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OCR for page 331
Append ix G
THE ASSOCIATION OF DNA DAMAGE WITH
CANCER-INITIATING EVENTS
Some of the reasons for associating cancer initiation
with damage to DNA are as follows:
1. Many carcinogenic agents are electrophilic in
nature (attracted to negatively charged particles) and
react with cellular macromolecules. There is an
association between the mutagenicity of compounds (their
reactivity with DNA) and their carcinogenicity, although
one must remember the necessity for activating inactive
mutagenic compounds. In animal carcinogenic test
systems, the animals contain the necessary activating
enzymes. Within families of active metabolites, such as
the diolepoxides of benzo(a)pyrene, there is a very close
association between mutagenicity and carcinogenicity, and
a similar association is found for nitrosamines in
liver-cell-activated mutagenicity and liver
carcinogenicity.
2. The disease xeroderma pigmentosum is associated
with a very high skin cancer prevalence, and the cancers
are on the sun-exposed areas of the body. The cells of
individuals with this disease are defective in one or
more mechanisms that repair ultraviolet damage to DNA.
Defects in repair are associated with a 103- to
104-fold higher skin cancer prevalence in xeroderma
pigmentosum individuals than in the average population.
3. If the thymidine in the DNA of cells in culture
is substituted by the analog bromodeoxyuridine, the cells
become very sensitive to W -B because bromodeoxyuridine
has a much higher absorption coefficient in the W-B than
does thymidine. Substitution with bromodeoxyuridine is a
way to sensitize cells to W-B and the sensitization may
be detected either in terms of cell killing, neoplastic
331
OCR for page 332
332
transformation, or the ability of W-B to make single
strand breaks in the DNA. In this system, there is a
close association between DNA damage and neoplastic
transformation. (Under normal conditions, cells in
culture do not grow indefinitely, but are inhibited when
they grow to sufficient numbers that they begin to
contact one another. This contact inhibition may be
destroyed by radiation so that the cells continue to
proliferate and make so-called "transformed" foci. In
many instances, such foci give rise to tumors when the
cells from a focus are transplanted into appropriate
mouse strains.)
4. Certain species of fish grow in clones. Cells
from one member of the clone may be removed, irradiated
in vitro, and injected back into other members of the
clone. When this is done for thyroid cells of the
species Poecilia Formosa, thyroid tumors develop in the
recipients. If, however, visible light exposure follows
the ultraviolet exposure, that is to say, the cells are
subjected to photoreactivation, no tumors develop. Since
photoreactivation is diagnostic for pyrimidine dimers
(Chapter 3) in DNA, these experiments not only imply
damage to DNA in tumor production but also implicate a
specific photoproduct--pyrimidine dimers.
5. The action spectrum for neoplastic transformation
is similar to that for affecting DNA in mammalian cells
(Chapter 3).
Representative terms from entire chapter:
tumors develop
