Summary: | 碩士 === 國立臺灣大學 === 藥學研究所 === 88 === Abstract
PINE 98-1, developed in this laboratory, exhibited selective cytotoxicity on overexpressed ras-tansformed NIH 3T3 cancer cells. It also showed interesting antitumor activities against SW620 colon, T24 bladder and PC3 prostate human cancer cell lines. In order to evaluate the in vivo antitumor activity, formulation and pharmacokinetic studies were conducted prior to the antitumor studies in mice.
A series of vehicles such as Cremophor EL/Ethanol, PEG 400, 1000 and 4000, Glycofurol and derivatives of β-cyclodextrins were used as cosolvents for solublizing PINE 98-1 in water. Solutions of PINE 98-1 with various concentrations were injected i.v. or i.p. into Wistar rats. Blood samples withdrawn at time intervals between 0 to 3 hours were subjected to acetonitrile denature prior to assay by HPLC in Rp-select B column coupled with UV detector using 0.1M ammonia acetate aqueous solution and acetonitrile (40: 60) as the eluent. The result indicated that PINE 98-1 had the highest solubility in the solvent system consisting 70 % of glycofurol, 30 % of Cremophor EL / Ethanol or 50 % of hydroxypropyl-β-cyclodextrin. The plasma concentration—time profile indicated that i.p. administration of the solution of PINE 98-1 (25mg/kg) in 10% of hydroxypropyl-β-cyclodextrin exhibited the most satisfactory steady-state concentration.
Antitumor studies were conducted with the optimized formulation on SCID mice bearing SW620 human colon cancer cells. PINE 98-1 at the dose level of 25mg/kg/day was i. p. injected into SCID mice 3 days after the inoculation of SW620 colon cancer cells (1.5×107 cells) to dorsal subcutaneous of the animals. Measuring the tumor volume between day 17 and day 60 evaluated the inhibition of tumor growth. As tumor mass was observed in all ten mice in control group, the tumor was detected in 5 out of 10 mice in the test group after 21 days of drug treatment. The tumor volumes were 2634.7±549.9 mm3 and 518.9±722.3 mm3 respectively in mice of the control and the test groups after 58 days of drug treatment. The results indicated that PINE 98-1 significantly inhibited the growth SW620 colon cancer cells (p<0.05). Formulation studies for the optimization of pharmacokinetic profile were achieved in this study. The application of pharmacokinetic profile for the optimization of pharmacodynamic efficacy was successfully demonstrated in this study using PINE 98-1 as an example.
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