Abstract
Background: At present, program chemotherapy represents the main approach to the treatment of patients with acute myeloid leukemia (AML). Chemotherapy is directed to the eradication of tumor clones and restoration of normal hematopoiesis. Using “7 + 3” protocol, including standard doses of cytosine arabinoside (ara-C) and daunorubicin (DNR) it is possible to obtain complete remission in 60–70% of patients. However, several vascular complications may take place during chemotherapy that could be related to vascular endothelium injury.
Aims: To investigate the effects of ara-C and DNR on cultured human vascular endothelial cells (ECs) and to confirm endothelial injury by the detection of circulating ECs.
Methods: Experiments were performed on cultured human umbilical vein ECs; cytostatic drugs were studied at therapeutical concentrations ranging from 1 ng/ml to 1 mg/ml. Effects were screened using phase-contrast microscopy, cell viability test, BRDU incorporation, immunocytochemistry, and flow cytometry.
Results: At various concentrations, ara-C and DNR induced EC monolayer changes associated with either cytostatic or cytotoxic action. DNR provoked irreversible cell changes and monolayer damage; the action of ara-C leaded to elimination of mitotic ECs from self-renewing monolayer and to significant decrease of its density. Simultaneously, remaining ECs increased the expression of the cell adhesion molecules (P- and E-selectins, VCAM-1, ICAM-1, and PECAM-1) and enhanced their adhesiveness to blood mononuclear cells. Comparing the level of ECs circulating in peripheral blood of healthy donors and AML patients undergoing chemotherapy, we have find remarkable differences. In the studied group, the concentration of circulating ECs could be as high as 250–750 cells per 1 ml of blood.
Conclusions: Obtained results allow to conclude that cytostatic therapy may cause systemic injury of the vascular endothelium related to functional cell alterations and/or massive EC loss.
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