Antitumor activity, optimum administration method and pharmacokinetics of 13,14-dihydro-15-deoxy-Delta(7)-prostaglandin A(1) methyl ester (TEI-9826) integrated in lipid microspheres (Lipo TEI-9826)

Citation
S. Fukushima et al., Antitumor activity, optimum administration method and pharmacokinetics of 13,14-dihydro-15-deoxy-Delta(7)-prostaglandin A(1) methyl ester (TEI-9826) integrated in lipid microspheres (Lipo TEI-9826), ANTI-CANC D, 12(3), 2001, pp. 221-234
Citations number
42
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology,"Onconogenesis & Cancer Research
Journal title
ANTI-CANCER DRUGS
ISSN journal
0959-4973 → ACNP
Volume
12
Issue
3
Year of publication
2001
Pages
221 - 234
Database
ISI
SICI code
0959-4973(200103)12:3<221:AAOAMA>2.0.ZU;2-6
Abstract
13,14-Dihydro-15-deoxy-Delta (7)-prostaglandin A(1) methyl eater (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 wel l as Delta (12)-prostaglandin J(2) (PGJ(2)) were found to be stable in rat, mouse and human serum in vitro. TEI-9826 exhibited nearly identical or gre ater potential antitumor activity compared to Delta (12)-PGJ(2) and Delta ( 7)-PGA(1) in vitro against Colon26 tumor cells. Further evaluation of TEI-9 826 using the 38 human cancer cell lines panel and COMPARE analysis suggest ed that its mode of action is quite different from other anticancer agents that are currently used, TEI-9826 was integrated into lipid microspheres (L ipo TEI-9826) for dosing. Growth inhibition by Lipo TEI-9826 against Colon2 6 tumor inoculated s.c. in mice depended on administration route, i.e. at 8 0 mg/kg, no growth suppressive effect was observed for daily bolus i.v., bu t 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 t umor growth-suppressive effects were cytostatic and the tumor started to re grow at the end or a few days after the end of administration. The pharmaco kinetic study suggested that maintaining the blood level of TEI-9826 and/or TOK-4528 was essential for their antitumor effects. These results show tha t continuous i.v, infusion might be the most suitable administration method of Lipo TEI-9826 for clinical trial. [(C) 2001 Lippincott Williams & Wilki ns].