'Accidental' anti-angiogenic drugs: anti-oncogene directed signal transduction inhibitors and conventional chemotherapeutic agents as examples

A number of drugs currently bring tested in clinical trials as possible ang iogenesis inhibitors were not originally developed with the intention of su ppressing tumour angiogenesis. Thalidomide and interferon alpha are obvious examples of such drugs. This list at 'accidental' angiogenesis inhibitors may include established agents such as conventional cytotoxic chemotherapeu tic drugs as well as the new generation of anticancer drugs known as anti-o ncoprotein signal transduction inhibitors. With respect to the former, the potential of such drugs to inhibit angiogenesis could be the result of thei r ability to cause collateral damaging effects on cycling endothelial cells found in newly formed blood vessels, or inhibiting other vital endothelial cell functions necessary for angiogenesis. The antitumour vascular side-ef fects of chemotherapy may be optimised by administering such drugs continuo usly on a more frequent (e.g.. weekly or even daily) basis at levels well b elow the maximum tolerated dose (MTD), especially when this is done in comb ination with newly developed anti-angiogenic drugs such as vascular endothe lial cell growth factor (VEGF) receptor blocking antibodies. This strategy may minimise or delay the problems of host toxicity and acquired drug resis tance. The possibility of anti-angiogenic effects mediated by signal transd uction inhibitors such as ras farnesyltransferase inhibitors (ras FTI's), o r drugs which block receptor tyrosine kinases (e.g. ErbB2/neu) such as Herc eptin. may be the consequence of such oncogenes inducing or upregulating va rious pro-angiogenic molecules such as VEGF (vascular endothelial cell grow th factor) in tumour cells. Hence, treatment of tumour cells with such drug s can lead to downregulation of tumour cell-associated VEGF expression and this can contribute to an anti-angiogenic effect of the drug in vivo. In ad dition, some of these drugs may also affect certain 'activated' endothelial cell functions directly so as to block angiogenesis. An awareness of the p otential of such conventional or experimental anticancer drugs to affect tu mour growth through blockade or suppression of angiogenesis has implication s for how anticancer drugs may be used clinically, either alone, or in comb ination with other drugs to optimally treat cancer. (C) 2000 Elsevier Scien ce Ltd. All rights reserved.