Chemoprevention of intestinal adenomas in the ApcMin mouse by piroxicam: kinetics, strain effects and resistance to chemosuppression

• Published in: Carcinogenesis (New York) Vol. 20; no. 1; pp. 51 - 58
• Main Authors: Ritland, Steve R., Gendler, Sandra J.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.01.1999; Oxford Publishing Limited (England)
• Subjects: 129 or 1; 129Sv/J; AAALAC; Adenoma - drug therapy; Adenoma - prevention & control; American Association for the Accreditation of Laboratory Animal Care; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Anti-Inflammatory Agents, Non-Steroidal - toxicity; Anticarcinogenic Agents - pharmacology; Anticarcinogenic Agents - therapeutic use; Anticarcinogenic Agents - toxicity; Apoptosis - drug effects; B6 or B; Biological and medical sciences; C57Bl/6J; Carcinogenesis, carcinogens and anticarcinogens; Chemical agents; Colonic Neoplasms - drug therapy; Colonic Neoplasms - prevention & control; colorectal cancer; CRC; Crosses, Genetic; Cyclooxygenase Inhibitors - pharmacology; Cyclooxygenase Inhibitors - therapeutic use; Cyclooxygenase Inhibitors - toxicity; Diet; Dose-Response Relationship, Drug; Drug Resistance; Duodenal Neoplasms - drug therapy; Duodenal Neoplasms - prevention & control; Female; FVB; Genes, APC; Genetic Predisposition to Disease; Intestinal Diseases - chemically induced; Intestinal Neoplasms - drug therapy; Intestinal Neoplasms - prevention & control; LOH; Loss of Heterozygosity; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; non-steroidal antiinflammatory drugs; NSAIDs; PCR; Piroxicam - pharmacology; Piroxicam - therapeutic use; polymerase chain reaction; specific pathogen-free; SPF; TSG; tumor suppressor gene; Tumors; Ulcer - chemically induced; Oxicam derivatives; Treatment efficiency; Tumoral tissue; Rodentia; Gut; Oral administration; Adenoma; Anticarcinogen; Non steroidal antiinflammatory agent; Vertebrata; Piroxicam; Mammalia; Treatment; Mouse; Animal; Chemical protection; Digestive diseases; Intestinal disease; Benign neoplasm
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/20.1.51

Previous cancer chemoprevention studies have demonstrated that NSAIDs can be effective in suppressing the development of intestinal tumors. To further explore this issue, we performed cross-over chemoprevention studies using the drug piroxicam in the ApcMin mouse to evaluate the kinetics of NSAID-mediated tumor regression, the effects of genetic background and the incidence of resistance to chemoprevention. Starting at the time of weaning, C57Bl/6J-ApcMin mice were fed either the control diet (AIN-93G) or AIN-93G plus 200 p.p.m. piroxicam. Tumor multiplicity was significantly reduced in ApcMin mice that were fed 200 p.p.m. piroxicam until 100 or 200 days of age (94.4 and 95.7% reduction in tumor number, respectively; P < 0.001 versus AIN-93G controls). When the administration of piroxicam was delayed until 100 days of age and the mice were killed at 200 days of age, tumor multiplicity was reduced by 96.2% (P < 0.001 versus controls). Alternatively, when the administration of piroxicam was suspended at 100 days of age and the mice were killed at 200 days of age, tumor multiplicity was reduced by 68.0% (P < 0.001 versus controls). Short-term drug treatment periods for ApcMin animals with established tumors revealed that the kinetics of piroxicam-induced tumor regression were rapid: >90% reduction in tumor multiplicity was observed after 1 week of treatment with 200 p.p.m. piroxicam. The distribution of residual tumors in piroxicam-treated mice suggests that tumors of the duodenum and colon were relatively resistant to chemosuppression. Treatment of interspecific hybrid ApcMin mice with 200 p.p.m. piroxicam revealed that there was a strain-related effect on chemosuppression, suggesting the existence of genetic elements which modulate NSAID chemosensitivity. Finally, whole-genome allelic loss studies showed that there were few unique chromosomal deletions in the NSAID-resistant tumors from F1 mice, implying that loss-of-function mutations secondary to Apc inactivation are not likely to account for the observed difference in chemoresistance.