Praz and colleagues report in this issue on the relationship between the occurrence of a polymorphism of ERCC1 in tumor tissues of patients with colorectal cancer and the rate of disease response to the combination of oxaliplatin and 5-fluorouracil (1). This polymorphism is associated with reduced translation of the gene, and presumably, reduced DNA repair capability. Their report suggests that the ability of cells/tissues to up-regulate ERCC1 seems to be correlated with whether or not the patient will respond to oxaliplatin-based therapy. This ERCC1 polymorphism, and its implications, was first reported by others (2, 3). It is important to understand the molecular pharmacology of oxaliplatin, as well as the basic issues about ERCC1.

Oxaliplatin is the third platinum analogue to be approved by the Food and Drug Administration for clinical use. Cisplatin, carboplatin, and oxaliplatin have a number of molecular differences, but are similar in critical ways (4). The most important similarities revolve around the cis configuration of the two reactive groups of the platinum core of the molecule. This cis bond angle is relatively fixed and results in covalent bonding with DNA and other molecules, where the target molecule conforms to fit the bond angle of the platinum moiety. In the case of platinum-DNA adduct, this fixed bond angle for platinum results in bifunctional DNA lesions that contort the DNA to accommodate the platinum. Thus, DNA kinking is a major feature of platinum-DNA damage, which is recognized and repaired by the nucleotide excision repair pathway. Structurally, similar lesions are formed with DNA after interactions with UV light and with polycyclic aromatic hydrocarbons, all of which are recognized and repaired by nucleotide excision repair. There are four basic DNA repair pathways: nucleotide excision repair, base excision repair, mismatch repair, and double-strand break repair (5–7). Each pathway has its own set of proteins that function entirely independently of the other pathways. Experimental data suggest that there is also crossfunctionality of these pathways, but for the most part, these four pathways are separate. Nucleotide excision repair processes bulky lesions such as UV dimers, 6-4 UV photoproducts, polycyclic aromatic hydrocarbons, and cisplatin-DNA lesions. Base excision repair processes oxidative DNA damage and