title: Pharmacokinetic-directed dosing of vandetanib and docetaxel in a mouse model of human squamous cell carcinoma.
abstract: Docetaxel, usually administered according to maximum tolerated dose (MTD), can inhibit endothelial cell proliferation at low nanomolar concentrations. Docetaxel may exert antiangiogenic effects if dosed so plasma levels are maintained at low nanomolar concentrations over a prolonged time. We evaluated metronomic and MTD-based dosing of docetaxel with and without vandetanib, a vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinase inhibitor with antiangiogenic and antitumor activity, in a head and neck xenograft model. A murine physiologically based pharmacokinetic model was modified to predict docetaxel distribution following i.p. administration to design dosing regimens that target prespecified plasma concentrations, for antiendothelial effects (metronomic), or exposure, to mimic 30 mg/m2 (weekly/MTD) docetaxel in humans. Animals were treated for 28 days with 1 mg/kg/d (DTX1) or 6 mg/kg q4d (DTX6) docetaxel with or without vandetanib (15 mg/kg/d p.o.) in mice bearing UMSCC2 tumor xenografts. The DTX1 dosing scheme was adjusted to treatment for 10 days followed by 9 days off due to severe gastrointestinal toxicity. All treatment groups significantly reduced tumor volume, tumor proliferation (Ki-67), and tumor endothelial cell proliferation (Ki-67/von Willebrand factor) compared with control. Addition of vandetanib to docetaxel treatment significantly enhanced tumor growth inhibition over single-agent therapy. A positive correlation of tumor endothelial cell proliferation with tumor growth rates demonstrates vandetanib and docetaxel antiangiogenic effects. Due to the morbidity observed with DTX1 treatment, it is difficult to clearly ascertain if metronomic schedules will be effective for treatment. Docetaxel with vandetanib is effective in treating UMSCC2 xenografts at concentrations relevant to exposures in humans.
authors.affiliation: Division of Medical Oncology, School of Medicine, University of Colorado Health Sciences Center, 12801 East 17th Avenue, Room L18-8401G, P.O. Box 6511, MS 8117, Aurora, CO 80045, USA. Erica.Pierce@uchsc.edu
authors.forename: Erica L
authors.initials: EL
authors.lastname: Bradshaw-Pierce
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Steinhauer
authors.forename: David
authors.initials: D
authors.lastname: Raben
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Gustafson
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D000077143:Docetaxel; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D010880:Piperidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D010880:Piperidines; D011799:Quinazolines; D043823:Taxoids; D000077143:Docetaxel; C452423:vandetanib
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