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

Abstract 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 -PtCl 2 residues. However, the cis -PtCl 2 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. 1 H- and 13 C-NMR spectroscopic data together with the elemental analysis indicate that the complex is a stoichiometric oligomer of formula [( cis -PtCl 2 ) 3 (pentamidine) 3 ][PtCl 4 ] 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 LD 50 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 LD 50 for the same treatment schedule. Moreover, it was found that the nephro-hepatotoxicity of the complex is low.