Fukushima S, Takeuchi Y, Kishimoto S, Yamashita S, Uetsuki K, Shirakawa S, Suzuki M, Furuta K, Noyori R, Sasaki H, Kikuchi Y, Kita T, Yamori T, Sawada J, Kojima M, Hazato A, Kurozumi S, Fukushima M
Department of Pharmaceutics, Faculty of Pharmaceutical Science and High Technology Research Center, Kobe Gakuin University, Nishiku, Kobe 651-2180, Japan.
Anticancer Drugs. 2001 Mar;12(3):221-34. doi: 10.1097/00001813-200103000-00008.
13,14-Dihydro-15-deoxy-Delta7-prostaglandin A1 methyl ester (TEI-9826), an antitumor prostaglandin analog, is a candidate for clinical trial. In the present study, we examined its biological stability in vitro, antitumor activity in vitro and in vivo, and pharmacokinetics. Although TEI-9826 was rapidly hydrolyzed to the carboxylic acid form (TOK-4528), TOK-4528 as well as Delta12-prostaglandin J2 (PGJ2) were found to be stable in rat, mouse and human serum in vitro. TEI-9826 exhibited nearly identical or greater potential antitumor activity compared to Delta12-PGJ2 and Delta7-PGA1 in vitro against Colon26 tumor cells. Further evaluation of TEI-9826 using the 38 human cancer cell lines panel and COMPARE analysis suggested that its mode of action is quite different from other anticancer agents that are currently used. TEI-9826 was integrated into lipid microspheres (Lipo TEI-9826) for dosing. Growth inhibition by Lipo TEI-9826 against Colon26 tumor inoculated s.c. in mice depended on administration route, i.e. at 80 mg/kg, no growth suppressive effect was observed for daily bolus i.v., but significant growth suppressive effect was observed for daily i.p., daily s.c. every other day s.c. and 4 times a day continuous (5 min) i.v. These tumor growth-suppressive effects were cytostatic and the tumor started to regrow at the end or a few days after the end of administration. The pharmacokinetic study suggested that maintaining the blood level of TEI-9826 and/or TOK-4528 was essential for their antitumor effects. These results show that continuous i.v. infusion might be the most suitable administration method of Lipo TEI-9826 for clinical trial.
13,14-二氢-15-脱氧-Δ7-前列腺素A1甲酯（TEI-9826）是一种抗肿瘤前列腺素类似物，是临床试验的候选药物。在本研究中，我们检测了其体外生物学稳定性、体外和体内抗肿瘤活性以及药代动力学。尽管TEI-9826迅速水解为羧酸形式（TOK-4528），但发现TOK-4528以及Δ12-前列腺素J2（PGJ2）在体外大鼠、小鼠和人血清中是稳定的。TEI-9826在体外对Colon26肿瘤细胞显示出与Δ12-PGJ2和Δ7-PGA1几乎相同或更强的潜在抗肿瘤活性。使用38种人类癌细胞系面板对TEI-9826进行的进一步评估和COMPARE分析表明，其作用模式与目前使用的其他抗癌药物有很大不同。TEI-9826被整合到脂质微球中（脂质体TEI-9826）用于给药。脂质体TEI-9826对皮下接种Colon26肿瘤的小鼠的生长抑制作用取决于给药途径，即80mg/kg时，每日静脉推注未观察到生长抑制作用，但每日腹腔注射、每日皮下注射、隔日皮下注射和每日4次连续（5分钟）静脉注射均观察到显著的生长抑制作用。这些肿瘤生长抑制作用是细胞抑制性的，肿瘤在给药结束时或结束后几天开始重新生长。药代动力学研究表明，维持TEI-9826和/或TOK-4528的血药浓度对其抗肿瘤作用至关重要。这些结果表明，持续静脉输注可能是脂质体TEI-9826临床试验最合适的给药方法。
