Kinetics of tissue disposition of cis-ammine/cyclohexylamine-dichloroplatinum(II) and cisplatin in mice bearing FSaIIC tumors.
The clinical potential of mixed amine platinum(IV) complexes has been identified, and interest in this new class of antitumor agents has been heightened by demonstration of their activity in cisplatin-resistant neoplasms. These tetravalent platinum agents are expected to undergo a reductive reaction to form the corresponding platinum(II) drug prior to eliciting biological activity. cis-Ammine/cyclohexylamine-dichloroplatinum(II) is one such product that we evaluated with cisplatin in vivo, and we found the two complexes given i.v. or i.p. to have comparable activities against a solid murine fibrosarcoma. Following i.v. administration of the two compounds at equitoxic dose levels (20 mg/kg) to tumor-bearing mice, platinum levels in the plasma were consistently higher for cisplatin. Tissue platinum levels, in contrast, were comparable between the agents or higher for the mixed amine analog at the earliest (3-h) time point. The temporal profiles determined for the concentrations over 48 h were tissue- and/or drug-specific and could be described by terminal-phase constants or half-lives of platinum in most tissues. In the plasma, kidney, lung, and jejunum, platinum levels arising from both compounds decayed with half-lives of 24-92 h. The terminal-phase constants of platinum determined in the heart for the two complexes were not significantly different from zero, indicative of levels remaining steady, whereas the constants were negative in the spleen, indicative of an increase in tissue drug concentration. In the tumor, liver, and testes, positive values for the decay-phase constants corresponding to half-lives of 47, 256, and 79 h, respectively, were seen with the mixed amine complex; this pattern contrasted with that found for cisplatin, for which the terminal-phase constant was either zero or negative. In vitro binding studies demonstrated the mixed amine complex to be more reactive. Thus, the presence of one ammine and one cyclohexylamine carrier ligand in the mixed amine complex, as opposed to the diammine ligands in cisplatin, leads to an increase in drug distribution and an alteration in the kinetics of tissue binding and removal of platinum.
Yoshida
M
M
Department of Clinical Investigation, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Khokhar
A R
AR
Zhang
Y P
YP
Thai
G
G
Siddik
Z H
ZH
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D002945:Cisplatin / Q000493:pharmacokinetics*; D005354:Fibrosarcoma / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics*; D013054:Spectrophotometry, Atomic; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C089160:(ammine)cyclohexylaminedichloroplatinum(II); D002945:Cisplatin