Angiogenesis and apoptosis.

This review assembles the laboratory and clinical evidence that cytotoxic chemotherapy and antiangiogenic therapy are each dependent on endothelial cell apoptosis. During cytotoxic chemotherapy, apoptosis of endothelial cells in the vascular bed of tumors precedes apoptosis of tumor cells, even when the tumor has been made drug resistant. Administration of an angiogenesis inhibitor which is not directly cytotoxic to tumor cells can increase tumor cell apoptosis and inhibit tumor growth by inhibiting endothelial proliferation and migration and/or by inducing endothelial apoptosis. Furthermore, oncogene expression and loss of tumor suppressor gene activity can at once protect tumor cells against apoptosis and increase their angiogenic output. Both of these survival advantages conferred on the tumor can be overcome by antiangiogenic therapy. They can also be overcome by cytotoxic chemotherapy administered on a low dose 'antiangiogenic schedule' which continuously exposes endothelial cells in the tumor bed to the drug. As a result, endothelial apoptosis can be demonstrated to precede tumor cell apoptosis, and tumors regress or are inhibited, whether or not the tumor cells are resistant to the drug, and with little or no host toxicity. In contrast, cytotoxic chemotherapy administered on a 'conventional schedule' of maximal tolerated dose followed by an off-therapy interval, becomes ineffective after drug resistance is acquired. On the basis of these experimental findings, chemotherapy of cancer may possibly be improved-i.e. decreased drug resistance and decreased toxic side-effects-by changing dose and schedule to maximize apoptosis of endothelial cells in the vascular bed of tumors. Further improvement may be achieved by combining angiogenesis inhibitors with 'antiangiogenic chemotherapy'.