Deoxyribonucleic acid and cellular thiols (DNA/Thiols)

Deoxyribonucleic acid (DNA) and cellular thiols represent a dual-target system central to the pharmacology of platinum-based and alkylating chemotherapeutic agents. DNA serves as the primary therapeutic target, where drugs like cisplatin form covalent intra-strand and inter-strand crosslinks, primarily at the N7 position of guanine residues (Source: PubMed, PMID: 17628236). These adducts distort the DNA helix, inhibiting essential processes such as replication and transcription, which ultimately triggers apoptosis in malignant cells (Source: NIH, National Cancer Institute). Cellular thiols, including glutathione (GSH) and metallothioneins, act as significant off-targets or resistance factors by providing nucleophilic sulfhydryl groups that react with electrophilic drug molecules (Source: PubMed, PMID: 11485356). This sequestration prevents the drugs from reaching the nucleus, thereby reducing their cytotoxic efficacy and contributing to clinical drug resistance (Source: StatPearls, Cisplatin). The interaction between these drugs and thiols is also linked to systemic toxicities, such as nephrotoxicity, where thiol depletion in renal cells exacerbates oxidative stress (Source: PubMed, PMID: 24591140). Understanding the balance between DNA damage and thiol-mediated detoxification is crucial for optimizing dosing and developing strategies to overcome resistance in cancer therapy.

Other names

DNA and glutathioneDNA and sulfhydryl groupsGenomic DNA and intracellular thiols

Covalent binding to DNA bases (primarily N7 of guanine) to form adducts and crosslinks, combined with nucleophilic sequestration and detoxification by thiol-containing molecules such as glutathione.