title: Tetravalent platinum complexes with ammine/amine carrier ligand configuration: circumvention of platinum resistance in vivo.
abstract: A platinum(II) and three platinum(IV) ammine/cycloalkylamine homologous series, the latter possessing either chloro, acetato or hydroxo axial ligands, were evaluated for efficacies in mice bearing tumor cells sensitive (leukemia L.1210/0 and reticulosarcoma M5076) or resistant to cisplatin (L1210/DDP) and tetraplatin (L1210/DACH). Within each series, which contained four homologs, potency increased (optimal dose decreased) as alicyclic ring size increased incrementally from cyclopropane to cyclohexane. All analogs were active at maximally tolerated doses against L1210/0 (%T/C = 125-426), with good associated therapeutic ratios of 2 to > 8 that, like the therapeutic index, provided indications of the drug's safety margin. Most complexes had activities that were similar to cisplatin (%T/C = 239) and tetraplatin (%T/C = 310). Antitumor activities were seen for all four platinum(II) complexes against L1210/DDP cells (%T/C = 133-167). In the three platinum(IV) series, on the other hand, only cyclopentane (C5) and cyclohexane (C6) analogs met or exceeded the minimum criterion for activity. These activities were similar to that seen with the positive control agent tetraplatin (%T/C = 133), but higher than that of cisplatin (%T/C = 94). Long-term survivors, which were frequently observed with these complexes in the L1210/0 model, were also seen in the L1210/DDP model, but to a lesser extent. Against L1210/DACH cells, which were sensitive to cisplatin (%T/C = 155), but resistant to tetraplatin (%T/C = 113), the C5 and C6 congeners in the platinum(IV) series were effective with %T/C in the range 148-189, while corresponding members in the platinum(II) series were only marginally active. In the solid M5076 model, complexes C5 in platinum(II) and in the acetato- and hydroxoplatinum(IV) series, and C6 from the hydroxo-platinum(IV) series, were as effective or more effective than cisplatin, which itself gave a tumor growth delay of 27.5 days. In summary, the results indicate that alicyclic ring size and, in the platinum(IV) series, axial ligand, are important modulators of efficacies of ammine/cycloalkylamine platinum congeners in both sensitive and platinum-resistant models. However, the cyclopentylamine or cyclohexylamine carrier ligand with acetato or hydroxo axial ligands in the platinum(IV) configuration are optimal combinations for circumventing both cisplatin and tetraplatin resistances.
authors.affiliation: Department of Clinical Investigation, University of Texas, M.D. Anderson Cancer Center, Houston 77030.
authors.forename: Z H
authors.initials: ZH
authors.lastname: Siddik
authors.forename: G
authors.initials: G
authors.lastname: Thai
authors.forename: M
authors.initials: M
authors.lastname: Yoshida
authors.forename: Y P
authors.initials: YP
authors.lastname: Zhang
authors.forename: A R
authors.initials: AR
authors.lastname: Khokhar
mesh_terms: D000588:Amines / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D002945:Cisplatin / Q000627:therapeutic use; D003510:Cyclohexanes / Q000737:chemistry; D003517:Cyclopentanes / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005260:Female; D007939:Leukemia L1210; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D017671:Platinum Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D000588:Amines; D000970:Antineoplastic Agents; D003510:Cyclohexanes; D003517:Cyclopentanes; D009944:Organoplatinum Compounds; D017671:Platinum Compounds; D002945:Cisplatin; C049777:ormaplatin