title: Metronomic dosing of BH3 mimetic small molecule yields robust antiangiogenic and antitumor effects.
abstract: Bcl-2 is an antiapoptotic protein that has also been found to function as a proangiogenic signaling molecule. Improvements in antiangiogenic therapy can be engendered by metronomic dosing. Thus, we hypothesized that BH3-mimetic drugs that antagonize Bcl-2 family proteins may exert a greater efficacy when dosed metronomically. To examine this hypothesis, we employed AT101, an orally available and well-tolerated BH3-mimetic drug that has been established as effective. In a mouse xenograft model of human squamous cell carcinomas (SCC) that includes a humanized vasculature, we explored the effects of docetaxel in combination with either daily (metronomic) or weekly (bolus) doses of AT101. In addition, we explored the effect of single or combination therapy on angiogenesis and survival of endothelial or SCC cells in vitro. Metronomic AT101 therapy increased mouse survival, decreased tumor mitotic index, and decreased tumor microvessel density, compared with bolus therapy. Therapeutic potentiation was achieved by similar overall drug exposure and without altering systemic toxicities. Combinations of AT101 and docetaxel produced additive toxicity in both endothelial and SCC tumor cells. Notably, subapoptotic concentrations of AT101 potently inhibited the angiogenic potential of endothelial cells. Taken together, our findings unveil the efficacious benefits that can be achieved by metronomic delivery of BH3-mimetic drugs, in particular suggesting that SCC patients with might benefit from low-dose continuous administration of these drugs.
authors.affiliation: Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Imai
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Zeitlin
authors.forename: Fernanda
authors.initials: F
authors.lastname: Visioli
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Dong
authors.forename: Zhaocheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Sudha
authors.initials: S
authors.lastname: Krishnamurthy
authors.forename: Emily
authors.initials: E
authors.lastname: Light
authors.forename: Frank
authors.initials: F
authors.lastname: Worden
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
authors.forename: Jacques E
authors.initials: JE
authors.lastname: Nör
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006072:Gossypol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D020128:Inhibitory Concentration 50; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D043823:Taxoids; D000077143:Docetaxel; D006072:Gossypol; C028178:gossypol acetic acid