Mechanisms of tumor resistance to small-molecule vascular disrupting agents: Treatment and rationale of combination therapy

Small-molecule vascular disrupting agents (VDAs) target the established tumor blood vessels, resulting in rapidly and selectively widespread ischemia and necrosis of central tumor; meanwhile, blood flow in normal tissues is relatively unaffected. Although VDAs therapy is considered an important option for treatment, its use is still limited. The tumor cells at the periphery are less sensitive to vascular shutdown than those at the center, and subsequently avoid a nutrient-deprived environment. This phenomenon is referred to as tumor resistance to VDAs treatment. The viable periphery rim of tumor cells contributes to tumor regeneration, metastasis, and ongoing progression. However, there is no systematic review of the plausible mechanisms of repopulation of the viable tumor cells following VDAs therapy. The purpose of this review is to provide insights into mechanisms of tumor surviving small-molecule VDAs therapy, and the synergetic treatment to the remaining viable tumor cells at the periphery.