Low-dose oral metronomic chemotherapy prevents mobilization of endothelial progenitor cells into the blood of cancer patients.
Circulating endothelial progenitor cells (EPCs) actively supply cells that may participate in tumor angiogenesis. The differing effects of low-dose metronomic trofosfamide as opposed to conventional dose-dense chemotherapy on plasma levels of vascular endothelial growth factor (VEGF) and the numbers of circulating EPC are reported.


METHODS
Blood samples were obtained from cancer patients, 18 receiving oral metronomic chemotherapy of trofosfamide with or without celecoxib, and 24 receiving conventional dose-dense chemotherapy, eight of them in adjuvant intention. Mononuclear cells were analyzed by flow cytometry for CD34, CD45 and vascular endothelial growth factor-receptor 2 (VEGF-R2) coexpression, defining EPCs, and for plasma levels of VEGF by ELISA at day 0, 10 and 21 of therapy.


RESULTS
After conventional dose-dense chemotherapy, the numbers of circulating EPCs and the VEGF plasma concentrations increased sharply, doubling pretherapeutic levels at day 21. In contrast, under low-dose metronomic chemotherapy, the numbers of circulating EPCs decreased significantly and VEGF plasma concentrations remained unchanged.


CONCLUSIONS
These observations provide evidence that conventional dose-dense chemotherapy leads to rebound EPC mobilization even when given with adjuvant intention, while low-dose metronomic scheduling of cytotoxic substances such as trofosfamide may sharply reduce EPC release into the circulation.
Stoelting
Stephanie
S
Division of Hematology, Medical Department I, Medical University of Schleswig-Holstein-Luebeck, Luebeck, Germany.
Trefzer
Tanja
T
Kisro
Jens
J
Steinke
A
A
Wagner
Thomas
T
Peters
Stefan O
SO
D000284:Administration, Oral; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D005260:Female; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000517:prevention & control
D003520:Cyclophosphamide; C003726:trofosfamide