surface in order to affect intracellular pathways that lead to increased cell proliferation. 4There are two general categories of promoters: specific promoters that interact with receptors on or in target cells of defined tissues and nonspecific promoters that alter gene expression without the presence of a known receptor. Promoters are often specific for a particular tissue or species due to their interaction with receptors that are present in different amounts in different tissue types.
While the risk of tumor growth with promoter application is dose-dependent, there is both a threshold and a maximum effect of promoters. Very low doses of promoters will not lead to tumor development and extremely high doses will not produce more risk than moderate levels of exposure. 5
Progression
In mice, repeated promoter applications on initiator-exposed skin
produces benign papillomas. Most of these papillomas regress after
treatment is stopped, but some progress to cancer. The frequency of
progression suggests that the papillomas that progress to cancer
have acquired an additional, spontaneous, mutation. 7The term
progression, coined by Leslie Foulds, refers to the stepwise
transformation of a benign tumor to a neoplasm and to malignancy.
Progression is associated with a karyotypic change since virtually
all tumors that advance are aneuploid (have the wrong number of
chromosomes). This karyotypic change is coupled with an increased
growth rate, invasiveness, metastasis and an alteration in
biochemistry and morphology