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.
Published
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
Pubmed Central ID
- 8080453
International Standard Serial Number (ISSN)
- 0006-2952
Digital Object Identifier (DOI)
- 10.1016/0006-2952(94)90058-2
Language
- eng
Conference Location
- England