Functional and structural changes of the human proximal small intestine after cytotoxic therapy.

Abstract

SUMMARY The effects of cytotoxic therapy on the structure and function of the proximal jejunum were studied in six patients receiving intravenous cyclophosphamide (300 mg/M2), methotrexate (40 mg/M2), and 5-fluorouracil (600 mg/M2) as adjuvant therapy for breast cancer. Using a steady state, triple lumen tube perfusion system the absorption of water and electrolytes was measured before and 48 h after administration of the cytotoxic agents. Jejunal biopsies were obtained at each perfusion. Median (range) water absorption fell from 126 (40-142) to 84 (46-142) ml/h/30 cm, with parallel changes for electrolytes; none of the changes was significant. Brush border disaccharidases did not change at 48 h after chemotherapy, while mature enterocytes appeared normal by both light and electron microscopy. Crypt cells and immature enterocytes, however, showed focal vacuolation by light microscopy, corresponding to the occurrence of large residual bodies (secondary lysosomes) containing partially degraded fragments of damaged crypt cells. The confinement of ultrastructural changes to the immature cell population may explain the failure of this study to show a consistent change in the absorptive function of the jejunum 48 h after chemotherapy.Cytotoxic therapy can cause structural and functional changes in the human proximal intestine. '-3 This effect may be important in the development of gastrointestinal symptoms such as diarrhoea and may lead to malabsorption of orally administered drugs, including cytotoxic agents.4 5 Smith et a!6 could find no change in xylose absorption and faecal fat estimation in patients with biopsy proved depression of crypt cell mitosis, but most previous studies of cytotoxic damage have examined changes of gastrointestinal function and structure independently.The technique of small intestinal perfusion is a sensitive method for detecting changes in the transport of water and electrolytes across the jejunal mucosa and might therefore show relatively minor abnormalities of enterocyte function more readily than conventional intestinal absorption tests.7 We have used small intestinal perfusion to investigate IPresent address:

Intestinal Toxicity Induced by 5-Fluorouracil in Pigs: A New Preclinical Model

“…Several studies, both in humans and rodents, have showed a correlation between the changes in the expression and/or activities of the brushborder glycohydrolytic enzymes and the severity of the gastrointestinal damage caused by 5-FU [5,55] . Cunninghan et al [56] failed to show any abnormality of disaccharidase activities in jejunal biopsies collected from patients 48 h after receiving a single intravenous dose of 5-FU. The inconsistency between the results of the present study and the Cunninghan work may be explained on the basis of the different regimen of 5-FU administration used, which induced a different pattern of histological alterations.…”

“…Studies in animals and humans have demonstrated that severity of the structural intestinal changes induced by 5-FU is directly related to the dose and regimen used in experimental or clinical protocols. Cunninghan et al [56] observed crypt cell damage of the proximal jejunum in patients that received a single intravenous bolus of 5-FU, 48 h after treatment, but failed to show any consistent change in the mature cells of the villous, and to detect any change abnormality in the absorptive function. However, in the present study, oral administration of 5-FU, following a multiple dose regimen of 5 day/week for 4 weeks, caused severe ultrastructural alterations not only in the area of the crypt but also along the maturation-migration axis.…”

Ganoderma lucidum polysaccharides reduce methotrexate-induced small intestinal damage in mice via induction of epithelial cell proliferation and migration

“…In the current report, the effects of Gl-PS on the intestinal epithelial barrier were investigated. Chemotherapy commonly produces structural damage to the intestinal mucosa in cancer patients [16] and causes side effects such as severe enterocolitis. In agreement with previous studies [17] , the results of the present study reveal that MTX induced small intestinal injury, which is characterized by villus shortening and fusion, epithelial atrophy, crypt loss, Table 3.…”

Basic Science for the Clinical Gastroenterologist: A Review of the Recent Literature on the Small Bowel (Part 1)

“…U ltrastructural changes may be confined to the immature crypt cell pop ulation (86). Some 48 h followi ng in travenous admi n istration of mi tomycin C to rats.…”