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AAPS J. 2016 Jul;18(4):923-32. doi: 10.1208/s12248-016-9909-y. Epub 2016 Mar 30.

Sorafenib Decreases Tumor Exposure to an Anti-carcinoembryonic Antigen Monoclonal Antibody in a Mouse Model of Colorectal Cancer.

Author information

1
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, 452 Kapoor Hall, Buffalo, New York, 14214, USA.
2
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, 452 Kapoor Hall, Buffalo, New York, 14214, USA. jb@acsu.buffalo.edu.

Abstract

In this investigation, we test the hypothesis that treatment with sorafenib, an anti-angiogenic agent, decreases tumor vascularization and, consequently, hinders the delivery of monoclonal antibodies (mAb) to xenograft tumors. Severe combined immunodeficiency mice bearing carcinoembryonic antigen (CEA) expressing tumor xenografts were divided into control and sorafenib-treated groups. Sorafenib was administered to the latter group at 50 mg/kg IP every 48 h, starting 4 days post-tumor implantation. When tumors attained a size of 200-300 mm(3), mice were evaluated for (a) tumor microvessel density (using immunohistochemical analysis), (b) tumor macromolecular extravasation (using Evans Blue Dye (EBD)), (c) pharmacokinetics of an anti-CEA mAb, T84.66, following an intravenous dose of 10 mg/kg, and (d) intra-tumoral spatial distribution of T84.66 (using autoradiography). Sorafenib treatment resulted in a substantial reduction in tumor growth rate, a visible reduction in tumor microvessel density, and in a 46.4% decrease in EBD extravasation in tumor tissue (p < 0.0455). For control and treated mice, no significant difference was found for the area under the mAb plasma concentration-time curve (AUC(0-7d): 1.67 × 10(3) ± 1.28 × 10(2) vs. 1.76 × 10(3) ± 1.75 × 10(2) nM × day, p = 0.51). However, tumor AUC(0-7d) was reduced by 40.8% in sorafenib-treated mice relative to that observed in control mice (5.61 × 10(2) ± 4.27 × 10(1) vs. 9.48 × 10(2) ± 5.61 × 10(1) nM × day, p < 0.001). Sorafenib therapy was also found to markedly alter mAb tumor spatial distribution. The results collectively suggest that sorafenib treatment causes a significant reduction in mAb delivery to, and distribution within, solid tumors.

KEYWORDS:

anti-angiogenesis; drug–drug interaction; monoclonal antibodies; pharmacokinetics

PMID:
27029796
DOI:
10.1208/s12248-016-9909-y
[Indexed for MEDLINE]

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