Mechanism of Action.
Cisplatin, carboplatin, and oxaliplatin enter cells by diffusion, and by an active Cu2+ transporter (Kruh, 2003). Inside the cell, the chloride atoms of cisplatin may be displaced and the compound may be inactivated directly by reaction with nucleophiles such as thiols. Chloride is replaced by water, yielding a positively charged molecule. In the primary cytotoxic reaction, the aquated species of the drug then reacts with nucleophilic sites on DNA and proteins. Aquation is favored at the low concentrations of chloride inside the cell and in the urine. High concentrations of chloride stabilize the drug, explaining the effectiveness of chloride diuresis in preventing nephrotoxicity (see below). Hydrolysis of carboplatin removes the bidentate cyclobutanedicarboxylato group; this activation reaction occurs slowly.
The platinum complexes can react with DNA, forming both intrastrand and interstrand cross-links. The N7 of guanine is a particularly reactive site, leading to platinum cross-links between adjacent guanines on the same DNA strand; guanine-adenine cross-links also readily form and may be critical to cytotoxicity (Parker et al., 1991). The formation of interstrand cross-links is less favored. DNA adducts formed by cisplatin inhibit DNA replication and transcription and lead to breaks and miscoding, and if recognized by p53 and other checkpoint proteins, induction of apoptosis. Although no conclusive association between platinum-DNA adduct formation and efficacy has been documented, the ability of patients to form and sustain platinum adducts appears to be an important predictor of clinical response (Reed et al., 1986). Preclinical data suggest that the formation of the platinum-adenosine-to-guanosine adduct may be the most critical adduct in terms of cytotoxicity.
The specificity of cisplatin with regard to phase of the cell cycle appears to differ among cell types, although the effects of cross-linking are most pronounced during the S phase. Cisplatin is mutagenic, teratogenic, and carcinogenic. The use of cisplatin- or carboplatin-based chemotherapy for women with ovarian cancer is associated with a fourfold increased risk of developing secondary leukemia (Travis et al., 1999).