In vitro antitumor activity, intracellular accumulation, and DNA adduct formation of cis-[((1R,2R)-1,2-cyclohexanediamine-N,N')bis(myristato)] platinum (II) suspended in lipiodol.
SM-11355, cis-[((1R,2R)-1,2-cyclohexanediamine-N,N')bis(myristato)] platinum (II), is a lipophilic platinum complex under clinical development that targets primary hepatocellular carcinoma using Lipiodol as a carrier. SM-11355 was compared with cisplatin (CDDP) using an in vitro evaluation system capable of examining the release characteristics and the cytotoxicity of drugs suspended in Lipiodol. SM-11355 suspended in Lipiodol (SM-11355/Lipiodol) and CDDP suspended in Lipiodol (CDDP/Lipiodol) showed cytotoxic activity against rat ascites hepatoma AH-109A cells in a dose-dependent manner. Their IC50 values following 7-day exposure were 22.3 and 0.40 microg/ml, respectively. Following the subsequent 7-day exposure, from day 7 to day 14 after preparation of the suspension, SM-11355/Lipiodol showed an almost equivalent activity, but CDDP/Lipiodol did not show any activity at all. SM-11355/Lipiodol showed a sustained release into the culture medium over the course of a 14-day exposure. Following the exposure to CDDP/Lipiodol, the platinum concentration in the medium was at its maximum on the first day and remained constant thereafter. Intracellular platinum uptake and formation of platinum-DNA adducts were dependent on the release characteristics of each drug suspension. For SM-11355/Lipiodol, the drug release, intracellular drug uptake, and formation of platinum-DNA adducts over the course of the subsequent 7-day exposure were similar to those observed during the first 7 days. DPC, one of the compounds released from SM-11355/Lipiodol, was taken up by cells and showed formation of platinum-DNA adducts. Thus, this study suggests that SM-11355/Lipiodol may release active platinum compound(s) that bind to nuclear DNA and mediate the cytotoxic activity of SM-11355/Lipiodol.
Kishimoto
S
S
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University. skisimot@pharm.kobegakuin.ac.jp
Miyazawa
K
K
Fukushima
S
S
Takeuchi
Y
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000493:pharmacokinetics*; D018736:DNA Adducts / Q000096:biosynthesis* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020128:Inhibitory Concentration 50; D007459:Iodized Oil / Q000494:pharmacology*; D009944:Organoplatinum Compounds / Q000378:metabolism* / Q000493:pharmacokinetics*; D010984:Platinum / Q000493:pharmacokinetics; D051381:Rats; D012997:Solvents / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured
C065354:1,2-cyclohexanediamine platinum(II)-DNA complex; D000970:Antineoplastic Agents; D018736:DNA Adducts; D009944:Organoplatinum Compounds; D012997:Solvents; D010984:Platinum; C406530:miriplatin; D007459:Iodized Oil; D002945:Cisplatin