Abstract
The cytostatic drug 5-fluorouracil (5-FU) has been shown to affect both morphology and function of vascular endothelium. These effects could be part of the pathophysiology for 5-FU induced cardiotoxicity. The present thesis explores the mechanisms of this endothelial toxicity.
In an animal model, treatment with thromboprophylactic doses of the low-molecular weight heparin (LMWH) dalteparin could not protect the endothelium from damage caused by 5-FU, although the secondary thrombosis was prevented. A subsequent study with three different LMWH (dalteparin, enoxaparin and tinzaparin) showed a moderate endothelial injury after treatment with LMWH alone for up to 60 days.
Probucol, a lipid-lowering drug with strong antioxidant properties, was given as prophylaxis for two weeks before 5-FU treatment. With this drug, the endothelium was protected from the negative effects of 5-FU and had a normal morphology.
Patients receiving 5-days infusion of 5-FU, combined with cisplatin, were studied for endothelial and cardiac effects. There was a significant increase in markers for endothelial injury (von Willebrand factor and soluble thrombomodulin) and in malondialdehyde, a marker for increased lipoperoxidation and possibly free radical production. Myocardial and echocardiographic parameters were not changed.
Human umbilical vein endothelial cells (HUVEC) were incubated with 5-FU. A dose-dependant increase in secretion of endothelin-1 (a potent vasoconstrictor) was shown. No influence of apoptosis was seen.
The results indicate increased oxidative stress caused by 5-FU, followed by endothelial damage and secretion of a vasoactive peptide. This could be part of the pathophysiological mechanisms of 5-FU induced cardiotoxicity.
In an animal model, treatment with thromboprophylactic doses of the low-molecular weight heparin (LMWH) dalteparin could not protect the endothelium from damage caused by 5-FU, although the secondary thrombosis was prevented. A subsequent study with three different LMWH (dalteparin, enoxaparin and tinzaparin) showed a moderate endothelial injury after treatment with LMWH alone for up to 60 days.
Probucol, a lipid-lowering drug with strong antioxidant properties, was given as prophylaxis for two weeks before 5-FU treatment. With this drug, the endothelium was protected from the negative effects of 5-FU and had a normal morphology.
Patients receiving 5-days infusion of 5-FU, combined with cisplatin, were studied for endothelial and cardiac effects. There was a significant increase in markers for endothelial injury (von Willebrand factor and soluble thrombomodulin) and in malondialdehyde, a marker for increased lipoperoxidation and possibly free radical production. Myocardial and echocardiographic parameters were not changed.
Human umbilical vein endothelial cells (HUVEC) were incubated with 5-FU. A dose-dependant increase in secretion of endothelin-1 (a potent vasoconstrictor) was shown. No influence of apoptosis was seen.
The results indicate increased oxidative stress caused by 5-FU, followed by endothelial damage and secretion of a vasoactive peptide. This could be part of the pathophysiological mechanisms of 5-FU induced cardiotoxicity.
| Original language | English |
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| Qualification | Doctor |
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| Supervisors/Advisors |
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| Award date | 2003 Dec 5 |
| Publisher | |
| ISBN (Print) | 91-628-5886-6 |
| Publication status | Published - 2003 |
Bibliographical note
Defence detailsDate: 2003-12-05
Time: 13:00
Place: Onkologiska klinikens föreläsningssal
External reviewer(s)
Name: Rutqvist, Lars-Erik
Title: Professor
Affiliation: Enheten för onkologi, Huddinge Universitetssjukhus-Södersjukhuset, Stockholm
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Article: I. Antithrombotic treatment in protection against thrombogenic effects of 5-fluorouracil on vascular endothelium: a scanning microscopy evaluation. Sara Kinhult, Maria Albertsson, Jan Eskilsson, Magdalena Cwikiel. Scanning 2001;23(1):1-8
Article: II. Endothelial damage after treatment with low-molecular weight heparins – a morphological study. Sara Kinhult, Jan Eskilsson, Maria Albertsson, Magdalena Cwikiel. Scand Cardiovasc J 2003; 37(1): 30-33
Article: III. Effects of probucol on endothelial damage by 5-fluororuracil. Sara Kinhult, Maria Albertsson, Jan Eskilsson, Magdalena Cwikiel. Acta Oncol 2003; 42(4):304-8
Article: IV. Endothelial damage and changes in lipid peroxidation, a possible link to 5-fluorouracil-associated cardiotoxicity. Sara Kinhult, Jan Eskilsson, Ann-Kristin Öhlin, Pär-Ola Bendahl, Hans Öhlin, Magdalena Cwikiel. Submitted.
Article: V. 5-Fluorouracil increases endothelin-1 release from human endothelial cells in vitro. Sara Kinhult, Inga Zelvyte, Magdalena Cwikiel, Jan Eskilsson, Sabina Janciauskiene. Manuscript.
Subject classification (UKÄ)
- Cancer and Oncology
Free keywords
- cancerology
- oncology
- Cytology
- endothelin
- onkologi
- Cytologi
- cancer
- von Willebrand factor
- thrombomodulin
- lipoperoxidation
- probucol
- low-molecular weight heparin
- scanning electron microscopy
- 5-fluorouracil
- endothelium
