Chemopreventive efficacy of combined piroxicam and difluoromethylornithinetreatment of Apc mutant Min mouse adenomas, and selective toxicity againstApc mutant embryos
Rf. Jacoby et al., Chemopreventive efficacy of combined piroxicam and difluoromethylornithinetreatment of Apc mutant Min mouse adenomas, and selective toxicity againstApc mutant embryos, CANCER RES, 60(7), 2000, pp. 1864-1870
Genetic knockout or pharmacological inhibition of cyclooxygenase-2? decreas
es the number and size of adenomas in mouse models of familial adenomatous
polyposis. Epidemiological and clinical studies in humans indicate that the
entire class of nonsteroidal anti-inflammatory drugs (NSAIDs! that inhibit
both COX-I and COX-2 enzymes are promising colon cancer chemopreventive ag
ents. We used the Ape mutant Min mouse model to test combinations of agents
that might maximize preventive benefit with minimal toxicity because they
act via different mechanisms, Min mice (n = 144) were exposed to low doses
of the nonselective COX inhibitor piroxicam and the ornithine decarboxylase
(ODC) inhibitor difluoromethylornithine (DFMO), beginning at the time they
were weaned and continuing throughout the duration of the experiment.
Piroxicam at 12, 25, and 50 ppm in the diet caused dose-dependent decreases
in the number of tumors in the middle and distal portions of the small int
estine. This decrease in tumor multiplicity was associated with a striking
decrease in the size of those tumors that did grow out, In contrast, none o
f the doses of piroxicam alone decreased tumor multiplicity in the proximal
portion of the intestine (duodenum). Exposure to DEMO (0.5 or 1.0% in wate
r) caused a dose-dependent decrease in tumor multiplicity in the middle and
distal portions of the small intestine. However, this decreased multiplici
ty was not associated with a striking decrease in the size of the tumors. C
ombined treatment of mice with piroxicam plus DEMO was much more effective
than either agent alone and resulted in a significant number of mice totall
y free of any intestinal adenomas (P < 0.001), in contrast to the 100% inci
dence and high multiplicity in control Min mice, In addition to this profou
nd effectiveness in reducing tumor number, the few residual tumors in mice
treated with the combined drugs were markedly smaller in size than tumors t
hat arose from control Min mice, These experiments suggest that selective C
OX-2 inhibition combined with ODC inhibition is a very promising approach f
or colon cancer prevention,
These COX-2 and ODC inhibitor drugs were not overtly toxic at the doses use
d when administered to mice after weaning. However, when treatment was begu
n in utero, the Mendelian expected progeny ratio of 1:I that we routinely o
btained in untreated control litters was no longer observed. Apc(Min/+) pro
geny of pregnant dams treated with piroxicam and/or DEMO were reduced in nu
mber and their ratio to Apc(+/+) progeny was decreased to approximate to 0.
28:1. Thus, these agents are effective against adenomas that have homozygou
s mutation of the APC gene and also select against fetuses bearing a hetero
zygous mutation in the APC gene.