Repair of DNA interstrand cross-links produced by cancer chemotherapeutic drugs

© Springer Science+Business Media, LLC 2013. All rights are reserved. It has been clear for over 50 years that bifunctional reactivity is an essential prerequisite for the potent cytotoxic and antitumour activity of agents such as the nitrogen mustards [1] . DNA was later identified as a target for these drugs [2, 3] , and the covalent modification of DNA almost certainly accounts for the antitumour activity of these drugs [1] . The fact that a bifunctional covalent reaction with DNA (cross-linking) is essential for the toxicity of these agents is evident from studies employing monofunctional analogues; for drugs such as the nitrogen mustard's mechlorethamine and melphalan, their monofunctional counterparts are many orders of magnitude less toxic [4, 5] . Cross-links can be formed on the same strand of DNA (intrastrand), between the two complementary strands of DNA (interstrand), or between a base on DNA and a reactive group on a protein (DNA-protein). For the bifunctional alkylating drugs (e.g. the nitrogen mustard class and mitomycin C), it is clear that the interstrand cross-link (ICL), although accounting for only a small proportion of the total DNA adducts, is the critical cytotoxic lesion [6, 7]. For the platinum drugs (e.g. cisplatin and carboplatin) the majority ( > 80%) of DNA adducts are intrastrand cross-links, although the < 5% of ICLs are critical cytotoxic lesions [8].