Effect of disulfiram on 1,2-dimethylhydrazine- and azoxymethane-induced aberrant crypt foci.
We have previously reported a method for visualizing the mucosal surface of fixed unsectioned rodent colons at the crypt level and have identified lesions, termed aberrant crypt foci (ACF), in the colons of carcinogen-treated rodents. We hypothesized that ACF represent the precursor lesions (PL) of colon cancer. In the present study, the effect of feeding disulfiram (DSF) added to a semi-synthetic diet (0.5% or 1% by wt) on 1,2-dimethylhydrazine (DMH) and azoxymethane (AOM) induced ACF was investigated. DSF has been shown to inhibit DMH and AOM-induced colon cancer. Therefore, it was reasoned that if ACF represent PL then their induction and growth should also be inhibited by DSF. CF1 female mice were randomly divided into three groups of 30 each. Group 1 was fed a diet containing 1% DSF for 9 days prior to and 1 day after receiving a single i.p. injection of either DMH, AOM or saline. Group 2 was fed a diet containing 1% DSF for 9 days prior to and 14 days after receiving a single i.p. injection of DMH, AOM or saline, whereas group 3 received control diet throughout the experimental duration. All animals were killed 5 weeks after receiving the injections. It was observed that feeding DSF, for 9 days prior to and for either 1 day or 14 days after the administration of a single injection of DMH, resulted in a complete inhibition of ACF. DSF feeding for 9 days prior to and 1 day after AOM injection resulted in a significantly greater number of ACF compared to the control group (12 +/- 2.3 vs 7.2 +/- 1.2); whereas DSF feeding for a longer duration (i.e. 9 days prior to and 14 days after AOM treatment) was associated with a significantly lower number of ACF compared to those fed DSF for only one day after AOM treatment (4.1 +/- 0.6 vs 12.4 +/- 2.3) and a lower number compared to the control group (4.1 +/- 0.6 vs 7.2 +/- 1.2).
McLellan
E
E
Imperial Cancer Research Fund, Lincoln's Inn Fields, London, UK.
Bird
R P
RP
D019813:1,2-Dimethylhydrazine; D000818:Animals; D001397:Azoxymethane / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D004127:Dimethylhydrazines / Q000633:toxicity*; D004221:Disulfiram / Q000494:pharmacology*; D005260:Female; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D051379:Mice; D011230:Precancerous Conditions / Q000139:chemically induced / Q000517:prevention & control*
D004127:Dimethylhydrazines; D019813:1,2-Dimethylhydrazine; D001397:Azoxymethane; D004221:Disulfiram