| ABSTRACT: |
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The chemopreventive action of 40 and 80% maximum tolerated dose (MTD)
levels of piroxicam, D,L-alpha-difluoromethylornithine (DMFO), 16
alpha-fluoro-5-androsten-17-one (DHEA analogue 8354), and ellagic acid
(EA) administered in diet individually and in combination before and
during initiation and postinitiation phases of azoxymethane-induced
neoplasia of the intestine was studied in male F344 rats. The MTD levels
of piroxicam, DFMO, DHEA analogue, and EA were determined in male F344
rats and found to be 500, 5,000, 500, and 10,000 ppm, respectively, in
modified AIN-76A diet. When these agents were fed in combination, the MTD
levels were: piroxicam plus DFMO, 250 and 2500 ppm; piroxicam plus DHEA
analogue, 250 and 250 ppm; piroxicam plus EA, 250 and 5000 ppm; piroxicam
plus DFMO plus DHEA analogue, 250, 2500, and 250 ppm; and piroxicam plus
DFMO plus EA, 250, 2500, and 5000 ppm. From these MTD values, 40 and 80%
MTD levels were calculated and tested for their efficacy. At 5 weeks of
age, animals were fed the modified AIN-76A (control) diet and experimental
diets containing 40 and 80% MTD levels of piroxicam, DFMO, DHEA analogue,
and EA individually and in combination. At 7 weeks of age, all animals
except the vehicle-treated groups were administrated s.c. injections of
azoxymethane (15 mg/kg body weight/week for 2 weeks). Animals intended for
vehicle treatment received s.c. injections of an equal volume of normal
saline. Fifty-two weeks after azoxymethane and saline treatment all the
animals were necropsied, and colon and small intestinal tumor incidence
(percentage of animals with tumors) and multiplicity (tumors/animal) were
compared among various dietary groups. The results indicate that 40 and
80% MTD levels of dietary piroxicam and DFMO significantly (P less than
0.001) inhibited colon and small intestinal tumor incidence and
multiplicity. DHEA analogue at 40% MTD level significantly decreased the
small intestinal and colon tumor incidences (P less than 0.05), whereas
80% MTD of DHEA analogue inhibited only small intestinal tumor incidence.
EA at 40 and 80% MTDs had no significant effect on colon tumor incidence
(P greater than 0.05), but 80% MTD of EA showed a significant inhibitory
effect on the incidence of small intestinal adenocarcinomas (P less than
0.01). In the combination study, 40 and 80% MTD levels of piroxicam plus
DFMO significantly (P less than 0.001) inhibited colon adenocarcinoma
incidence (8.3%) and multiplicity (0.08 +/- 0.04) (SE) when compared to
colon adenocarcinoma incidence (72.2%) and multiplicity (1.14 +/- 0.18) in
control diet-fed animals.(ABSTRACT TRUNCATED AT 400 WORDS) |