DNA interactions of new antitumor platinum complexes with trans geometry activated by a 2-metylbutylamine or sec-butylamine ligand.
The global modification of mammalian and plasmid DNAs by novel platinum compounds, trans-[PtCl(2)(NH(3))(Am)], where Am=2 -methylbutylamine or sec-butylamine was investigated in cell-free media using various biochemical and biophysical methods. These modifications were analyzed in the context of the activity of these new compounds in several tumor cell lines including those resistant to antitumor cis-diamminedichloroplatinum(II) (cisplatin). The results showed that the replacement of one amine group by 2-methylbutylamine or sec-butylamine ligand in clinically ineffective trans-diamminedichloroplatinum(II) (transplatin) resulted in a radical enhancement of its activity in tumor cell lines so that they are more cytotoxic than cisplatin and exhibited significant antitumor activity including activity in cisplatin-resistant tumor cells. Importantly, this replacement also markedly altered DNA binding mode of transplatin and reduced the efficiency of repair systems to remove the adducts of the new analogues from DNA. The results support the view that one strategy to activate trans geometry in bifunctional platinum(II) compounds including circumvention of resistance to cisplatin may consist in a chemical modification of the ineffective transplatin which results in an increased efficiency to form DNA interstrand cross-links.
Institute of Biophysics, Academy of Sciences of the Czech Republic, CZ-61265 Brno, Czech Republic. brabec@ibp.cz
Radim
R
Prokop
Jana
J
Kasparkova
Olga
O
Novakova
Victoria
V
Marini
Ana María
AM
Pizarro
Carmen
C
Navarro-Ranninger
Viktor
V
Brabec
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002457:Cell Extracts; D002942:Circular Dichroism; D002945:Cisplatin / Q000494:pharmacology; D003432:Cross-Linking Reagents; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
D000970:Antineoplastic Agents; D002457:Cell Extracts; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D024243:HMGB1 Protein; D009944:Organoplatinum Compounds; C034697:transplatin; D004247:DNA; D002945:Cisplatin