Evaluation of cisplatin and a novel platinum polymer conjugate for drug toxicity and drug distribution in mice.
The toxicity and distribution of cisplatin and two novel platinum (Pt) polymer conjugates (Pt-6 and Pt-7) were determined in serum and tissue of BALB/c mice at specific time points after i.p. administration of a drug bolus containing identical Pt concentrations. Pt concentrations were determined in serum, liver and kidney at 5 and 15 min, respectively, after drug administration by inductively coupled plasma mass spectrometry. It was found that the Pt polymer Pt-7 gave rise to a considerably lower Pt concentration in serum and considerably higher concentration in liver and kidney than cisplatin. LD25 measurements indicated that the Pt-7 polymer is considerably less toxic than cisplatin. In vitro experiments and determination of IC50 values in a variety of human tumor cell lines, normal lymphocytes and fibroblasts confirmed that Pt-6 and Pt-7 polymers are 40-500 times more toxic for tumor cells than for normal cells, perhaps reflecting preferential uptake. The toxicity of cisplatin was found to be only 1.6-40 times more effective in tumor cells. These inter-relationships are supported by the observation that the tumor enrichment factor (TEF) for cisplatin is only in the region of 6, and much lower than for Pt-6 and Pt-7, where TEFs are in the region of 40 and 150, respectively. These results demonstrate that the Pt polymer conjugates exhibit greater tumor specificity than cisplatin, killing tumor cells more effectively while being considerably less toxic for normal cells. It is concluded that the Pt polymer conjugates may be superior for cancer therapy and warrant further testing to assess their full clinical potential.
Smit
T
T
Department of Pharmacology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa.
Snyman
J R
JR
Neuse
E W
EW
Bohm
L
L
van Rensburg
C E J
CE
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D011108:Polymers; D014018:Tissue Distribution; D023382:Toxicity Tests, Acute
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D011108:Polymers; D002945:Cisplatin