Studies with the azoxymethane–rat preclinical model for assessing colon tumor development and chemoprevention

Abstract

During recent years, multidisciplinary studies in epidemiology and molecular biology have contributed to our understanding of the etiology of colorectal cancer; more importantly they have enabled us to approach its prevention. An impressive body of epidemiological data suggests an inverse relationship between colorectal cancer risk and consumption of diets rich in omega (omega)-3 fatty acids (n-3 PUFAs) or the regular use of nonsteroidal antiinflammatory drugs (NSAIDs), including aspirin. The development of strategies for the chemoprevention of colorectal cancer have been facilitated by the use of relevant animal models mimicking the neoplastic processes that occur in humans, including similarities in histopathology and molecular and genetic lesions during both the early and promotion/progression stages of carcinogenesis. Studies with the azoxymethane-F344 rat model indicate that diets rich in n-3 PUFAs, NSAIDs, selective cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) inhibitors, and curcumin can reduce the incidence of colon cancer. Advances in the knowledge of the mechanisms by which chemopreventive agents act offer opportunities to use combinations of specific chemopreventive agents, having clinically beneficial aggregate activity with minimal toxicity. This approach is extremely important when a promising chemopreventive agent demonstrates apparent efficacy but may produce toxic effects at high doses. Our studies show that a combination of very low doses of piroxicam (NSAID) and difluoromethylornithine, a specific inhibitor of ornithine decarboxylase, or very low doses of COX-2 and HMG-CoA reductase inhibitors are more effective in inhibiting colon carcinogenesis than administration of these compounds as single agents even at higher levels. The natural history of colorectal cancer, from dysplastic aberrant crypts to adenomas and adenocarcinomas, offers multiple opportunities for assessment and intervention. Of further importance is to identify whether the molecular targets that are critical in the growth and survival of the malignant colorectal cell are modulated by n-3 PUFAs, NSAIDs, or COX-2 and iNOS inhibitors.

Sulindac corrects defective apoptosis and suppresses azoxymethane‐induced colonic oncogenesis in p53 knockout mice

“…46 A recent article has compared the effect of dietary and chemopreventive agents on tumor incidence in rodent studies with those of clinical intervention studies of adenoma recurrence. Results for most agents tested were consistent across the animal and clinical models.…”

Signal Transducer and Activator of Transcription 3 - A Promising Target in Colitis-Associated Cancer

“…In addition, AOM-induced CRC appears to follow the concept in which tumor initiation is followed by tumor promotion and progression in a sequential manner. Specifically, AOM induces the onset of ACF, as the precursor lesion and Mucin depleted foci (Ashokkumar and Sudhandiran, 2008;Norazalina et al, 2010;Pandurangan et al, 2012) followed by the onset of adenocarcinoma (Ashokkumar and Sudhandiran, 2011;Shafie et al, 2013) most often of the distal colon, and, finally, metastasis to mesenteric lymph nodes and liver (Reddy, 2004).…”

Dietary Non-nutritive Factors in Targeting of Regulatory Molecules in Colorectal Cancer: An Update

“…Unique to the AOM rat model is the co-occurrence of both adenomas and adenocarcinomas, and it has been estimated that 70% of colon tumors are adenocarcinomas, while the remainder are adenomas. Histologically, adenomas of the colon are non-invasive with low-to high-grade dysplasia (Reddy, 2004).…”