Interest in DNA-intercalating ligands as anti-cancer drugs has developed greatly 
since the clinical success of doxorubicin. However, despite a great deal of 
'rational design' of synthetic DNA-intercalators, only a few such compounds have 
proved clinically useful. This review briefly surveys the history of 
DNA-intercalators as clinically-used anti-cancer drugs, summarizes the known 
structure-experimental activity relationships and modes of action, and concludes 
that a factor in the slow progress is that much of the work on these compounds 
has been carried out by chemists, who were generally more interested in 
ligand/DNA interactions than drug development. Future development of the class 
rests on a careful consideration of the biochemical reasons behind the common 
limitations of the present drugs. The most important are: the inherent 
resistance of non-cycling cells, the rapid development (even by cycling cells) 
of resistance by the expression of both P-glycoprotein and altered topoisomerase 
II, limitations on drug distribution to and transport into tumours, low 
extravascular pH in tumours and the cardiotoxic side-effects of quinonoid 
chromophores. These considerations provide a set of constraints on 
physicochemical properties which must be considered in future design. However, 
within these constraints, there are useful future avenues for the development of 
DNA-intercalators as anti-cancer drugs. These include: (i) the production of 
improved topoisomerase inhibitors (by consideration of drug/protein as well as 
drug/DNA interactions); (ii) the development of reductively-activated 
chromophores as hypoxia-selective agents; and (iii) the use of DNA-intercalators 
of known DNA binding orientation as 'carriers' for the delivery of other 
reactive functionality specifically (sequence-, regio- and site-specifically) to 
DNA.