Antitumor
prostaglandins(PGs) such as
Delta12-PGJ2 and Delta7-PGA1 possess a
cyclopentenone or cross-conjugated dienone structures. Antitumor PGs are actively incorporated through cell membrane and control gene expression. Very recent studies clarified that P53 independent expression of p21 and gadd 45, activation of
PPARgamma are involved in antitumor mechanism of these PGs. At the low concentration, these PGs exhibit physiological or pathological activity such as osteoblast calcification, promotion of
colon cancer cell proliferation. COMPARE PROGRAM using human 38 tumor cell lines suggested that antitumor mechanism of Delta7-PGA1 and 13, 14-dihydro-15-deoxy-Delta7-PGA1 methyl
ester (TEI-9826) are quite different from other
anticancer agents which are clinically used.
Lipid microspheres and
Lipiodol formulation were examined as
dosage form of the PGs and
lipid microspheres were selected for further study. At first
lipid microspheres integrated TEI-9038 (Lipo TEI-9038) was chosen as a candidate for clinical trial. However Lipo TEI-9038 failed to exhibit substantial antitumor effect because of its enzymatic instability and toxicity in vivo. Lipo
TEI-9826 was then selected as promising candidate for clinical trial because of its stability in serum. Lipo
TEI-9826 exhibited marked antitumor effect in several animal models including CDDP resistant nude mice model. Pharmacokinetic and toxicological studies using rats suggested that continuous infusion is the most suitable administration method for Lipo
TEI-9826. New type emulsifier, Controlled High Pressure Process Homogenizer (De-BEE 2000 and mini De-BEE) was developed during the preclinical studies on manufacturing process of Lipo
TEI-9826. These results warrant the clinical trial for Lipo
TEI-9826 in CDDP resistant
cancer.