chapter  13
22 Pages

Designing Studies and Rodent Models for Studying Prebiotics for Colorectal Cancer Prevention

ByUmar Asad, Nancy J. Emenaker, John A. Milner

CONTENTS Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264 Selecting Rodent Models for Colorectal Cancer Research . . . . . . . . . . . . . . . . . . 265

Species Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265 Rodent Genetic Backgrounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265 Tumor Induction and Multiplicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267

Chemical Induction by Carcinogenic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268 1,2-Dimethylhydrazine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268 Azoxymethane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269 2-Amino-1-Methyl-6-Phenylimidazo-[4,5-b]Pyridine . . . . . . . . . . . . . . . . 269

Induction by Genetic Manipulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270 Spontaneous Induction due to Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271

Transgenic Mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 Human and Murine Xenograft Implantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272

The Colonic Milieu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 Prebiotics and the Colon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274

Dietary Fiber . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 Resistant Starch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 The Fructans: Inulin and Fructooligosaccharides . . . . . . . . . . . . . . . . . . . . . 276 Galacto-and Xylo-Oligosaccharides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279

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Rodent models continue to play a critical role in identifying processes and mechanisms mediating human disease.1 Their relevance surfaces from cross-species hybridization studies demonstrating homology for several human genes. Preclinical studieswith rodentmodels are alreadywidely used to characterize the biological response to a host of compounds with potential anticancer activities and identify their specificmolecular targets.2-4 However, it is clear that these are models and thus their similarities and disparities to human beings must be considered when designing studies and interpreting findings. Regardless, rodent models (i.e., mice and rats) are widely used to provide mechanistic insights about many diseases including colorectal cancer. These easily manipulated preclinical models provide essential in vivo data across a number of cancer processes including carcinogen bioactivation, DNA repair, cell signaling pathways, apoptosis and so forth. A few important lessons learned from rodent models include the occurrence of candidate tumor suppressor genes and the elucidation of oncogenes involved in tumorigenesis and tumor maintenance. As new models are developed it will be systematically possible to evaluate more sensitive and targeted agents for cancer prevention and therapy, prior to evaluation in humans thus assisting in the identification of individuals who will benefit maximally whether with a drug or a bioactive food component.5−7 Nomodel perfectly replicates the complicatedwebof genetic andmetabolic

interactions necessary for studying human colorectal cancer pathobiology.8