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.
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.
Yoshida
M
M
Department of Clinical Investigation, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Khokhar
A R
AR
Kido
Y
Y
Ali-Osman
F
F
Siddik
Z H
ZH
D000818:Animals; D002945:Cisplatin / Q000494:pharmacology / Q000633:toxicity*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004247:DNA / Q000737:chemistry*; D005354:Fibrosarcoma / Q000097:blood / Q000188:drug therapy; D007674:Kidney Diseases / Q000139:chemically induced*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics / Q000633:toxicity*; D010984:Platinum / Q000097:blood
D003432:Cross-Linking Reagents; D009944:Organoplatinum Compounds; D010984:Platinum; D004247:DNA; C089160:(ammine)cyclohexylaminedichloroplatinum(II); D002945:Cisplatin