Chemoprevention of colon cancer carcinogenesis by balsalazide: inhibition of azoxymethane-induced aberrant crypt formation in the rat colon and intestinal tumor formation in the B6-Min/+ mouse.
Non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin have been shown to suppress colon carcinogenesis and in some cases reduce the size of colorectal polyps. Balsalazide disodium (BSZ) is a colon-specific prodrug of the salicylate, 5-aminosalicylic acid. The aim of the present study was to test the chemopreventive activity of BSZ in two established animal models of colon tumorigenesis, azoxymethane-induced aberrant crypt formation in the rat and intestinal tumor formation in the B6-Min/+ mouse. Aberrant crypt foci (ACF) were induced in Fischer 344 rats via 2 subcutaneous injections of azoxymethane (20 mg/kg). BSZ was supplied in the drinking water for 8 weeks and ACF quantitated. B6-Min/+ mice were treated from 55 days of age for 90 days and intestinal tumors scored for number, size and location. BSZ treatment of AOM-injected rats reduced ACF formation in a dose-dependent manner by 60% with the greatest effect observed on ACF with 4 or more crypts. In B6-Min/+ mice a dose-dependent reduction of intestinal tumor number was observed which reached 80% in the distal small intestine and colon. A preliminary mechanistic study in cultured human colon cancer cells showed that both BSZ and 5-ASA inhibited colon cancer cell proliferation in vitro. However, 5-ASA but not BSZ produced changes consistent with the induction of apoptosis. BSZ produces a dose-dependent chemopreventive effect on colon carcinogenesis. A possible mechanism is consistent with the inhibition of cellular proliferation and the induction of apoptosis.
MacGregor
D J
DJ
GI Research Lab, VA Medical Center, San Francisco, CA, USA.
Kim
Y S
YS
Sleisenger
M H
MH
Johnson
L K
LK
D000636:Aminosalicylic Acids / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001397:Azoxymethane / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D017491:Genes, APC; D006801:Humans; D007213:Indomethacin / Q000633:toxicity; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000473:pathology; D007414:Intestinal Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D019804:Mesalamine / Q000633:toxicity; D051379:Mice; D008817:Mice, Mutant Strains; D010659:Phenylhydrazines; D011355:Prodrugs / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344; D014407:Tumor Cells, Cultured
D000636:Aminosalicylic Acids; D000897:Anti-Ulcer Agents; D016588:Anticarcinogenic Agents; D010659:Phenylhydrazines; D011355:Prodrugs; D019804:Mesalamine; D001397:Azoxymethane; C038637:balsalazide; D007213:Indomethacin