Pathophysiologic Effects of Vascular-Targeting Agents and the Implications for Combination with Conventional Therapies

Abstract

A functional vascular supply is critical for the continued growth and development of solid tumors. It also plays a major role in metastatic spread of tumor cells. This importance has led to the concept of targeting the vasculature of the tumor as a form of cancer therapy. Two major types of vasculartargeting agent (VTA) have now emerged: those that prevent the angiogenic development of the neovasculature of the tumor and those that specifically damage the already established tumor vascular supply. When used alone neither approach readily leads to tumor control, and so, for VTAs to be most successful in the clinic they will need to be combined with more conventional therapies. However, by affecting the tumor vascular supply, these VTAs should induce pathophysiologic changes in variables, such as blood flow, pH, and oxygenation. Such changes could have negative or positive influences on the tumor response to more conventional therapies. This review aims to discuss the pathophysiologic changes induced by VTAs and the implications of these effects on the potential use of VTAs in combined modality therapy.

Phase Ib study of NGR–hTNF, a selective vascular targeting agent, administered at low doses in combination with doxorubicin to patients with advanced solid tumours

“…However, the synergism of anti-vascular agents and chemotherapy could be alternatively attributable simply to targeting two distinct cell populations (Horsman and Siemann, 2006).…”

Antivascular effects of combretastatin A4 phosphate in breast cancer xenograft assessed using dynamic bioluminescence imaging and confirmed by MRI

“…Therefore, extensive research has focused on developing strategies to attack tumor vasculature (16)(17)(18)(19). Tubulin binding agents, e.g., Combretastatin A-4-phosphate (CA4P) and ZD6126 represent one kind of vascular targeting agent (VTA) (17).…”

Reversing Resistance to Vascular-Disrupting Agents by Blocking Late Mobilization of Circulating Endothelial Progenitor Cells

“…On the basis of these findings, it seemed reasonable to postulate that combined complementary antiangiogenic strategies would readily translate into substantial tumor control and clinical benefit for patients (11,17). However, in preclinical studies authors also have underscored the importance of schedule intRoduction Rapid tumor revascularization and repopulation compromise the expected clinical efficacy of vascular-disrupting agent (VDA)-based therapy (1)(2)(3)(4). VDAs selectively target the already-established tumor vasculature and cause acute vascular shutdown (2,5,6), effectively resulting in severe tumor hypoxia, ischemia, and cell death (1,7).…”

“…However, in preclinical studies authors also have underscored the importance of schedule intRoduction Rapid tumor revascularization and repopulation compromise the expected clinical efficacy of vascular-disrupting agent (VDA)-based therapy (1)(2)(3)(4). VDAs selectively target the already-established tumor vasculature and cause acute vascular shutdown (2,5,6), effectively resulting in severe tumor hypoxia, ischemia, and cell death (1,7). Although VDAs are characterized by extensive necrosis of the tumor core, a viable peripheral rim is typically spared from which tumor cell repopulation and regrowth rapidly resumes (2,5,7).…”