Disturbance of purine nucleotide metabolism: a possible early key event in development of intestinal damage induced by chemotherapy.
Protective strategies to minimize the hematological toxicity in connection with bone marrow transplantation (BMT) have been successful, but toxicity to the gastrointestinal tract prevents further dose escalation and therefore limits the application of the treatment. As it is known that chemotherapy leads to disruption of the intestinal barrier and morphological changes of mitochondria in enterocytes, this study was conducted in order to investigate intestinal energy metabolism and permeability after intensive cytotoxic therapy in rats. Intestinal damage was produced by intraperitoneal administration of the cytostatic etoposide. Intestinal permeability was assessed by a [51Cr]EDTA absorption test and intestinal purine nucleotide content by a high-performance liquid chromatography (HPLC) technique. Four hours after the administration of etoposide, and the next 48 hr, there was a significant increase in the intestinal permeability (P < 0.05) and a significant reduction of the purine nucleotide content in the intestinal epithelial cells (P < 0.01) as compared to control animals. This early disturbance in enterocyte energy metabolism may be a key event in the development of the intestinal damage, induced by chemotherapy, and an explanation for the early disruption of the intestinal barrier demonstrable before morphological changes are evident.
Department of Haematology, Sahlgrenska University Hospital, University of Göteborg, Sweden.
J E
JE
Johansson
B
B
Soussi
U
U
Bagge
T
T
Ekman
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D002199:Capillary Permeability / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004734:Energy Metabolism / Q000187:drug effects; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects*; D007274:Injections, Intraperitoneal; D007410:Intestinal Diseases / Q000139:chemically induced* / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D007958:Leukocyte Count; D008297:Male; D011685:Purine Nucleotides / Q000032:analysis* / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D013997:Time Factors
D000970:Antineoplastic Agents; D011685:Purine Nucleotides; D005047:Etoposide