title: 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-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.
authors.affiliation: Centro de Biología Molecular, Universidad Autónoma de Madrid, Facultad de Ciencias, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Pérez
authors.forename: M C
authors.initials: MC
authors.lastname: Navarro-Ranninger
authors.forename: J M
authors.initials: JM
authors.lastname: Requena
authors.forename: A
authors.initials: A
authors.lastname: Jimenéz-Ruiz
authors.forename: E
authors.initials: E
authors.lastname: Parrondo
authors.forename: D
authors.initials: D
authors.lastname: Craciunescu
authors.forename: M C
authors.initials: MC
authors.lastname: López
authors.forename: C
authors.initials: C
authors.lastname: Alonso
mesh_terms: D000818:Animals; D016190:Carboplatin / Q000627:therapeutic use; D002945:Cisplatin / Q000627:therapeutic use / Q000633:toxicity; D004247:DNA / Q000378:metabolism*; D004355:Drug Stability; D007700:Kinetics; D007939:Leukemia L1210 / Q000188:drug therapy*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D009691:Nucleic Acid Denaturation; D009944:Organoplatinum Compounds / Q000378:metabolism* / Q000627:therapeutic use / Q000633:toxicity; D010419:Pentamidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity; D015719:Single-Strand Specific DNA and RNA Endonucleases / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D009944:Organoplatinum Compounds; C057919:platinum(II) pentamidine; D010419:Pentamidine; D004247:DNA; D016190:Carboplatin; D015719:Single-Strand Specific DNA and RNA Endonucleases; D002945:Cisplatin