The interaction of DNA-targeted platinum phenanthridinium complexes with DNA in human cells.
DNA-targeted platinum phenanthridinium complexes were investigated in intact human cells and in tumour-bearing mice. The DNA sequence specificity of platinum phenanthridinium complexes was examined in intact human cells using a Taq DNA polymerase stop assay. It was found that the platinum phenanthridinium complexes had a similar sequence specificity to that of cisplatin. However, the rate at which DNA was damaged in intact human cells was 6-fold greater for the platinum phenanthridinium chloride complexes compared with cisplatin. These results are consistent with a DNA-targeting hypothesis where the attachment of an intercalating group to cisplatin places the platinum in close proximity to DNA and increases the rate of DNA platination. Platinum phenanthridinium iodide complexes were also tested, but damaged DNA at a rate similar to cisplatin. The platinum phenanthridinium complexes with shorter linker chain lengths damaged DNA more efficiently than the longer linker chain length complexes. The platinum phenanthridinium chloride complexes also showed significant anti-tumour activity in tumour-bearing (P388) mice.
Whittaker
J
J
School of Biochemistry and Molecular Genetics, University of New South Wales, Sydney, NSW, Australia.
McFadyen
W D
WD
Baguley
B C
BC
Murray
V
V
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D003720:Densitometry; D006367:HeLa Cells; D006801:Humans; D007941:Leukemia P388; D009841:Oligonucleotides / Q000737:chemistry; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D010617:Phenanthridines / Q000494:pharmacology*; D020080:Tandem Repeat Sequences
D000970:Antineoplastic Agents; D009841:Oligonucleotides; D009944:Organoplatinum Compounds; D010617:Phenanthridines; D004247:DNA; D002945:Cisplatin