Synthesis, characterization and DNA modification induced by a novel Pt(IV)-bis(monoglutarate) complex which induces apoptosis in glioma cells.

Programmed cell death or apoptosis is a mechanism for the elimination of cells that occurs not only in physiological processes but also in drug-induced tumor cell death. Thus, because cisplatin, cis-diamminechloroplatinum (II), produces important damages on the DNA inducing apoptosis in several cell lines it has become a widely used antitumor drug. However, cisplatin possesses some dose-limiting toxicities mainly nephrotoxicity. Pt(IV) complexes, such as iproplatin, ormaplatin, and JM216 are a new class of platinum complexes that exhibits less toxicity than cisplatin. Some of these complexes have shown significant antitumor activity and a low cross-resistance to cisplatin. In the present paper, we have analyzed the DNA binding mode and the cytotoxicity of a novel Pt(IV)-bis (monoglutarate) complex. The data show that this novel complex produces DNA interstrand cross-links to a higher extent and with a faster kinetics than cisplatin. Also the Pt(IV)-bis (monoglutarate) complex kills glioma cells at drug concentrations significantly lower than those of cisplatin. Interestingly, this Pt(IV) complex produces in the glioma cells characteristic features of apoptosis such as 'DNA laddering' and fragmented nuclei. Moreover, the p53 protein accumulates early in glioma cells as a result of Pt(IV)-bis (monoglutarate) treatment. These data indicate that the Pt(IV)-bis (monoglutarate) complex induces apoptosis in glioma cells through a p53-dependent pathway.

DNA binding properties and antileukemic (L1210) activity of a Pt-pentamidine complex.

The DNA thermal stabilizing effect and the antileukemic properties of a Pt-pentamidine complex have been studied. The results indicate that the pentamidine ligands in Pt-pentamidine probably have an interaction with the DNA stronger than that of pentamidine alone because they are bound to the nucleic acid through the cis-PtCl2 residues. However, the cis-PtCl2 residues do not seem to significantly destabilize the helix. Two types of evidences are consistent with this hypothesis: (1) a decrease in the dielectric constant of the medium does not remove the pentamidine ligands from the Pt-pentamidine: DNA complex, and (2) the renaturation of the DNA in Pt-pentamidine:DNA complex is DNA concentration independent. 1H- and 13C-NMR spectroscopic data together with the elemental analysis indicate that the complex is a stoichiometric oligomer of formula [(cis-PtCl2)3(pentamidine)3] [PtCl4]2. This drug exhibits significant antineoplastic activity in BDF1 mice bearing i.p. L1210 leukemia. At a concentration of 50 mg/kg, about 15% of the LD50 for the 1,5 and 9 days schedule, the antitumor activity (T/C = 337%) is considerably superior to that of cis-DDP (T/C = 215%) or carboplatin (T/C = 220%) at doses representing 75% and 50%, respectively, of the LD50 for the same treatment schedule. Moreover, it was found that the nephro-hepatotoxicity of the complex is low.