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Differential effect of sunitinib on the distribution of temozolomide in an orthotopic glioma model

Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, Philadelphia, PA, USA

Address correspondence to James M. Gallo, Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, 3307 North Broad St., Philadelphia, PA 19140, USA (jmgallo{at}temple.edu).

Normalization of tumor vasculature by antiangiogenic agents may improve the delivery of cytotoxic drugs to the tumor, leading to more effective therapy. In this study, we used pharmacokinetic and pharmacodynamic approaches to investigate how sunitinib at different dose levels affects brain distribution of temozolomide (TMZ), and to ascertain the relationship between intratumoral TMZ concentrations and tumor vascularity in an orthotopic human glioma model. Three groups of intracerebral U87MG tumor-bearing mice were given either vehicle or sunitinib at 20 mg/kg or 60 mg/kg per day for 7 days before receiving a steady-state regimen of TMZ that consisted of an intravenous bolus and a 3-h intraarterial infusion. TMZ concentrations in plasma, normal brain, and brain tumor were determined, and several biomarkers related to the antiangiogenic activity of sunitinib were examined. TMZ distribution in the normal brain as indicated by the brain-to-plasma steady-state TMZ concentration ratios was analogous across the three treatment groups. The brain tumor-to-plasma steady-state TMZ concentration (ss C_t/C_p) ratio was significantly increased in the 20 mg/kg sunitinib group (0.98 ± 0.17) compared with the control (0.76 ± 0.17) and 60 mg/kg sunitinib (0.68 ± 0.09) groups. The ss C_t/C_p ratios were significantly correlated with the vascular normalization index (VNI), derived from the expression of CD31, collagen IV, and -smooth muscle actin, which represents the fraction of functioning vessels out of the total tumor vessels. In conclusion, the effect of sunitinib on the brain tumor distribution of TMZ was dose dependent and indicated that optimal tumor exposure was achieved at a lower dose and was associated with the VNI.

Key Words: antiangiogenic therapy • combination chemotherapy • pharmacokinetics • sunitinib • temozolomide • vascular normalization

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