Enzymological and morphological changes in rat intestinal mucosa following treatment with alkylating sugar alcohol derivatives.
Wistar rats were treated with alkylating sugar alcohol derivatives, dianhydrogalactitol (DAG) and diacetyldyanhydrogalactitol (Diac-DAG), respectively. The drugs were intravenously administered as a single, bolus injection. The applied doses 2.5, 5, 10, 17 mg/kg DAG and 5, 10, 20, 40 mg/kg Diac-DAG were roughly equitoxic. The effect of these cytostatic agents was studied on the different marker enzymes (thymidine kinase, xanthine oxidase, alkaline phosphatase, sucrase, maltase) of the separated mucosa cells derived from the functional and proliferating zone of the small intestine. Both DAG and Diac-DAG inhibited the enzyme activities of the proliferating and mature enterocytes in a dose dependent fashion, primarily acting on the crypt specific thymidine kinase. The time dependent sequence in the biochemical alterations correlated well with the cytomorphological changes. The drug-induced damage was most pronounced 48 hours after a single treatment. The regeneration of the intestinal mucosa began on days 3 and 4 and was completed by day 7. Diac-DAG at equimolar concentration proved to be more toxic than DAG on the intestine as judged by the significantly higher decrease of protein content and xanthine oxidase activity.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D003961:Dianhydrogalactitol / Q000031:analogs & derivatives / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051381:Rats; D013402:Sugar Alcohols / Q000494:pharmacology*; D013997:Time Factors
D000970:Antineoplastic Agents; D013402:Sugar Alcohols; D003961:Dianhydrogalactitol; C027991:dianhydro-3,4-diacetylgalactitol