Antitumor activity, optimum administration method and pharmacokinetics of 13,14-dihydro-15-deoxy-deoxy-Delta7 -prostaglandin A1 methyl ester (TEI-9826) integrated in lipid microspheres (Lipo TEI-9826).
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.
Fukushima
S
S
Department of Pharmaceutics, Faculty of Pharmaceutical Science and High Technology Research Center, Kobe Gakuin University, Nishiku, Kobe 651-2180, Japan. fukusima@pharm.kobegakuin.ac.jp
Takeuchi
Y
Y
Kishimoto
S
S
Yamashita
S
S
Uetsuki
K
K
Shirakawa
S
S
Suzuki
M
M
Furuta
K
K
Noyori
R
R
Sasaki
H
H
Kikuchi
Y
Y
Kita
T
T
Yamori
T
T
Sawada
J
J
Kojima
M
M
Hazato
A
A
Kurozumi
S
S
Fukushima
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D006801:Humans; D007262:Infusions, Intravenous; D008081:Liposomes; D008297:Male; D051379:Mice; D008863:Microspheres; D011454:Prostaglandins A / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D014410:Tumor Stem Cell Assay
C121171:13,14-dihydro-15-deoxy-delta-prostaglandin-A1-methyl ester; D000970:Antineoplastic Agents; D004337:Drug Carriers; D008081:Liposomes; D011454:Prostaglandins A