Impact of Angiogenesis Inhibition by Sunitinib on Tumor Distribution of Temozolomide

Abstract

As combination chemotherapy of antiangiogenic agents with conventional chemotherapeutic drugs continues to evolve, an understanding of the pharmacokinetic and pharmacodynamic variables associated with optimal treatment is needed. Thus, the effect of the multitargeted tyrosine kinase inhibitor sunitinib on tumor distribution of temozolomide was investigated to evaluate conditions for optimal combination chemotherapy. In mice bearing SF188V+ human glioma xenografts, measurements of temozolomide pharmacokinetic properties and sunitinib pharmacodynamic activities were evaluated, the latter including determinants for vascular normalization, including CD31, collagen IV, and alpha-SMA. Sunitinib given in a daily dose of either 10 or 40 mg/kg orally over 14 days increased temozolomide tumor distribution, as indicated by the tumor-to-plasma AUC ratio compared with control; however, only the 10 mg/kg group reached statistical significance (P < 0.05). From the pharmacodynamic analysis, a "vascular normalization index" incorporating the microvessel density (MVD) and protein expression of alpha-SMA and collagen IV was proposed as an indication of the number of tumor vessels with relatively good quality, which was found to be significantly correlated with the unbound temozolomide AUC in tumor interstitial fluid (P = 0.05). Furthermore, both sunitinib-treated groups maintained the molecular balance between angiopoietins Ang-1 and Ang-2, suggesting a critical role of angiopoietins in vascular normalization. Several important factors relevant to the antiangiogenic agent-induced tumor vascular normalization have been identified and incorporated into a vascular normalization index that may serve to correlate the angiogenic phenotype to the distribution of cytotoxic drugs in solid tumors.