Kuznyetsova G. The influence of cytostatic compound dihydropyrrol derivative on rat intestine morphofunctional state under chemical-induced colon carcinogenesis condition

Subject: Rat jejunum, colon and rectum under DMH, D1, 5-FU and their combinations influence. Objective: To examine the state of rat intestine under the influence of dihydropyrrol derivative and to evaluate its effect when used under 1,2-dimethylhydrazine-induced colon cancer compared with widespread antineoplastic drug 5-fluorouracil. Methods: Histological, morphometrical, biochemical, and methods of statistical analysis. Results: It was found that D1 at different periods of exposure (10 days, 6 weeks, 27 weeks) causes: minor violations of the capillary blood and lymph circulation in the intestine tunica mucosa, inhibition of colon mucosal cells functional activity under 10 days and 27 weeks impact. But less expressive D1 effects compared with the anticancer drug 5-fluorouracil (5-FU) ones were revealed. Under the action with 5-FU, as well as with oxidative stress inducer CoCl2, D1 partially eliminates the toxic effects of the latters in the jejunum, while 5-FU and CoCl2 effects are still dominated in the colon and rectum. Antitumor effects of D1 comparable to those of 5-FU were observed, the D1 influence mainly on the exophytic tumors were found. D1 also carries more gentle effects on the relatively healthy intestinal tunica mucosa compared with 5-FU ones, as well as partially normalizes the morpho-functional state of the colon tunica mucosa. When combined with 5-FU, D1 partially eliminates the toxic effects of 5-FU in the colon tunica mucosa under DMH-induced colorectal cancer condition. Novelty: For the first time the morpho-functional state of rat jejunum, colon and rectum was described after short-term (10 days) and long-term (7 and 27 weeks) exposure of potential new anticancer compound dihydropyrrol derivative (D1). The additional data on the histology of rat intestine under the influence of common anticancer drug 5-fluorouracil was obtained. More gentle effect of D1 on rat intestine compared to 5-FU one was shown. It was found that antitumor effect of D1 under rat bowel DMH-induced carcinogenesis is similar to 5-FU one. Repair of rat intestine morpho-functional state after D1 application under oxidative stress, chemo-induced carcinogenesis and combined action of 5-fluorouracil was established. Correlations between parameters of tumor growth and growth processes in surrounding tissue were revealed. Area use: Obtained results are the justification for further investigation of target compounds, in particular dihydropyrrol derivatives, and design of new drugs based on them. The results of histological analysis of surrounding tissue under chemo-induced colon carcinogenesis may be used to develop criteria in clinical practice for the diagnosis of precancerous conditions, in the appointment of medical interventions and to evaluate the effectiveness of the treatment.