ISSN:
1432-0843
Keywords:
Key words SKI 2053R
;
In vitro cytotoxicity
;
Pharmacokinetics
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract 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-dioxolane]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 × 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 × 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 μg/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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/s002800050716
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