103 A recent study has underscored the potential of DNA adducts as biomarkers to predict patient responses to cancer chemotherapy, offering promising avenues for personalised medicine. The research, detailed in the Journal of Medicinal Chemistry, focuses on the formation and impact of DNA adducts resulting from various chemotherapy drugs. These findings could revolutionise cancer treatment, improving drug efficacy and reducing adverse effects. DNA adducts are formed when chemotherapy drugs covalently bind to DNA, causing structural modifications that interfere with cancer cell replication and survival. The research, which was led by Yupeng Li, looks into the different types of DNA adducts that are made by alkylating agents and platinum-containing drugs, which are two main types of chemotherapy drugs. Nitrogen mustards and nitrosoureas are examples of alkylating agents that attach alkyl groups to DNA. This makes DNA cross-links and strand breaks. This disrupts the DNA replication process, ultimately causing cell death. Platinum-containing drugs, including cisplatin and oxaliplatin, form DNA adducts through a similar mechanism, substituting chloride leaving groups with water molecules before binding to DNA. This binding creates cross-links that prevent DNA from uncoiling and replicating properly, which is particularly effective against rapidly dividing cancer cells. The study emphasises the importance of DNA adducts in predicting the efficacy of chemotherapy. By quantifying DNA adduct levels in patients, clinicians can potentially identify those who are more likely to respond positively to specific treatments. This approach aligns with the principles of precision medicine, where treatments are tailored to individual patient profiles. For instance, the research highlights the use of platinum-DNA adducts in blood as biomarkers. Studies have shown that higher levels of these adducts correlate with better responses in ovarian cancer patients undergoing platinum-based chemotherapy. In one study, patients who responded to treatment had much higher levels of platinum-DNA adducts than patients who did not respond. This suggests that these adducts could be a good way to tell if treatment worked. A significant challenge in utilising DNA adducts as biomarkers has been the limitations of analytical methods. Traditional techniques like 32P-postlabeling, despite their sensitivity, lacked structural specificity. However, advancements in mass spectrometry have revolutionised this field. High-resolution mass spectrometry provides detailed structural information on DNA adducts while maintaining high detection sensitivity. This enables researchers to identify specific adducts formed by chemotherapy drugs and correlate them with clinical outcomes more accurately. The adductomic approach, which Balbo and colleagues introduced, represents a significant advancement. This method allows for comprehensive profiling of DNA adducts, identifying those with high abundance and occurrence across multiple samples. Such detailed profiles can help in synthesising specific adducts for quantification, facilitating their use as biomarkers. The study also explores the potential of newly developed DNA adducting drugs, such as hypoxia-activated nitrogen mustard prodrugs. These drugs, including PR-104 and OBI-3424, show improved tumour-suppressive efficacy and reduced toxic side effects. Their effectiveness is attributed to their ability to form specific DNA adducts under hypoxic conditions prevalent in tumours. Identifying and quantifying these adducts could provide direct evidence of drug selectivity and efficacy, paving the way for their use in clinical settings. Moreover, the research points to the development of drugs targeting DNA repair pathways. PARP inhibitors, which are important enzymes for DNA repair, have already shown promise in helping treat cancers with BRCA1/2 mutations. The success of these inhibitors has spurred interest in targeting other DNA repair mechanisms, potentially enhancing the efficacy of DNA adducting drugs and overcoming drug resistance.