TAILIEUCHUNG - Chapter 080. Cancer Cell Biology and Angiogenesis (Part 19)

Several general principles have arisen from these studies. Bevacizumab appears to potentiate the effects of many different types of active chemotherapeutic regimens used to treat a variety of different tumor types. No phase III trials have demonstrated single-agent activity for bevacizumab; colon and lung cancer trials have demonstrated a lack of activity when used alone. An exception may be renal cell cancer (RCC), a tumor that is specifically dependent upon VEGF as the result of deletion of the VHL tumor suppressor and activation of the HIF-1α transcription factor (see above). A randomized phase II study of single-agent bevacizumab given. | Chapter 080. Cancer Cell Biology and Angiogenesis Part 19 Several general principles have arisen from these studies. Bevacizumab appears to potentiate the effects of many different types of active chemotherapeutic regimens used to treat a variety of different tumor types. No phase III trials have demonstrated single-agent activity for bevacizumab colon and lung cancer trials have demonstrated a lack of activity when used alone. An exception may be renal cell cancer RCC a tumor that is specifically dependent upon VEGF as the result of deletion of the VHL tumor suppressor and activation of the HIF-1a transcription factor see above . A randomized phase II study of single-agent bevacizumab given at low or high dose compared to placebo in patients with advanced RCC demonstrated a significant prolongation of time to disease progression a finding that merits further study. The mechanisms by which bevacizumab enhances the activity of chemotherapy and possibly radiotherapy have been studied Table 80-4 . Inhibition of VEGF especially in the early stages of treatment has been postulated to result in the normalization of blood flow in tumors Fig. 80-10 . When given in combination with chemotherapy this may enhance the delivery of cytotoxic agents to the tumor where death of tumor cells and proliferating endothelial cells may result. As antiangiogenic therapy continues growth of new tumor vessels is inhibited leading to nutritional deprivation and death of tumor cells. Table 80-4 Mechanisms of Bevacizumab Action 1. Inhibition of VEGF-dependent signaling pathways required for the proliferation and survival of endothelial cells within the tumor vasculature. This may enhance the direct toxic effects of chemotherapy on tumor endothelial cells. 2. Inhibition of vascular permeability decreasing interstitial pressure in tumors and promoting delivery of therapeutic drugs and oxygen a process termed vessel normalization . 3. Prevention of neoangiogenesis between cycles of chemotherapy .

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