The events that occur when cisplatin encounters cells

The chemical studies on the cellular response to platinum anticancer complexes are reviewed by treating the cell as a complex reacting system comprising several critical targets. In this multiple-target system, the contributions of non-DNA targets cannot be underestimated. The biological events observed in the response should be interpreted as the step-by-step results of a process in which the concert of related chemical reactions generates a sequence of chemical events. According to the multiple-target model the molecules in the plasma membrane, phospholipids and proteins, are the frontier targets. It is shown, on the basis of thermodynamic considerations, that the membrane proteins are attacked preferentially, while platinum binding to the phospholipids is relatively weak and reversible, Nevertheless, the weak and transient interaction with the phospholipids causes alterations in conformation which are transmitted and amplified further, resulting in changes in the structure and function of membranes, such as the permeability. The chemical events that occur in the course of platinum-phospholipid interactions include platinum binding, the subsequent conformational changes of the phospholipids and a change in the structure of the bilayer. In addition, the action of platinum complexes on the cytoskeleton is summarized in terms of a perturbation of the process of polymerization of skeletal protein, The sequence of chemical events, platinum binding to the monomeric protein and the induced conformational change and perturbations to the self-association of the monomer, is shown to be important in the cell damaging process. Platinum binding to actin was shown to be fatal to the cell by inducing cross-linking and aggregation and depolymerization and disorganization of the microfilaments. Various platinum complexes have been compared and several trends in their structure-activity are discussed, The other relevant events, apoptosis and drug resistance are also emphasized with the involvement of targets other than DNA.