Chemopreventive efficacy of combined piroxicam and difluoromethylornithinetreatment of Apc mutant Min mouse adenomas, and selective toxicity againstApc mutant embryos

Citation
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
Citations number
37
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER RESEARCH
ISSN journal
00085472 → ACNP
Volume
60
Issue
7
Year of publication
2000
Pages
1864 - 1870
Database
ISI
SICI code
0008-5472(20000401)60:7<1864:CEOCPA>2.0.ZU;2-7
Abstract
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.