title: Cellular and molecular effects of metronomic vinorelbine and 4-O-deacetylvinorelbine on human umbilical vein endothelial cells.
abstract: Metronomic oral vinorelbine (VRL; Navelbine) was shown in clinical trials to yield sustainable antitumor activity possibly through antiangiogenic mechanisms. We investigated the effects of protracted low-dose VRL on human umbilical vein endothelial cells, compared with a conventional chemotherapy model. Human umbilical vein endothelial cell cultures were treated with different concentrations of VRL (0.001 nmol/l to 1 mmol/l) for 4, 24 and 96 h. The effects of different drug concentrations on cell growth, cell cycle, apoptosis and expression of the angiogenesis-modulating genes interleukin-8, cyclooxygenase-2, CD36 and peroxisome proliferator-activated receptor γ were assessed using the metronomic or conventional chemotherapy model. Apoptosis and cell-cycle effects were assessed by flow cytometry. Gene expression was measured at the transcript level by quantitative reverse transcriptase-PCR, protein expression by immunoblotting and levels of proteins secreted in the cell medium by enzyme-linked immunosorbent assay. Activation of the nuclear factor-κB pathway was investigated by immunoblot analysis of cytosolic and nuclear protein extracts. The half-maximal inhibitory concentrations (IC50) of VRL at 96 h were four orders lower compared with those after a 24-h exposure (1.23 nmol/l vs. 32 mmol/l for VRL). Drug concentrations at high nanomolar levels and above, which are relevant to conventional pulsatile dosing of VRL, induced a dose-dependent and nuclear factor-κB-related increase in proangiogenic interleukin-8 and cyclooxygenase-2 and a decrease in the thrombospondin-1 receptor CD36 and peroxisome proliferator-activated receptor γ at mRNA and protein levels. In contrast, the opposite was evident with protracted picomolar to low nanomolar concentrations (metronomic dosing). Our data provide experimental support for metronomic VRL by showing that a protracted low dose outperforms pulsed high-dose administration in inducing antiangiogenic effects in proliferating human endothelial cells.
authors.affiliation: aDepartment of Pharmacology, School of Medicine bInterscience Molecular Laboratory, Cancer Biobank Center cDepartment of Haematology, Division of Medicine, School of Life Sciences, Ioannina, Greece dMolecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
authors.forename: Eirini
authors.initials: E
authors.lastname: Biziota
authors.forename: Evangelos
authors.initials: E
authors.lastname: Briasoulis
authors.forename: Leonidas
authors.initials: L
authors.lastname: Mavroeidis
authors.forename: Marios
authors.initials: M
authors.lastname: Marselos
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.forename: Periklis
authors.initials: P
authors.lastname: Pappas
mesh_terms: D059250:Administration, Metronomic; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077235:Vinorelbine
chemical_list: C520600:4-O-deacetyl vinorelbine; D000970:Antineoplastic Agents; D018955:CD36 Antigens; D016209:Interleukin-8; D016328:NF-kappa B; D047495:PPAR gamma; D012333:RNA, Messenger; D014747:Vinblastine; D051546:Cyclooxygenase 2; D000077235:Vinorelbine