effect of methotrexate on the small intestine of the mouse: VI-mitotic activity

ABSTRACT

The normal jejunal crypt epithelium shows numerous mitoses. Mitotic counts show that the percentage of crypt cells undergoing mitosis is in the average of 2.92% and goblet cell counts about 6%. Newly formed cells resulting from mitosis in crypts of Lieberkuhn migrate along the villi and are extruded at the tips of villi. MTX induced marked reduction of crypt mitoses in all experimental groups associated with occasional abnormal mitotic figures [chromosomal abnormalities]. MTX inhibition of mitosis most probably occurs in the S-phase and not in the metaphase stage. The reduction in mitotic counts is evident within 2 h of a single sublethal dose, and remains depressed until 6 h. During the period of mitotic reduction, many small spherical DNA-containing inclusion bodies appear in the cytoplasm of crypt cells, indicating the early death of these cells. After 12 h in GI and after 5 weekly doses in GIV, mitosis increases to peak values which are greater than in controls. The existence of waves of increased activity suggests, synchronization in a portion of the crypt cell population which is not destroyed by MTX. There is no definite correlation between the number of mitoses and the cumulative doses of MTX. The duration of mitotic inhibition correlates with the duration of MTX action on DNA synthesis, and is dose and timeinterval dependent. This inhibition, though sometimes marked, is transient, and the epithelial defects are rapidly repaired following resumption of DNA synthesis, after cessation of treatment