Comparative nephrotoxicity of cisplatin and new octahedral Pt(IV) complexes.
OBJECTIVE
Previously, we have reported that the newly synthesized octahedral Pt(IV) compound, trans,cis-Pt(acetato)(2)Cl(2)(1,4-butanediamine), K101 and trans,cis-Pt(trifluoroacetato)(2)Cl(2)(1,4-butanediamine), K102 showed potent antitumor activities in vitro and in vivo. In order to compare the nephrotoxicity of the newly synthesized Pt(IV) complexes, K102 and K102 with cisplatin, we performed various tests.


METHODS
We performed a single dose acute toxicity test for LD(50) values determination, biochemical assays in blood serum, acid phosphatase enzyme histochemistry and transmission electron microscopic studies in renal proximal tubular cells in mice in vivo. The route of drugs administration is intraperitoneal injection.


RESULTS
In biochemical assays, the serum levels of BUN were significantly elevated at 6 h (p < 0.001), 1 day (p < 0.05) and 3 days (p < 0.001) after injection in cisplatin treated mice (6 mg/kg, single dose, i.p.). On the other hand, the serum levels of BUN were slightly elevated at 6 h (p < 0.01) only in K101 treated mice (8.2 mg/kg, single dose, i.p.), and were significantly raised at 6 h, 1 and 3 days (p < 0.05) after injection in K102 treated mice (6.2 mg/kg, single dose, i.p.). The higher serum BUN level in K102 treated mice is considered that K102 possesses more lipophilic fluoro group than acetyl group in K101. The values of creatinine and uric acid were similar in all groups. The ultrastructural morphological changes of K101- or K102-administrated mice were less remarkable than cisplatin-administrated mice. In acid phosphatase enzyme histochemistry, cisplatin treatment induced relevant changes in the distribution pattern of enzyme activity compared with K101 or K102 treatment at 7 days after injection.


CONCLUSIONS
In conclusion, these results show that K101 is less nephrotoxic than cisplatin and a promising new platinum complex.
Kim
Won-Kyu
WK
College of Medicine, Hanyang University, Haengdang-dong, Seongdong-gu, Seoul 133-791, Republic of Korea.
Kwon
Young-Ee
YE
D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D002945:Cisplatin / Q000493:pharmacokinetics / Q000633:toxicity*; D003896:Desmosomes / Q000187:drug effects / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D005260:Female; D007274:Injections, Intraperitoneal; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D046529:Microscopy, Electron, Transmission; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics / Q000633:toxicity*
D000970:Antineoplastic Agents; C515994:K101 compound; D009944:Organoplatinum Compounds; D000135:Acid Phosphatase; D002945:Cisplatin