use of novel interstrand cross-linked DNA duplexes to investigate resistance to bifunctional alkylating chemotherapeutic agents

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Covalent DNA lesions play important roles in the treatment of cancer. Therapeutic alkylating agents, among some of the oldest anti-cancer agents, may be monofunctional or bifunctional; the latter category includes nitrogen mustards, chloroethyl-nitrosoureas and methyl methane sulfonates. These agents form interstrand cross-links, which if left unrepaired, prevent DNA strand separation and normal mitosis, interfere with transcription and induce apoptosis. A problem presented in cancer treatment is the development of resistance to the effects of these antitumor agents, often due to enhanced repair of the damage. Our group, through the synthesis and investigation of oligonucleotides that contain mimics of clinically relevant lesions formed during chemotherapy, hopes to advance our understanding of the mechanisms involved in their repair, an important step towards elucidating how some patients develop resistance to the effects of these chemotherapeutic agents.