Effect of chemopreventive agents on intermediate biomarkers during different stages of azoxymethane-induced colon carcinogenesis.
Chemoprevention of colon cancer is emerging as an alternative to therapy with a broad potential for reducing cancer incidence in defined high-risk groups and the general population. Besides several chemopreventive agents in use and under investigation, D,L-alpha-difluoromethylornithine (DFMO) and piroxicam have been shown to effectively inhibit colon carcinogenesis in rodents. A variety of proliferation-related parameters have been suggested as potential intermediate markers of cancer risk that could be used to monitor the progress of chemoprevention in clinical trials. We have investigated the effect of chemopreventive agents, DFMO, and piroxicam on mucosal ornithine decarboxylase (ODC) and tyrosine-specific protein kinase (TPK) activities during different stages of azoxymethane (AOM)-induced colonic carcinogenesis in male F344 rats in order to examine the plausibility of using these enzymes as intermediate biochemical markers of colon cancer. Groups of male F344 rats were fed modified AIN-76A diets containing 0 or 150 ppm piroxicam or 4000 ppm DFMO and given s.c. injections of AOM dissolved in normal saline at a dose of 15 mg/kg body weight/week, once weekly, for 4 weeks. Vehicle control groups received s.c. equal volumes of normal saline. Groups of animals were then sacrificed at 0, 4, 16, 24, and 32 weeks after AOM or saline treatment, and their colonic mucosa was analyzed for ODC and TPK activities. AOM treatment significantly increased mucosal ODC as well as TPK activities. AOM-induced ODC and TPK activities were significantly suppressed by dietary DFMO progressively at all stages of colon carcinogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Singh
J
J
American Health Foundation, Division of Nutritional Carcinogenesis, Valhalla, New York 10595.
Kelloff
G
G
Reddy
B S
BS
D000818:Animals; D001397:Azoxymethane; D014408:Biomarkers, Tumor / Q000032:analysis; D001835:Body Weight; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000453:epidemiology / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical; D000518:Eflornithine / Q000494:pharmacology / Q000627:therapeutic use*; D015994:Incidence; D007413:Intestinal Mucosa / Q000737:chemistry; D008297:Male; D009955:Ornithine Decarboxylase / Q000032:analysis / Q000187:drug effects*; D010894:Piroxicam / Q000494:pharmacology / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000187:drug effects*; D051381:Rats; D011916:Rats, Inbred F344
D014408:Biomarkers, Tumor; D010894:Piroxicam; D011505:Protein-Tyrosine Kinases; D009955:Ornithine Decarboxylase; D001397:Azoxymethane; D000518:Eflornithine