title: Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells.
abstract: There is growing evidence that vasculogenesis (progenitor cell-derived generation of new blood vessels) is required for the growth of some neoplastic diseases. Here we show that the administration of cyclophosphamide (CTX) at the maximum tolerable dose with 21-day breaks or at more frequent low-dose (metronomic) schedules have opposite effects on the mobilization and viability of circulating endothelial progenitors (CEPs) in immunodeficient mice bearing human lymphoma cells. Animals treated with the maximum tolerable dose CTX experienced a robust CEP mobilization a few days after the end of a cycle of drug administration, and tumors rapidly became drug resistant. Conversely, the administration of metronomic CTX was associated with a consistent decrease in CEP numbers and viability and with more durable inhibition of tumor growth. Our findings suggest that metronomic low-dose chemotherapy regimens are particularly promising for avoiding CEP mobilization and, hence, to potentially reduce vasculogenesis-dependent mechanisms of tumor growth.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, IFOM-Fondazione Italiana per la Ricerca sul Cancro, Institute of Molecular Oncology, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy. francesco.bertolini@ieo.it
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertolini
authors.forename: Saki
authors.initials: S
authors.lastname: Paul
authors.forename: Patrizia
authors.initials: P
authors.lastname: Mancuso
authors.forename: Silvia
authors.initials: S
authors.lastname: Monestiroli
authors.forename: Alberto
authors.initials: A
authors.lastname: Gobbi
authors.forename: Yuval
authors.initials: Y
authors.lastname: Shaked
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kerbel
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D002051:Burkitt Lymphoma / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003520:Cyclophosphamide / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D005434:Flow Cytometry; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000097:blood* / Q000473:pathology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide