Effect of the geometry of the central coordination sphere in antitumor trinuclear platinum complexes on DNA binding.
Polynuclear platinum compounds comprise a unique class of anticancer agents with chemical and biological properties different from mononuclear platinum drugs. The lead compound of this class is bifunctional trinuclear platinum complex [[trans-PtCl(NH(3))(2)](2)mu-trans-Pt(NH(3))(2)[H(2)N(CH(2))(6)NH(2)](2)](4+) (1,0,1/t,t,t, BBR 3464). Interestingly, the geometry of the coordination spheres in this compound affects potency. For example, the central cis unit of [[trans-PtCl(NH(3))(2)](2)mu-cis-Pt(NH(3))(2)[H(2)N(CH(2))(6)NH(2)](2)](4+) (1,0,1/t,c,t, BBR 3499) results in substantially reduced cytotoxicity. It has been shown that the interactions of polynuclear platinum drugs with target DNA are distinct from the mononuclear-based cisplatin family. In the present work the DNA binding of 1,0,1/t,c,t in cell-free media was examined by the methods of molecular biophysics and compared to the binding of 1,0,1/t,t,t. The binding of 1,0,1/t,c,t is slower and less sequence specific. 1,0,1/t,c,t also forms on DNA long-range delocalized intrastrand and interstrand cross-links similarly as 1,0,1/t,t,t, although the frequency of interstrand adducts is markedly enhanced. Importantly, the adducts of 1,0,1/t,c,t distort DNA conformation and are repaired by cell-free extracts considerably more than the adducts of 1,0,1/t,t,t. It has been suggested that the unique properties of long-range interstrand cross-links of bifunctional trinuclear platinum complexes and resulting conformational alterations in DNA have critical consequences for their antitumor effects.
Kasparkova
Jana
J
Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, CZ-61265 Brno, Czech Republic.
Vrana
Oldrich
O
Farrell
Nicholas
N
Brabec
Viktor
V
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001483:Base Sequence; D002417:Cattle; D002457:Cell Extracts; D002942:Circular Dichroism; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism*; D004260:DNA Repair; D004261:DNA Replication; D004278:DNA, Superhelical / Q000737:chemistry / Q000378:metabolism; D004996:Ethidium / Q000737:chemistry; D005453:Fluorescence; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D017671:Platinum Compounds / Q000737:chemistry* / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence
D000970:Antineoplastic Agents; D002457:Cell Extracts; D018736:DNA Adducts; D004278:DNA, Superhelical; D017671:Platinum Compounds; D004996:Ethidium