Activation of trans geometry in bifunctional mononuclear platinum complexes by a piperidine ligand. Mechanistic studies on antitumor action.
A paradigm for the structure-pharmacological activity relationship of bifunctional platinum antitumor drugs is that the trans isomer of antitumor cisplatin (transplatin) is clinically ineffective. To this end, however, several new complexes of the trans structure have been identified that exhibit cytotoxicity in tumor cells that is even better than that of the analogous cis isomers. We reported recently (Kasparkova, J., Marini, V., Najajreh, Y., Gibson, D., and Brabec, V. (2003) Biochemistry 42, 6321-6332) that the replacement of one ammine ligand by the heterocyclic ligand, such as piperidine, piperazine, or 4-picoline in the molecule of transplatin resulted in a radical enhancement of its cytotoxicity. We examined oligodeoxyribonucleotide duplexes bearing a site-specific cross-link of the transplatin analogue containing the piperidine ligand by biochemical methods. The results indicate that in contrast to transplatin, trans-(PtCl2(NH3)(piperidine)) forms stable 1,3-intrastrand cross-links in double-helical DNA that distort DNA and are not readily removed from DNA by nucleotide excision repair system. Hence, the intrastrand cross-links of trans-(PtCl2(NH3)(piperidine)) could persist for a sufficiently long time, potentiating its toxicity toward tumor cells. trans-(PtCl2(NH3)(piperidine)) also forms in DNA minor interstrand cross-links that are similar to those of transplatin so that these adducts appear less likely candidates for genotoxic lesion responsible for antitumor effects of trans-(PtCl2(NH3)(piperidine)). Hence, the role of structurally unique intrastrand cross-links in the anti-tumor effects of transplatin analogues in which one ammine group is replaced by a heterocyclic ligand may predominate.
Kasparkova
Jana
J
Institute of Biophysics, Academy of Sciences of the Czech Republic, CZ-61265 Brno, Czech Republic. jana@ibp.cz
Novakova
Olga
O
Marini
Victoria
V
Najajreh
Yousef
Y
Gibson
Dan
D
Perez
Jose-Manuel
JM
Brabec
Viktor
V
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D016466:CHO Cells; D002945:Cisplatin / Q000493:pharmacokinetics*; D006224:Cricetinae; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D018736:DNA Adducts / Q000737:chemistry; D004256:DNA Polymerase I / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D054303:HIV Reverse Transcriptase / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D017665:Hydroxyl Radical; D008024:Ligands; D008956:Models, Chemical; D008962:Models, Theoretical; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry*; D010984:Platinum / Q000737:chemistry*; D013997:Time Factors
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D008024:Ligands; D009841:Oligonucleotides; D010880:Piperidines; C034697:transplatin; D017665:Hydroxyl Radical; D010984:Platinum; C032727:piperidine; D004247:DNA; D054303:HIV Reverse Transcriptase; D004256:DNA Polymerase I; D002945:Cisplatin