DNA repair mechanisms associated with cellular resistance to antitumor drugs: potential novel targets.

The 1990s have already heralded an enormous expansion of our knowledge of DNA repair. Gene by gene, protein by protein, each partner in the molecular processes of DNA repair is being identified and characterized, not only in bacteria and yeast, but also in mammalian cellular systems. Several distinctive mechanisms are now explained at a molecular level, even if certain specific parts still remain to be elucidated fully. The techniques used to study DNA repair have also profited from this progress with a plethora of novel in vitro assays, specific antibodies, together with DNA or RNA probes becoming available. The increased use of these tools has permitted a multiplicity of studies on DNA repair which are now not exclusively mechanistically based. Thus, certain studies have now implicated DNA repair processes as likely to be involved in the multifactorial phenomenon of drug resistance to anticancer drugs. Under these circumstances, DNA repair mechanisms should provide useful pharmacological targets to attack with novel inhibitors, with the aim of reducing and/or sensitizing tumor cells to anticancer drugs which damage DNA. Our increased knowledge of the molecular mechanisms associated with DNA repair permits us now to consider such new pharmacological targeting. In this article, we review the present status of these DNA-repair-related pharmacological studies, and discuss both the likely and possible approaches which might have potential therapeutic applications.