Abstract
A key problem in solid tumor therapy is tumor regrowth from a residual viable rim after treatment with a vascular disrupting agent (VDA). As a potential solution, we studied a combined treatment of a VDA and antiangiogenic. This study was approved by the institutional ethical committee for the use and care of laboratory animals. Rats with implanted liver tumors were randomized into four treatment groups: 1) Zd6126 (Zd); 2) Thalidomide (Tha); 3) Zd in combination with Tha (ZdTha); and 4) controls. Multiparametric MRIs were performed and quantified before and after treatment. Circulating endothelial progenitor cells (EPCs) and plasma stromal cell-derived factor-1α (SDF-1α) were monitored. Tumor apoptosis, necrosis, and microvessels were verified by histopathology. A single use of Zd or Tha did not significantly delay tumor growth. The combined ZdTha showed enhanced antitumor efficacy due to synergistic effects; it induced a cumulative tumor apoptosis or necrosis, which resulted in significant delay in tumor growth and reduction in the viable tumor rim; it also reduced tumor vessel permeability; and it improved tumor hemodynamic indexes, most likely via a transient normalization of tumor vasculature induced by Tha. A stepwise linear regression analysis showed that the apparent diffusion coefficient was an independent predictor of tumor growth. We found no significant increases in Zd-induced circulating EPCs or plasma SDF-1α. ZdTha showed improved therapeutic efficacy in solid tumors compared to either agent alone. The therapeutic effects were successfully tracked in vivo with multiparametric MRI.
Highlights
Tumor vasculature has become an attractive target for therapy, because blood vessels are crucial for maintaining tumor growth with a supply of oxygen and other nutrients, and provides a primary escape route for metastases
The present study demonstrated that a single dose of Zd caused rapid vascular shutdown at 4 h, followed by tumor necrosis at 2 d, which delayed tumor growth compared to control tumors
Tumor growth was not completely inhibited, and tumors began to relapse after 2 d, despite a massive central necrotic area in the tumor induced by the agent
Summary
Tumor vasculature has become an attractive target for therapy, because blood vessels are crucial for maintaining tumor growth with a supply of oxygen and other nutrients, and provides a primary escape route for metastases. Antivascular approaches with vascular disrupting agents (VDAs) have recently emerged as a novel antitumor strategy [1,2]. Several small molecular VDAs, including CA-4-P and Zd6126, are currently in clinical trials or undergoing preclinical testing [4]. The effect of VDAs might be improved by combining them with other approaches to prevent tumor rebound, like conventional chemotherapies, radiotherapies, or recently described antiangiogenic agents [5]. Current efforts have gradually shifted from single use to combinations of agents in both preclinical and clinical settings [6,7]. The combination of VDAs and antiangiogenics holds great promise, because VDAs will induce acute vascular collapse, and antiangiogenics inhibit recruitment and growth of new tumor vessels. The two approaches are likely to have synergistic therapeutic efficacy
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