Mechanism of Action of Carboplatin
Carboplatin produces predominantly interstrand DNA cross-links in a cell-cycle nonspecific manner, which is the primary mechanism by which it exerts its antineoplastic effect. 1
Chemical Structure and Activation
- Carboplatin is a second-generation platinum compound with the chemical structure diammine(1-cyclobutanedicarboxylato)platinum(II), which provides greater chemical stability compared to cisplatin 2
- The drug undergoes aquation (reaction with water) to produce the active species, though this occurs at a slower rate than with cisplatin 1
- Despite the slower aquation rate, both carboplatin and cisplatin induce equal numbers of drug-DNA cross-links, causing equivalent lesions and biological effects 1
DNA Binding Mechanism
- Carboplatin binds preferentially to DNA forming covalent monoadducts, in contrast to cisplatin which is hydrolyzed more easily and presents higher efficiency in forming covalent diadducts along the double-helix 3
- The drug produces interstrand DNA cross-links rather than DNA-protein cross-links 1
- These cross-links interfere with DNA replication and transcription, ultimately leading to cell death 1
- The effect is cell-cycle nonspecific, meaning it can kill cancer cells regardless of which phase of the cell cycle they are in 1
Comparative Reactivity
- Carboplatin's greater chemical stability accounts for its lower reactivity with nucleophilic sites of DNA compared to cisplatin, which explains why higher doses are necessary to achieve similar antitumor effects 2
- The lower reactivity with proteins is related to the observed reduction in nephrotoxicity compared to cisplatin 2
- Carboplatin is much less sensitive to ionic strength changes when compared to cisplatin, which may contribute to its different toxicity profile 3
Protein Binding and Distribution
- Carboplatin is not bound to plasma proteins initially, and no significant quantities of protein-free, ultrafilterable platinum-containing species other than carboplatin are present in plasma 1
- However, platinum from carboplatin becomes irreversibly bound to plasma proteins over time and is slowly eliminated with a minimum half-life of 5 days 1
- Protein binding is limited compared to cisplatin, which contributes to carboplatin's different pharmacokinetic profile 2
Clinical Implications of Mechanism
- The differences in potencies between carboplatin and cisplatin appear to be directly related to the difference in aquation rates 1
- The mechanism results in dose-limiting myelosuppression (particularly thrombocytopenia) rather than the nephrotoxicity, neurotoxicity, and ototoxicity characteristic of cisplatin 4
- The slower aquation and preferential monoadduct formation may contribute to carboplatin's more favorable toxicity profile while maintaining therapeutic efficacy 3, 2