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.
Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, CZ-61265 Brno, Czech Republic.
Jana
J
Kasparkova
Oldrich
O
Vrana
Nicholas
N
Farrell
Viktor
V
Brabec
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