Cancer Control Research
5R01CA015957-11
PI Name is not available.
INTESTINAL CARCINOGENESIS IN CONVENTIONAL AND GERMFREE R
AbstractA protocol has been developed with Lobund Sprague-Dawley (S-D) rats for
experiments on chemically-induced autochthonous intestinal cancer. The S-D
rat is highly susceptible to DMH and related agents, yielding reproducable
and statistically-significant data in 20 weeks. Indomethacin (Indo) is
useful because it blocks the synthesis of prostaglandins (PGs) at the
cyclooxygenase level. It has interfered (a) with the development of
intestinal tumors when administered as long as 35 days after DMH or MAM;
and (b) with tumors induced by 4 agents, which suggests operation of a
common drug-sensitive cancer-related factor(s). The Indo action is either
antipromotional, antitumorigenic, or immunostimulatory. Tumors induced by
a single marginal dose of DMH, MAM, or DMN Oac (and MNU) will be examined
for PG production, and its modulation by Indo for possible less toxic
piroxicam) administered in drinking water (20 mg/liter). The antitumor
effect will be determined at various stages of tumorigenesis: with
treatments at early, late, and intermediate stages of tumor development, in
order to determine over longer periods of observation if tumors are only
suppressed or actually prevented. PGE levels will be determined in serums
and in tumors of Indo-treated and untreated rats. The promotional effect
of high fat diets on tumor development will be assessed in DMH-treated rats
in relation to production of PG, as well as bile acids. Groups of S-D
rats, treated with DMH, will be fed diets high or low in fat; and subgroups
therein will be treated with Indo in water. This is amined at
clarification of whether the promotional effect is related to bile acids
and/or to PG activities. PGs are produced by body cells, but in higher
levels by tumor cells. Indo has demonstrated an anti-tumor effect. The
goal of this research program is to determine if inhibition of PG synthesis
by blocking agents is aimed at an intrinsic mechanism in tumor cells or is
it merely a conincidental event, and unrelated to PG synthesis?
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