Advanced

Pathophysiology of 5-fluorouracil induced cardiotoxicity : a clinical and experimental study

Cwikiel, Magdalena LU (1996)
Abstract
This thesis concerns the pathophysiology of 5-fluorouracil (5-FU) induced cardiotoxicity. The aim of the clinical studies was to determine whether hemorheological factors might explain 5-FU cardiotoxicity (I) and if the syndrome was associated with free radical (FR) generation and lipid peroxidation (II). Changes in blood and plasma viscosity, fibrinogen, hematocrit, and thiobarbituric acid-reactive substances (TBARS) were studied in patients with esophageal or head and neck carcinoma during treatment with 5-FU. The study showed a decrease in blood and plasma viscosity, probably caused by a decrease in fibrinogen. Study of TBARS did not support the hypothesis that FRs could be involved in the cardiotoxicity of 5-FU. In the experimental... (More)
This thesis concerns the pathophysiology of 5-fluorouracil (5-FU) induced cardiotoxicity. The aim of the clinical studies was to determine whether hemorheological factors might explain 5-FU cardiotoxicity (I) and if the syndrome was associated with free radical (FR) generation and lipid peroxidation (II). Changes in blood and plasma viscosity, fibrinogen, hematocrit, and thiobarbituric acid-reactive substances (TBARS) were studied in patients with esophageal or head and neck carcinoma during treatment with 5-FU. The study showed a decrease in blood and plasma viscosity, probably caused by a decrease in fibrinogen. Study of TBARS did not support the hypothesis that FRs could be involved in the cardiotoxicity of 5-FU. In the experimental studies in rabbits (III,IV) we examined the early and late, local and systemic effect of 5-FU on endothelium, using scanning and transmission electron microscopic evaluation of small arteries, after in vivo treatment with 5-FU. Perfusion fixation was used. The following parameters were evaluated: vessel wall and endothelial cell (EC) contraction, EC edema, cytolysis, denuded areas, platelet accumulation, fibrin formation. The studies showed severe damage to ECs with accompanying thrombus formation, supporting the hypothesis that the thrombogenic effect of 5-FU, secondary to its direct cytotoxic effect on the endothelium is the pathophysiological mechanism of 5-FU cardiotoxicity. The influence of 5-FU on endothelial cell lines in a cell culture model was studied with regard to DNA synthesis, cell death and release of prostacyclin (V). Methotrexate (MTX), an antimetabolite without cardiotoxic properties, was tested in the same way. (3H)thymidine incorporation, total cellular protein, loss of (3H)thymidine from prelabelled cells, 6-keto-prostaglandin F1* were measured. DNA synthesis decreased significantly and the release of prostacyclin by ECs increased significantly when incubated with 5-FU; this effect was not seen for MTX. The study indicate specific susceptibility of benign EC for 5-FU. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Prof Kellokumpu-Lehtinen, Pirkko
organization
publishing date
type
Thesis
publication status
published
subject
keywords
oncology, Cytology, cell culture., scanning and transmission electron microscopy, endothelium, lipid peroxidation, free radical, fibrinogen, 5-fluorouracil, blood and plasma viscosity, cardiotoxicity, cancerology, Cytologi, onkologi, cancer, Pharmacological sciences, pharmacognosy, pharmacy, toxicology, Farmakologi, farmakognosi, farmaci, toxikologi
pages
112 pages
publisher
Magdalena Cwikiel, Dep of Oncology, University Hospital, 221 85 LUND, Sweden,
defense location
Auditory Dep of Oncology, University Hospital, 221 85 LUND, Sweden
defense date
1996-09-17 10:15
external identifiers
  • Other:ISRN: LUMEDW/MEOK--96/1004--SE
ISBN
91-628-2132-6
language
English
LU publication?
yes
id
4e0180c9-1939-42f2-a1bc-2d587a67401c (old id 28722)
date added to LUP
2007-06-12 13:38:09
date last changed
2016-09-19 08:45:12
@phdthesis{4e0180c9-1939-42f2-a1bc-2d587a67401c,
  abstract     = {This thesis concerns the pathophysiology of 5-fluorouracil (5-FU) induced cardiotoxicity. The aim of the clinical studies was to determine whether hemorheological factors might explain 5-FU cardiotoxicity (I) and if the syndrome was associated with free radical (FR) generation and lipid peroxidation (II). Changes in blood and plasma viscosity, fibrinogen, hematocrit, and thiobarbituric acid-reactive substances (TBARS) were studied in patients with esophageal or head and neck carcinoma during treatment with 5-FU. The study showed a decrease in blood and plasma viscosity, probably caused by a decrease in fibrinogen. Study of TBARS did not support the hypothesis that FRs could be involved in the cardiotoxicity of 5-FU. In the experimental studies in rabbits (III,IV) we examined the early and late, local and systemic effect of 5-FU on endothelium, using scanning and transmission electron microscopic evaluation of small arteries, after in vivo treatment with 5-FU. Perfusion fixation was used. The following parameters were evaluated: vessel wall and endothelial cell (EC) contraction, EC edema, cytolysis, denuded areas, platelet accumulation, fibrin formation. The studies showed severe damage to ECs with accompanying thrombus formation, supporting the hypothesis that the thrombogenic effect of 5-FU, secondary to its direct cytotoxic effect on the endothelium is the pathophysiological mechanism of 5-FU cardiotoxicity. The influence of 5-FU on endothelial cell lines in a cell culture model was studied with regard to DNA synthesis, cell death and release of prostacyclin (V). Methotrexate (MTX), an antimetabolite without cardiotoxic properties, was tested in the same way. (3H)thymidine incorporation, total cellular protein, loss of (3H)thymidine from prelabelled cells, 6-keto-prostaglandin F1* were measured. DNA synthesis decreased significantly and the release of prostacyclin by ECs increased significantly when incubated with 5-FU; this effect was not seen for MTX. The study indicate specific susceptibility of benign EC for 5-FU.},
  author       = {Cwikiel, Magdalena},
  isbn         = {91-628-2132-6},
  keyword      = {oncology,Cytology,cell culture.,scanning and transmission electron microscopy,endothelium,lipid peroxidation,free radical,fibrinogen,5-fluorouracil,blood and plasma viscosity,cardiotoxicity,cancerology,Cytologi,onkologi,cancer,Pharmacological sciences,pharmacognosy,pharmacy,toxicology,Farmakologi,farmakognosi,farmaci,toxikologi},
  language     = {eng},
  pages        = {112},
  publisher    = {Magdalena Cwikiel, Dep of Oncology, University Hospital, 221 85 LUND, Sweden,},
  school       = {Lund University},
  title        = {Pathophysiology of 5-fluorouracil induced cardiotoxicity : a clinical and experimental study},
  year         = {1996},
}