| Abstract
| - The global modification of mammalian and plasmid DNAs by novel platinum compounds,cis- or trans-[PtCl2(NH3)(Am)], where Am = NH3, nonplanar heterocycle piperidine, piperazine, or aromaticplanar heterocycle 4-picoline, was investigated in cell-free media using various biochemical and biophysicalmethods. These modifications have been compared with the activity of these new compounds in severaltumor cell lines including those resistant to antitumor cis-diamminedichloroplatinum(II) (cisplatin). Theresults show that the replacement of the NH3 group in cisplatin by the heterocyclic ligands does notconsiderably affect the DNA binding mode of this drug. Cytotoxicity studies have revealed that thereplacement lowers the activity of the platinum compound in both sensitive and resistant cell lines. It hasbeen suggested that the reduced activity of these analogues of cisplatin is associated with some featuresof the damaged DNA and/or its cellular processing. Alternatively, the reduced activity of the analoguesof cisplatin might also be due to the factors that do not operate directly at the level of the target DNA,such as intracellular platinum uptake. In contrast to the analogues of cisplatin, the replacement of oneammine group by the heterocyclic ligand in its clinically ineffective trans isomer (transplatin) results ina radical enhancement of its activity in tumor cell lines. Importantly, this replacement also markedlyalters the DNA binding mode of transplatin. The results support the view that one strategy of how toactivate the trans geometry in bifunctional platinum(II) compounds including circumvention of resistanceto cisplatin may consist of a chemical modification of the ineffective transplatin that results in an increasedstability of its intrastrand cross-links in double-helical DNA and/or in an increased efficiency to forminterstrand cross-links.
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