The evolving role of DNA inter-strand crosslinks in chemotherapy

Abstract

DNA crosslinking agents make up a broad class of chemotherapy agents that target rapidly dividing cancer cells by disrupting DNA synthesis. These drugs differ widely in both chemical structure and biological effect. In cells, crosslinking agents can form multiple types of DNA lesions with varying efficiencies. Inter-strand crosslinks (ICLs) are considered to be the most cytotoxic lesion, creating a covalent roadblock to replication and transcription. Despite over 50 years in the clinic, the use of crosslinking agents that specialize in the formation of ICLs remains limited, largely due to high toxicity in patients. Current ICL-based therapeutics have focused on late-stage and drug-resistant tumors, or localized treatments that limit exposure. In this article, we review the development of clinical crosslinking agents, our understanding of how cells respond to different lesions, and the potential to improve ICL-based chemotherapeutics in the future.

Figure 1. DNA lesions formed by crosslinking agents

Crosslinking agents are highly reactive molecules that can form multiple types of DNA lesions in cells.

Figure 2. Diversity of ICL lesions

There are four major subgroups of DNA crosslinking agents. The ICLs produced by each group can vary widely in chemical structure and their effect on DNA topology. Nitrogen Mustard ICLs cause mild DNA bending and unwinding. Mitomycin C ICLs cause minimal distortion to DNA. Psoralen ICLs cause moderate DNA unwinding. Cisplatin ICLs cause severe DNA bending and unwinding.

Figure 3. Clinical use of DNA crosslinking agents over time

The number of clinical trials registered each year with ClinicalTrials.gov is graphed for the most commonly used crosslinking agents from each major subgroup. ClinicalTrials.gov consists of privately and publicly funded clinical studies conducted around the world. The database was established by the Food and Drug Administration Modernization Act of 1997 (FDAMA) and is maintained by the National Library of Medicine (NLM) at the National Institutes of Health (NIH).