Correlation of total and interstrand DNA adducts in tumor and kidney with antitumor efficacies and differential nephrotoxicities of cis-ammine/cyclohexylamine-dichloroplatinum(II) and cisplatin.

Journal Article

Mixed amine platinum complexes have been identified as a new class of antitumor agents with activity in some cisplatin-resistant tumor models. cis-Ammine/cyclohexylamine-dichloroplatinum(II) is one such analog that we have evaluated in vivo and found it to have antitumor activity that was comparable to that of cisplatin in a solid murine fibrosarcoma tumor model. In contrast to the nephrotoxicity observed with cisplatin, the analog was free from inducing this side-effect. Pharmacokinetics of the two compounds administered i.v. at equitoxic dose levels to tumor-bearing mice indicated similar decay kinetics of total platinum in plasma, kidney and the tumor. Furthermore, DNA-platinum adducts of the two agents were similar in the tumor. Total adduct levels in the kidney, on the other hand, were significantly greater (P < 0.5) by up to 4-fold for cisplatin compared with the mixed amine analog. Likewise, the levels of interstrand cross-links of the two platinum complexes were comparable in the tumor, but significantly greater (P < 0.05) in the kidney for cisplatin. The data indicate that the greater renal levels of total and interstrand DNA-platinum adducts formed by cisplatin correlate with renal damage associated with this agent, and suggest that adduct levels, and not total tissue platinum levels, provide a more useful correlation with pharmacodynamic observations.

Full Text

Duke Authors

Cited Authors

  • Yoshida, M; Khokhar, AR; Kido, Y; Ali-Osman, F; Siddik, ZH

Published Date

  • August 17, 1994

Published In

Volume / Issue

  • 48 / 4

Start / End Page

  • 793 - 799

PubMed ID

  • 8080453

International Standard Serial Number (ISSN)

  • 0006-2952


  • eng

Conference Location

  • England