Circulating endothelial cells as a therapeutic marker for thalidomide in combined therapy with chemotherapy drugs in a human prostate cancer model.
OBJECTIVE
To investigate how thalidomide confers its survival benefit in prostate cancer, by assessing its effect on circulating endothelial cells (CECs) and progenitors (CEPs) in a combined therapy of thalidomide and chemotherapy drugs in a human prostate cancer xenograft model, as in clinical trials patients treated with both thalidomide and docetaxel had a >50% decrease in prostate-specific antigen (PSA) levels and longer median overall survival than those treated with docetaxel monotherapy.


METHODS
A human prostate cancer xenograft model was used to evaluate the effect of either thalidomide, docetaxel or a combination of the two drugs on circulating ECs. Drug treatment was continued for 17 days, and tumours were measured two or three times a week. Blood samples were taken at three different time points: before the treatments, 4 days and 17 days into the treatments, and CECs and CEPs were measured by flow cytometry analysis.


RESULTS
There was an increased level of apoptotic/dead CECs shortly after the intravenous injection of docetaxel, and the addition of thalidomide further increased the apoptotic/dead CEC level, showing that thalidomide enhances the cytotoxicity of docetaxel against tumour vascular ECs.


CONCLUSIONS
Thalidomide increased the apoptotic/dead CEC level and enhanced the cytotoxicity of docetaxel against tumour vascular ECs, confirming its antiangiogenic property in vivo in combined anticancer treatments. In addition, there was a correlation between the increased apoptotic/dead CEC levels early in the treatment and antitumour efficacy later, suggesting that the apoptotic/dead CEC level could be used as a marker, at an early stage, to predict tumour response to antiangiogenic therapies.
Li
Haiqing
H
Molecular Pharmacology Section, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Raia
Valentina
V
Bertolini
Francesco
F
Price
Douglas K
DK
Figg
William D
WD
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D000077143:Docetaxel; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects*; D004961:Estramustine / Q000008:administration & dosage; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011897:Random Allocation; D013234:Stem Cells / Q000187:drug effects; D043823:Taxoids / Q000008:administration & dosage / Q000627:therapeutic use*; D013792:Thalidomide / Q000008:administration & dosage / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
D020533:Angiogenesis Inhibitors; D043823:Taxoids; D000077143:Docetaxel; D004961:Estramustine; D013792:Thalidomide; D002945:Cisplatin