Differential anti-proliferative properties of novel hydroxydicarboxylatoplatinum(II) complexes with high or low reactivity with thiols.
We have examined the anti-proliferative effect of 13 recently synthesised platinum dicarboxylate complexes, very similar in their chemical, structural and kinetic properties to carboplatin. We used the L5178Y model: two murine lymphoma sublines, which differ in nucleotide excision repair ability and hence, in sensitivity to those platinum complexes that react with DNA. The anti-proliferative effect of the examined compounds mainly depends on the kind of amine ligand. Complexes with the primary amine (ethylenediamine) are more effective than complexes containing the tertiary amine (1-alkylimidazole). The ethylenediaminemalatoplatinum(II) complexes show a differential in vitro anti-proliferative activity in the L5178Y model; hence, it may be expected that they inflict DNA lesions that are repaired by the nucleotide excision system. The cytotoxicity of these complexes is directly correlated with reactivity with glutathione (GSH). The 1-alkylimidazole complexes are of low toxicity and moderate to low reactivity with GSH; in contrast to the ethylenediaminemalatoplatinum(II) complexes, their cytotoxicity is inversely correlated with reactivity with GSH. Two of the 1-alkylimidazole complexes, bis(1-ethylimidazole)(L-malato)platinum(II) and bis(1-propylimidazole (L-malato)platinum(II), show a considerable ability to arrest cells in G2 phase. We expect that the properties of these two groups of platinum complexes may be exploited in combined platinum complex treatment and irradiation.
Buraczewska
I
I
Department of Radiobiology and Health Protection, Institute of Nuclear Chemistry and Technology, Dorodna 03-195, Warsaw, Poland.
Bouzyk
E
E
Kuduk-Jaworska
J
J
Waszkiewicz
K
K
Gasińska
A
A
Szumiel
I
I
D000588:Amines; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D002945:Cisplatin; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D003959:Diamines; D003998:Dicarboxylic Acids; D004492:Edetic Acid; D007093:Imidazoles; D007940:Leukemia L5178; D051379:Mice; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity*; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D014407:Tumor Cells, Cultured
D000588:Amines; D000970:Antineoplastic Agents; D003959:Diamines; D003998:Dicarboxylic Acids; D007093:Imidazoles; D009944:Organoplatinum Compounds; D013438:Sulfhydryl Compounds; D004492:Edetic Acid; D002945:Cisplatin