Platinum-based chemotherapy metabolites

Platinum-based chemotherapy metabolites are the reactive, aquated species formed from the systemic administration of platinum-containing antineoplastic agents such as cisplatin, carboplatin, and oxaliplatin (Dasari & Tchounwou, 2014). These metabolites are not biological targets themselves; rather, they are the active pharmacological agents that covalently modify cellular components, most notably genomic DNA (Ghosh, 2019). Upon entering the intracellular environment, the displacement of labile ligands by water molecules generates electrophilic platinum complexes that react with the N7 position of purine bases, primarily guanine. This interaction results in the formation of bulky DNA-platinum adducts, including 1,2-intrastrand crosslinks, which distort the DNA architecture and impede the progression of DNA polymerase and RNA polymerase (Rottenberg et al., 2021). The persistence of these adducts triggers DNA damage response pathways, leading to cell cycle arrest and the induction of apoptosis in rapidly dividing malignant cells. While these metabolites are cornerstones of treatment for solid tumors like ovarian and lung cancer, their non-specific reactivity with proteins and mitochondrial DNA in healthy tissues underlies significant clinical toxicities, including nephrotoxicity and peripheral neuropathy.

Other names

Platinum-DNA adductsAquated platinum speciesCisplatin metabolitesCarboplatin metabolitesOxaliplatin metabolitesPlatinum coordination complexesReactive platinum intermediates

Platinum-based drugs act as pro-drugs that undergo intracellular activation via aquation to form reactive metabolites. These metabolites function as potent electrophiles that form covalent intra-strand and inter-strand crosslinks with DNA, primarily at the N7 position of guanine residues, which inhibits DNA replication and transcription, ultimately triggering apoptosis (Dasari & Tchounwou, 2014; Ghosh, 2019).