Antitumor activity and nephrotoxicity of a novel platinum complex, [1,3-bis(diphenylphosphino)propane](trans-1-dach)platinum(I I) dinitrate.
We have developed a new class of platinum complex [Pt(trans-l-dach)(1,3-bis(phosphino)propane)] dinitrate (KHPC-001) with potent antitumor activity and low nephrotoxicity, confirmed in vitro and compared in vivo with cisplatin, KHPC-001 or cisplatin was intraperitoneally injected on days 1, 5, and 9 into P388-bearing mice and the antitumor effects were compared. In vitro cytotoxicity, Pt accumulation, and DNA cross-link index were measured in P388 and LLC-PK1 cells after treatment with KHPC-001 or cisplatin. Twenty mg/kg (below one-tenth of LD50) of KHPC-001 had stronger antitumor effects than 2 mg/kg (about one-fifth of LD50) of cisplatin and cured 2 out of 6 mice without any toxicity. While the cytotoxicity of KHPC-001 and cisplatin were similar on P388 mouse leukemia cells, this new compound was much less cytotoxic to a kidney-derived line, LLC-PK1. This lower toxicity on the kidney cells was based on its low accumulation, causing less DNA crosslinking. KHPC-001 is a unique third-generation platinum complex with potent antitumor activity and low nephrotoxicity.
Baek
M S
MS
Department of Pharmacochemistry, College of Pharmacy, Kyung Hee University, Seoul, Korea.
Rho
Y S
YS
Jung
J C
JC
Chang
S G
SG
Nomura
M
M
Miyamoto
K J
KJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D002945:Cisplatin / Q000494:pharmacology; D005260:Female; D007668:Kidney / Q000187:drug effects*; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009944:Organoplatinum Compounds / Q000494:pharmacology* / Q000633:toxicity
D000970:Antineoplastic Agents; C105764:KHPC 001; D009944:Organoplatinum Compounds; D002945:Cisplatin