Cis-Diammineplatinum(II) Complexes Tethered to DNA-Affinic Ligands: Antitumour Activity and DNA-Binding Properties
Much of the driving force for the development of the “second generation” platinum antitumour agents was associated with the desire to produce compounds that exhibited reduced toxicity (especially kidney toxicity) without a significant reduction in antitumour activity (with respect to cisplatin). Consequently, efforts were generally directed towards altering the pharmaco-kinetics of cisplatin and this was achieved by replacing the labile chloro ligands with other leaving groups and extension of the stable amine ligands to series of either cyclic or acyclic alkylamines. The clinical agent carboplatin is one of a number of cisplatin analogues which have emerged from this type of program (Fig.l)1. An additional factor which severely limits the therapeutic potential of this class of antitumour agent is the onset of cellular resistance. This feature of platinum drug action has received increasing attention in recent years and has been shown2 to occur by a number of mechanisms including: increased inactivation of drug by elevated levels of cellular low-molecular weight thiols (particularly glutathione)3, decreased uptake of drug4,5 and increased efficiency of repair of platinum-DNA lesions6,7. Furthermore, it is now accepted that DNA is the cellular target for the platinum drugs and that their cytotoxicity derives from their ability to form DNA crosslinks8,9. However, cisplatin and its simple analogues have no inherent affinity for DNA, although since the actual reactive species is known8 to be a positively charged aquated complex, some affinity for the polyanionic DNA might be expected. Therefore, one strategy for further platinum drug development, which has so far received little attention and which may overcome the problem of resistance and lead to compounds with enhanced antitumour activity, is to target the complexes to DNA.
KeywordsAcridine Orange Antitumour Activity Platinum Complex P388 Cell Line Dimethyl Malonate
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