Sequence preferences of DNA interstrand cross-linking agents: Importance of minimal DNA structural reorganization in the cross-linking reactions of mechlorethamine, cisplatin and mitomycin C

Interstrand cross-linking of DNA is believed to account for the cytotoxicity of many bifunctional alkylating agents, some of which are useful in the treatment of human cancer. The nucleotide sequences at which these cross-links are formed have been defined at single nucleotide resolution in DNA fragments for several agents, including mechlorethamine, cisplatin, mitomycin C, and some structurally related agents. Taken together, the structure of duplex DNA, the sequences which are cross-linked, and the atomic sites on DNA which are linked, indicate that cross-linking occurs preferentially at locations which will result in minimal distortion of B-DNA. The proposal that this preference is primarily expressed by minimizing the energy of the transition state for conversion of monoadducts to cross-links is supported by experiments with mechlorethamine. It is suggested that extension of the modest sequence-recognizing capacity of these cross-linking agents by conjugation to highly sequence-selective "delivery vehicles" may yield second generation, targeted antitumor drugs.