N-ethyl-N-nitrosourea treatment of multiple intestinal neoplasia (Min) mice: age-related effects on the formation of intestinal adenomas, cystic crypts, and epidermoid cysts.

The timing of intestinal tumor initiation in B6-Min/+ mice has been examined by treating mice at 5-35 days of age with a single i.p. injection of the direct-acting alkylating agent N-ethyl-N-nitrosourea (ENU). Treatment of Min/+ mice at 5-14 days of age resulted in a 3.8-fold increase in intestinal tumor multiplicity over untreated mice. Mice treated at 20-35 days of age showed only a 1.6-fold increase in tumor number. These results, in conjunction with examination of tumor multiplicities of untreated Min/+ mice as a function of age, suggest that the majority of intestinal tumors in Min/+ mice are initiated relatively early in life. Min/+ mice treated with ENU also showed an increase in the number of cystic intestinal crypts. However, the relationship between age at ENU treatment and cystic crypt multiplicity was distinct from that seen for intestinal adenomas. Mice treated at 5-9 days of age showed only a 1.9-fold increase in cystic crypts over untreated animals. By contrast, the increase in average cystic crypt multiplicity for mice treated at 10-35 days of age was 4.5-fold. In addition, 60% of Min/+ mice treated with ENU before 25 days of age developed epidermoid cysts, an extracolonic manifestation commonly associated with familial adenomatous polyposis in humans.