DNA synthesis and crosslinking pathways

DNA synthesis and crosslinking pathways encompass the essential biological processes required for genomic replication and the maintenance of structural integrity in DNA. These pathways are frequently targeted in oncology to arrest the rapid proliferation of malignant cells by inducing lethal DNA damage or metabolic starvation. DNA synthesis inhibitors, such as antimetabolites like 5-fluorouracil and methotrexate, act by depleting the pool of available nucleotides or by directly inhibiting enzymes like DNA polymerase and thymidylate synthase (StatPearls, 2023). Conversely, DNA crosslinking agents, including platinum-based compounds like cisplatin and alkylating agents like cyclophosphamide, induce covalent linkages between or within DNA strands, creating physical lesions that block replication forks and transcription machinery (NIH, 2022). The failure to repair these crosslinks or complete synthesis typically triggers programmed cell death via apoptosis (PubMed, 2021). While highly effective against many solid tumors and hematologic malignancies, these interventions often lack specificity, leading to significant systemic toxicities in rapidly dividing healthy tissues, such as the bone marrow and gastrointestinal lining (StatPearls, 2024).

Other names

DNA replication and repair pathwaysNucleic acid synthesis inhibitionDNA damaging pathwaysDNA adduct formation pathways

Drugs targeting these pathways act by inhibiting nucleotide biosynthesis (antimetabolites), directly forming covalent interstrand or intrastrand crosslinks in DNA (alkylating and platinum agents), or inhibiting the enzymatic activity of DNA polymerases and topoisomerases to prevent replication and transcription.