Medicinal chemistry of combretastatin A4: present and future directions.

A growing solid tumor relies on a developing vasculature to meet its needs in terms of oxygen, nutrients, depuration, etc. This implies that if the vascular bed that has developed within the tumoral mass can be made to collapse, tumoral growth can be significantly hampered. Indeed, the first proof of principle that this could be achieved was provided more than 10 years ago when a ricin-conjugated antibody directed against an endothelial protein was able to eradicate the tumoral mass in mice.1-4 Therapeutically, two pharmacological strategies can be foreseen that stand on this observation: (1) the development of the growing tumoral vasculature can be arrested by drugs; (2) the established vasculature perfusing the tumoral mass can be destroyed by drugs. Among the crucial questions in the field is how to specifically target the endothelial cells participating in the tumoral neovasculature without causing damage to vasculature elsewhere. A wide body of data has emerged over this issue. 3 It has now been shown that the developing vasculature and the tumoral vasculature express unique proteins and that this uniqueness can be used for selective pharmacological targeting. Indeed, if we consider a plasma membrane protein expressed solely on the undesired vasculature, we could envisage the use of specific antibodies conjugated with toxins, vaccines, etc.3 Yet it is also possible that the neovasculature is more sensitive over normal tissues to more traditional small-molecule drugs. Indeed, this strategy has also been exploited, and a number of compounds have entered or are entering clinical trials (these drugs are cumulatively referred to as low molecular weight vasculature-disrupting agents). 4 For example, the growth of the neovasculature is dependent on activation of the vascular endothelial growth factor receptor, and therefore, a number of receptor antagonists have been devised and are currently tested or employed. 5 Disruption of tubulin polymerization also disrupts the formation of tumoral vasculature, and it is therefore no surprise that a number of agents have been brought forward into the drug pipeline that share this mechanism of action. The present review will concentrate primarily on the medicinal chemistry of one of these drugs, combretastatin A4 (CA-4 a