Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy.
Chemotherapeutic drugs chronically administered to tumor-bearing mice, using a frequent schedule at doses substantially lower than the maximum tolerated dose (MTD) (i.e., metronomic dosing), can cause sustained and potent antiangiogenic effects by targeting the endothelial cells of newly growing tumor blood vessels. These effects appear to occur in the absence of an increase in the severity of side effects caused by destruction of other cell types normally sensitive to MTD chemotherapy, suggesting a marked and selective sensitivity of activated endothelial cells, the basis of which is unknown. Here we report that protracted exposure of endothelial cells in vitro to low concentrations of several different anticancer agents, including microtubule inhibitors and an alkylating agent, caused marked induction of gene and protein expression of TSP-1, a potent and endothelial-specific inhibitor of angiogenesis. Increases in circulating TSP-1 were also detected in the plasma of human tumor-bearing severe combined immunodeficient mice treated with metronomic low-dose cyclophosphamide. Most importantly, the antiangiogenic and antitumor effects of low-dose continuous cyclophosphamide were lost in TSP-1-null C57BL/6 mice, whereas, in contrast, these effects were retained by using a MTD schedule of the same drug. Taken together, the results implicate TSP-1 as a secondary mediator of the antiangiogenic effects of at least some low-dose metronomic chemotherapy regimens.
Bocci
Guido
G
Molecular and Cellular Biology Research, Sunnybrook and Women's College Health Sciences Centre, and Department of Medical Biophysics, University of Toronto, S-217, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.
Francia
Giulio
G
Man
Shan
S
Lawler
Jack
J
Kerbel
Robert S
RS
D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002478:Cells, Cultured; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000633:toxicity; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008833:Microcirculation; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D019700:Thrombospondin 1 / Q000172:deficiency / Q000187:drug effects / Q000502:physiology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins / Q000187:drug effects / Q000502:physiology
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D019700:Thrombospondin 1; D003520:Cyclophosphamide