Pérez J M, Navarro-Ranninger M C, Requena J M, Jimenéz-Ruiz A, Parrondo E, Craciunescu D, López M C, Alonso C
Centro de Biología Molecular, Universidad Autónoma de Madrid, Facultad de Ciencias, Spain.
Chem Biol Interact. 1991;77(3):341-55. doi: 10.1016/0009-2797(91)90042-6.
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.
对一种铂-喷他脒配合物的DNA热稳定作用和抗白血病特性进行了研究。结果表明，铂-喷他脒中的喷他脒配体与DNA的相互作用可能比单独的喷他脒更强，因为它们通过顺式PtCl2残基与核酸结合。然而，顺式PtCl2残基似乎并未显著破坏螺旋结构。有两类证据支持这一假设：（1）介质介电常数的降低并未使喷他脒配体从铂-喷他脒：DNA复合物中脱离，（2）铂-喷他脒：DNA复合物中DNA的复性与DNA浓度无关。1H-和13C-NMR光谱数据以及元素分析表明，该配合物是化学计量比的低聚物，分子式为[(顺式-PtCl2)3(喷他脒)3][PtCl4]2。这种药物对腹腔接种L1210白血病的BDF1小鼠表现出显著的抗肿瘤活性。在浓度为50mg/kg时，对于1、5和9天的给药方案，约为LD50的15%，其抗肿瘤活性（T/C = 337%）明显优于顺铂（T/C = 215%）或卡铂（T/C = 220%），顺铂和卡铂在相同治疗方案下的剂量分别为LD50的75%和50%。此外，还发现该配合物的肾肝毒性较低。
