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DNA Damaging Agents in Chemical Biology and Cancer
Basilius Sauter1, Dennis Gillingham1
1University of Basel, Department of Chemistry, St. Johanns-Ring 19, Basel, Switzerland;,
Abstract:
Despite their toxicity, DNA alkylating drugs remain a cornerstone of anticancer therapy. The classical thinking was that rapidly dividing tumour cells left more of its DNA in an exposed single-stranded state, making these rapidly dividing cells more susceptible to alkylating drugs. As our understanding of DNA repair pathways has matured it is becoming clear that compromised DNA repair - a hallmark of cancer - plays a role as well in defining the therapeutic window of these toxic drugs. Hence, although new alkylating motifs are unlikely to progress through the clinic, the legacy of these medicines is that we now understand the therapeutic potential of targeting DNA damage repair pathways. Here we look at the history of alkylating agents as anticancer drugs, while also summarizing the different mechanistic approaches to covalent DNA modification. We also provide several case studies on how insights into compromised DNA repair pathways are paving the way for potent and less toxic targeted medicines against the DNA damage response.
Insights
DNA alkylating drugs are vital cancer treatments. Understanding cancer
Area of Science:
- Oncology and Molecular Biology
Background:
- DNA alkylating agents are established anticancer drugs.
- Classical theory suggested rapid tumor cell division increases susceptibility.
- Emerging understanding highlights the role of DNA repair deficiencies in cancer.
Purpose of the Study:
- To review the history and mechanisms of alkylating agents in cancer therapy.
- To explore the link between DNA repair pathways and therapeutic efficacy.
- To present case studies on targeted therapies for DNA damage response.
Main Methods:
- Historical review of alkylating agents.
- Summary of mechanisms for covalent DNA modification.
- Analysis of case studies on DNA repair targeting.
Main Results:
- Alkylating agents remain crucial despite toxicity.
- Compromised DNA repair in cancer influences drug effectiveness.
- Targeting DNA damage repair pathways offers therapeutic potential.
Conclusions:
- While new alkylating agents are unlikely, their legacy is understanding DNA repair targeting.
- Insights into DNA repair deficiencies are driving development of targeted, less toxic medicines.
- Targeting the DNA damage response is a promising strategy in oncology.
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