Cytotoxicity, mutagenicity, cellular uptake, DNA and glutathione interactions of lipophilic trans-platinum complexes tethered to 1-adamantylamine.
Cytotoxicity and mutagenicity of trans,trans,trans-[PtCl2(CH3COO)2(NH3)(1-adamantylamine)] [trans-adamplatin(IV)] and its reduced analog trans-[PtCl2(NH3)(1-adamantylamine)] [trans-adamplatin(II)] were examined. In addition, the several factors underlying biological effects of these trans-platinum compounds using various biochemical methods were investigated. A notable feature of the growth inhibition studies was the remarkable circumvention of both acquired and intrinsic cisplatin resistance by the two lipophilic trans-compounds. Interestingly, trans-adamplatin(IV) was considerably less mutagenic than cisplatin. Consistent with the lipophilic character of trans-adamplatin complexes, their total accumulation in A2780 cells was considerably greater than that of cisplatin. The results also demonstrate that trans-adamplatin(II) exhibits DNA binding mode markedly different from that of ineffective transplatin. In addition, the reduced deactivation of trans-adamplatin(II) by glutathione seems to be an important determinant of the cytotoxic effects of the complexes tested in the present work. The factors associated with cytotoxic and mutagenic effects of trans-adamplatin complexes in tumor cell lines examined in the present work are likely to play a significant role in the overall antitumor activity of these complexes.
Halámiková
Anna
A
Institute of Biophysics, Academy of Sciences of the Czech Republic, vvi, CZ-61265 Brno, Czech Republic.
Heringová
Pavla
P
Kaspárková
Jana
J
Intini
Francesco P
FP
Natile
Giovanni
G
Nemirovski
Alina
A
Gibson
Dan
D
Brabec
Viktor
V
D000547:Amantadine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry*; D018736:DNA Adducts / Q000737:chemistry; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000187:drug effects / Q000235:genetics; D009153:Mutagens / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology*; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D018736:DNA Adducts; D009153:Mutagens; D009944:Organoplatinum Compounds; D004247:DNA; D000547:Amantadine; D007041:Hypoxanthine Phosphoribosyltransferase