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Carcinogenesis |
University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin 53792 [R. F. J., C. E. C., K. T., M. A. N.], and Chemoprevention Branch, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland 20892 [G. K., E. T. H., R. A. L.]
Genetic knockout or pharmacological inhibition of cyclooxygenase-2 decreases 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-1 and COX-2 enzymes are promising colon cancer chemopreventive agents. We used the Apc 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 intestine. This decrease in tumor multiplicity was associated with a striking decrease in the size of those tumors that did grow out. In contrast, none of the doses of piroxicam alone decreased tumor multiplicity in the proximal portion of the intestine (duodenum). Exposure to DFMO (0.5 or 1.0% in water) caused a dose-dependent decrease in tumor multiplicity in the middle and distal portions of the small intestine. However, this decreased multiplicity was not associated with a striking decrease in the size of the tumors. Combined treatment of mice with piroxicam plus DFMO was much more effective than either agent alone and resulted in a significant number of mice totally free of any intestinal adenomas (P < 0.001), in contrast to the 100% incidence and high multiplicity in control Min mice. In addition to this profound effectiveness in reducing tumor number, the few residual tumors in mice treated with the combined drugs were markedly smaller in size than tumors that arose from control Min mice. These experiments suggest that selective COX-2 inhibition combined with ODC inhibition is a very promising approach for colon cancer prevention.
These COX-2 and ODC inhibitor drugs were not overtly toxic at the doses
used when administered to mice after weaning. However, when treatment
was begun in utero, the Mendelian expected progeny ratio
of 1:1 that we routinely obtained in untreated control litters
was no longer observed. ApcMin/+ progeny
of pregnant dams treated with piroxicam and/or DFMO were reduced in
number and their ratio to Apc+/+ progeny was
decreased to 
0.28:1. Thus, these agents are effective against
adenomas that have homozygous mutation of the APC gene and
also select against fetuses bearing a heterozygous mutation in the
APC gene.
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