Influence of exposure and infusion times on the cytotoxicity and pharmacokinetics of cis-malonato[(4R, 5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) .
The effect of exposure time on the in vitro cytotoxicity of a new platinum complex, cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolan e]platinum(II) (SKI 2053R) and cisplatin (CDDP) toward two human lung-adenocarcinoma cell lines (PC-9, PC-14) and two human stomach-adenocarcinoma cell lines (KATO III, MKN-45) was investigated by variation of the exposure time (1, 4, 12, and 24 h) and drug concentration to yield a constant product of drug concentration times exposure time (C x T). Exposure of cancer cells to low concentrations of SKI 2053R for 12 or 24 h resulted in a greater killing effect than did 1- or 4-h exposure to 24- or 6-fold higher concentrations; the inhibitory effects of SKI 2053R on the colony formation of all tumor cell lines except for KATO III were significantly increased with increasing exposure time (P < 0.05). However, the inhibitory effects of CDDP against all tumor cell lines tested except for PC-14 were inversely correlated with increasing exposure time (P < 0.05). The intracellular accumulation of SKI 2053R and CDDP was measured under the same conditions used in the cell-survival assay using MKN-45 cells. The amount of platinum accumulated from SKI 2053R into MKN-45 cells was greater for the treatment involving low concentrations and long-term exposures (12 and 24 h) than for that using high concentrations and short-term exposures (1 and 4 h) at the constant C x T values; however, the increased accumulation of CDDP was more prominent as the concentration was increased, even if the exposure time became shorter. The pharmacokinetics studies of SKI 2053R following 1-, 4-, 12-, and 24-h infusions were performed in beagle dogs. A single dose of SKI 2053R (5.0 mg/kg) was successively given over various infusion periods to three beagle dogs at 3-week intervals. The peak levels of ultrafiltrable platinum observed for SKI 2053R at the 1-, 4-, 12-, and 24-h infusions were 3.10+/-0.49 (mean +/- SD), 1.24+/-0.06, 0.43+/-0.07, and 0.25+/-0.04 microg/ml, respectively. The mean binding ratios of platinum from SKI 2053R to plasma protein at the end of 1-, 4-, 12-, and 24-h infusions were approximately 91%, 73%, 53%, and 51%, respectively. The steady-state level of free platinum was maintained during long-term infusions (12 and 24 h) after short periods (1-3 h) from the start of the infusion. This study strongly suggests that the therapeutic efficacy of SKI 2053R given by continuous long-term infusion should be investigated in future clinical studies.
Kim
H T
HT
Life Science Research Center, Sunkyong Industries, Kyungki-Do, Korea.
Kim
D K
DK
Cho
Y B
YB
Kim
T S
TS
Jung
I
I
Kim
K H
KH
Heo
D S
DS
Bang
Y J
YJ
Shin
S G
SG
Kim
N K
NK
D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity; D019540:Area Under Curve; D002945:Cisplatin / Q000493:pharmacokinetics / Q000627:therapeutic use; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy*; D008314:Malonates / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity; D013274:Stomach Neoplasms / Q000188:drug therapy*; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D000970:Antineoplastic Agents; D008314:Malonates; D009944:Organoplatinum Compounds; C090717:SKI 2053R; D002945:Cisplatin