9-deoxy-9-10-didehydro-12-13-didehydro-13-14-dihydroprostaglandin-d2 and Neoplasms

Antitumor Prostaglandins such as delta 12PGJ2 and delta 7PGA1 possess a cross-conjugated dienone unit and exhibit unique antitumor effect. Lipid microshere (w/o type emulsion) was selected as pharmaceutical formulation because of physicochemical properties of prostaglandin. 13,14-Dihydro-15-deoxy-delta 7-PGA1 methyl ester (TEI-9826) were selected as a candidate for clinical trial. In a rat and mouse serum in vitro, TEI-9826 rapidly metabolized to 13,14-dihydro-15-deoxy-delta 7-PGA1 (TOK-4528), but TOK-4528 is stable as well as delta 12PGJ2. Lipid microshere containing TEI-9826 at the content of 5 mg/ml exhibited administration route and schedule dependent antitumor effect in vivo using Colon 26 bearing mouse model, which suggested that duration of serum concentration was important for antitumor effect. One of the antitumor mechanism of antitumor PG might be an induction of the cyclin-dependent kinase inhibitor p21. PPAR gamma also might be important. New type homogenizer, high pressure jet flow type homogenizer was developed in the study of antitumor prostaglandin.

Topics: Animals; Antineoplastic Agents; Cell Division; Drug Administration Schedule; Drug Carriers; Drug Delivery Systems; Humans; Lipids; Mice; Microspheres; Neoplasms; Prostaglandin D2; Prostaglandins A, Synthetic; Rats; Technology, Pharmaceutical

We have been investigating the synergistic cytotoxic interactions between tamoxifen (TAM) and cisplatin (DDP) in human malignant cell lines. Recent data have demonstrated that TAM activates phospholipase D, which can increase the production of prostaglandin D2. Prostaglandin D2 has been shown to have growth inhibitory properties in several malignant cell lines. delta 12-Prostaglandin-J2 (delta 12-PG J2) is a derivative of prostaglandin D2 that has been shown to have similar inhibitory properties. We hypothesized that TAM may increase the production of delta 12-PG J2, which in turn may synergize with DDP. To begin our investigation of this interaction, we sought to determine if delta 12-PG J2 was cytotoxic and synergistic in our melanoma system and then expanded our observations to include a wide range of malignant cells. We have demonstrated that delta 12-PG J2 is cytotoxic to multiple malignant cell lines including melanoma, ovarian, prostate, colon, pancreas, small cell lung cancer, and breast cancer lines. The IC50s ranged from 0.70 microM (small cell lung cancer) to 3.30 microM (DDP-resistant melanoma). Additionally, delta 12-PG J2 exhibited synergistic cytotoxicity with both DDP and ionizing radiation. These data suggest that delta 12-PG J2 should be further evaluated in an in vivo model to confirm activity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Drug Resistance, Neoplasm; Drug Synergism; Female; Humans; Male; Neoplasms; Prostaglandin D2; Tamoxifen; Tumor Cells, Cultured; Tumor Stem Cell Assay

Some PG derivatives have been shown to be inhibitory for tumor cell growth. To elucidate the underlying mechanism(s) for this, we examined various DNA polymerase activities in PG-treated cultured cells. Human KBIII cells were exposed for one day to each of PGJ2, delta 7-PGA1 and delta 12-PGJ2 at a concentration of 5 micrograms/ml. The cells were harvested and homogenized, and the cell-free extracts were analyzed by phosphocellulose column chromatography for separation, identification, and quantification of each of the DNA polymerases. The results obtained were as follows: The activity of DNA polymerase alpha, which is responsible for DNA replication, has remained almost unchanged by any of the PG derivatives tested (77-87%), whereas the activity of DNA polymerase beta (repair enzyme) was found to dramatically decrease to 13 to 20% of that of the nontreated control cells by treatment with any of these PG derivatives. The results indicate that (a) these PG derivatives inhibit, either directly or indirectly, the synthesis of DNA polymerase beta in the KBIII cell, and (b) DNA polymerase beta may also participate in DNA replication other than DNA repair.

Topics: Antineoplastic Agents; Cell Division; Cell Line; Humans; Neoplasms; Nucleic Acid Synthesis Inhibitors; Prostaglandin D2; Prostaglandins A, Synthetic; Prostaglandins D; Prostaglandins, Synthetic