Investigation of Two Dosing Schedules of Vandetanib (ZD6474), an Inhibitor of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor Signaling, in Combination with Irinotecan in a Human Colon Cancer Xenograft Model

Abstract

Purpose: This in vivo study was designed to determine the optimal doses and schedules of vandetanib, a dual epidermal growth factor receptor (EGFR)-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in combination with irinotecan in a murine xenograft model of human colon cancer. Experimental Design: HT-29 tumor-bearing nude mice were treated with two doses of vandetanib (12.5 and 25 mg/kg/d) with or without irinotecan (100 mg/kg) using either sequential or concurrent schedules for 30 days. Tumor size was measured using standard variables, whereas the antiangiogenic response was evaluated using dynamic contrast-enhanced magnetic resonance imaging. Additionally, effects on EGFR-dependent signal transduction pathways and proliferation were assessed using immunohistochemistry. These pharmacodynamic end points were then evaluated for associations with antitumor efficacy and/or to plasma/tumor concentrations of vandetanib. Results: The greatest antitumor efficacy was observed in the groups receiving the highest dose of vandetanib given continuously (concurrent schedule), alone or in combination with irinotecan. These dosing schedules resulted in significant effects on tumor vasculature, with decreased volume transfer constants, area under the curve, and permeability surface factor as well as increased gadolinium clearance after 30 days of treatment. In addition, these groups showed the greatest inhibition of EGFR signaling. Interestingly, tumor concentrations of vandetanib were increased by irinotecan in the concurrent schedule, possibly due to decreased tumor perfusion in this group. Conclusions: These data suggest that higher, sustained concentrations of vandetanib (versus intermittent), alone and in combination with irinotecan, result in optimal antitumor efficacy in this model and may have implications for the design of future clinical studies with this drug.

Combination of Vandetanib, Radiotherapy, and Irinotecan in the LoVo Human Colorectal Cancer Xenograft Model

“…In particular, these treatment combinations resulted in a slow tumor growth rate during the 2 weeks of vandetanib administration. These results confirm an earlier study by Troiani et al, 26 in which vandetanib showed a correlation between this dosing schedule and enhanced EGFR and VEGFR signal inhibition.…”

Oncologic Imaging End-Points for the Assessment of Therapy Response

“…Troiani et al [72] show in a mouse model of CRC that the most responsive tumors showed the greatest decreases in IAUC, AUC and K trans , compared to vehicle treated tumors. In another study, Checkley et al [71] show a dose-dependent decrease in K trans and v e in a mouse model of prostate cancer reflecting decreases in vascular permeability and perfusion.…”

“…Several preclinical and clinical studies have been conducted which show the utility of quantitative DCE-MRI endpoints to assess therapeutic efficacy and the antivascular activity of novel targeted agents [64][65][66][70][71][72][73]. Troiani et al [72] show in a mouse model of CRC that the most responsive tumors showed the greatest decreases in IAUC, AUC and K trans , compared to vehicle treated tumors.…”

“…Predictor of anti-vascular therapy response [60], [62][63][64][65][66], [69][70][71][72][73], [182][183][184][185] [191]…”

Angiogenesis Inhibitors: Implications for Combination with Conventional Therapies

“…Moreover, antitumor response can be improved by combining axitinib with the chemotherapeutic prodrug cyclophosphamide despite a substantial decrease in tumor uptake of the active drug [62]. Antitumor activity is also enhanced in combination therapies with the antiangiogenic TKRI vandetanib under conditions where tumor blood flow and drug uptake are reduced [63]. Clearly, in these cases, the antiangiogenic TKRI may induce a direct antitumor response through angiogenesis inhibition-induced tumor cell starvation, which is independent of, but complementary to, the cytotoxic response to chemo/radiotherapy.…”