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Cyclooxygenase
as a Target for Prevention of UV-induced Skin Carcinogenesis
Fischer, Susan1,
Lo, Herng1 and Lubet, Ronald2
Univ. Texas MD Anderson Cancer Center1
Div. Cancer Prevention and Control, NIH2
Abstract-
One of the characteristics of ultraviolet (UV) light irradiation of
skin is the subsequent erythemic and inflammatory response. A major
mediator of the inflammatory response is the release and metabolism
of arachidonic acid by the cyclooxygenases (COX-1 and COX-2) to their
prostaglandin (PG) products. The goal of our studies was to determine
the role or contribution of PGs to UV-induced skin carcinogenesis, using
SKH hairless mice. First, we investigated the regulation of COX-2, the
inducible isoform of COX, by UV and in tumors. UV exposure was shown
to cause a transient upregulation of COX-2 mRNA and protein in the skin
of SKH hairless mice but little effect on the expression of COX-1 was
observed. Skin tumors induced by UV constitutively expressed COX-2 at
high levels, while only small changes in COX-1 expression were noted.
Next, pharmacological approaches were used to show that PGs are required
for tumor development and continued growth. Topical or oral administration
of several different nonsteroidal anti-inflammatory drugs (NSAIDs),
including piroxicam, indomethacin and celecoxib, a COX-2 selective inhibitor,
during UV carcinogenesis resulted in significant inhibition (up to ~85
%) of tumor development. Topical administration of indomethacin after
each UV exposure was also effective, suggesting that a post-exposure
approach to skin cancer prevention may be effective. To determine whether
celecoxib also has therapeutic efficacy against existing tumors, it
was co-administered with the ornithine decarboxylase inhibitor difluoromethylornithine,
which we recently demonstrated has therapeutic activity. This combination
was found to have strong therapeutic effects such that an 80 % reduction
in tumor number occurred within 3 weeks. Collectively, these studies
suggest that PGs play a critical role in UV-induced skin cancer development
and that COX-2 is an excellent target for prevention and treatment.
Keywords: prostaglandins,
cyclooxygenase, cancer, skin
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