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 p latinum dicarboxylate complexes, very similar in their chemical, structural and kinetic properties to carboplatin. We used the L5178Y model: two murin e 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) ar e more effective than complexes containing the tertiary amine (1-alkylimida zole). 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 an repaired by the nucleotide e xcision 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 inverse ly correlated with reactivity with GSH. Two of the 1-alkylimidazole complex es, bis(1-ethylimidazole)(L-malato)platinum(II) and bis(1-propylimidazole)( L-malato)platinum(II), show a considerable ability to arrest cells in G2 ph ase. We expect that the propel ties of these two groups of platinum complex es may be exploited in combined platinum complex treatment and irradiation. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.