Preclinical perspectives on platinum resistance

In the 30 years since the introduction of cisplatin into the clinic, laboratory studies have provided considerable information as to both how the drug exerts its antitumour effects and how some tumours are, or become, resistant. Once inside a cell, the chlorine groups of cisplatin are exchanged for water (aqua) species, which are more chemically reactive. The intracellular target for cisplatin is DNA, where a variety of adducts are formed, some on the same strand of DNA (intrastrand adducts) and others between strands (interstrand adducts). Of the 4 bases, guanine is the preferred site for binding and the most common adduct involves linkages on 2 adjacent guanines on the same strand of DNA. It remains uncertain which of the various types of adduct is the most important in terms of producing antitumour effects. Resistance to cisplatin has been studied extensively using tumour cells repeatedly exposed to the drug in vitro. In these cell models, resistance is generally due to a combination of mechanisms, some resulting in reduced damage to DNA and others following DNA damage. Resistance due to inadequate binding to DNA has been shown to be caused by reduced drug uptake (influx rather than efflux) and inactivation by thiol-containing species such as glutathione and metallothioneins. Resistance occurring post-DNA binding may be due to changes in DNA repair pathways [an increase in nucleotide excision repair (NER) or a loss of DNA mismatch repair (MMR)]. Conversely, the hypersensitivity of some cell lines to cisplatin has been shown to be due to defective NER, through loss or reduced expression of NER proteins such as XPG and XPA. Resistance may also be mediated through alterations in proteins involved in programmed cell death (apoptosis) such as p53 and the BCL2 family. A basic understanding of cisplatin resistance pathways has made a major impact in the development of new platinum analogues capable of circumventing resistance. Examples (which are now undergoing clinical trial) include ZD0473 (which, relative to cisplatin, possesses a reduced reactivity towards inactivating thiol-containing molecules) and the trinuclear platinum BBR3464 (which has markedly different DNA binding properties compared with cisplatin).