title: Potentiation of cyclophosphamide chemotherapy using the anti-angiogenic drug thalidomide: importance of optimal scheduling to exploit the 'normalization' window of the tumor vasculature.
abstract: The aim of this work was to study how administration schedule affects potentiation of cyclophosphamide, an alkylating agent, by thalidomide, an anti-angiogenic agent. Tumor oxygenation after thalidomide administration was determined over time by EPR oximetry. Such measurements provide a surrogate marker for determining the timing of 'normalization' of tumor vasculature. Re-growth delays were measured using different combinations and schedules of treatments. Additionally, the uptake of the metabolite of cyclophosphamide (hydroxycyclophosphamide or OH-CP) into tumors was determined by high performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS). A significant increase in pO(2) was observed after 2 and 3 days of treatment before eventually declining on day 4. Thalidomide potentiated the effect of cyclophosphamide only when cyclophosphamide was administered after 2 days of treatment with thalidomide (no significant benefit using other schedules). In this time frame, the HPLC/MS/MS measurements showed that the quantity of OH-CP penetrating into the tumor was about twice in mice treated by thalidomide compared to controls. In conclusion, the present study demonstrates that the benefit of combined therapy using an anti-angiogenic agent with a cytotoxic agent requires knowledge of the time window during which the vessels initially become normalized.
authors.affiliation: Laboratory of Biomedical Magnetic Resonance, Université Catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Jérome
authors.initials: J
authors.lastname: Segers
authors.forename: Vincent
authors.initials: V
authors.lastname: Di Fazio
authors.forename: Réginald
authors.initials: R
authors.lastname: Ansiaux
authors.forename: Philippe
authors.initials: P
authors.lastname: Martinive
authors.forename: Olivier
authors.initials: O
authors.lastname: Feron
authors.forename: Pierre
authors.initials: P
authors.lastname: Wallemacq
authors.forename: Bernard
authors.initials: B
authors.lastname: Gallez
mesh_terms: D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003520:Cyclophosphamide / Q000494:pharmacology*; D004357:Drug Synergism; D008175:Lung Neoplasms / Q000098:blood supply*; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000098:blood supply; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D053719:Tandem Mass Spectrometry; D013792:Thalidomide / Q000494:pharmacology*
chemical_list: D020533:Angiogenesis Inhibitors; D018906:Antineoplastic Agents, Alkylating; D013792:Thalidomide; D003520:Cyclophosphamide