Vascular damage in testicular cancer patients: a study on endothelial activation by bleomycin and cisplatin in vitro.
Following treatment with bleomycin- and cisplatin-containing chemotherapy, testicular cancer patients frequently develop vascular complications, which may result from damage to endothelial cells. Understanding bleomycin- and cisplatin-induced endothelial alterations may help to develop strategies to prevent or reduce vascular toxicity. The effects of bleomycin and cisplatin on proliferation and apoptosis of the human dermal microvascular endothelial cell line HMEC-1 were determined. In addition, modulation of drug-induced cytotoxicity by the free radical scavenger amifostine, the low molecular weight heparin dalteparin, the iron-chelator dexrazoxane, the HMG-CoA reductase inhibitor rosuvastatin and the PPAR agonist troglitazone was tested. Furthermore, the effects of bleomycin and cisplatin on endothelial activation measured by the expression of the intercellular adhesion molecule-1 (ICAM-1) and on two main proteins involved in fibrinolysis, tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor type 1 (PAI-1), were measured. Decreased endothelial cell survival induced by bleomycin and cisplatin coincided with the induction of apoptosis. Only troglitazone was able to protect the endothelial cells from both bleomycin- and cisplatin-induced cytotoxicity. At high concentrations, amifostine and dexrazoxane also protected HMEC-1 from drug-induced cytotoxicity. However, due to the required high (toxic) concentrations of both modulators no absolute cell survival benefit could be achieved. Both bleomycin and cisplatin induced up-regulation of ICAM-1, tPA and PAI-1. Summarizing, bleomycin and cisplatin induce alterations in the function of endothelial cells regarding proliferation, inflammation and fibrinolysis in vitro. Strategies aimed at these functions should be developed in order to ameliorate or prevent cytostatic agent-induced vascular damage.
Nuver
Janine
J
Department of Medical Oncology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
De Haas
Esther C
EC
Van Zweeden
Martine
M
Gietema
Jourik A
JA
Meijer
Coby
C
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001761:Bleomycin / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism; D004727:Endothelium / Q000473:pathology*; D006801:Humans; D020128:Inhibitory Concentration 50; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D008297:Male; D008833:Microcirculation; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000473:pathology*
D000970:Antineoplastic Agents; D001761:Bleomycin; D018799:Intercellular Adhesion Molecule-1; D002945:Cisplatin