APEC Harmonization Center: challenges and issues relating to multiregional clinical trials in the APEC region.

The Asia-Pacific Economic Cooperation (APEC) Harmonization Center (AHC) was established in 2009 with the purpose of promoting harmonization of regulatory processes for drugs and medical devices. The AHC held three training workshops on multiregional clinical trials (MRCTs); these workshops provided forums for discussing the value and potential benefits of MRCTs. Participants from regulatory agencies, the pharmaceutical industry, and academia identified many issues and made recommendations for resolving major challenges with the aim of improving the capacity of the Asia-Pacific region to carry out MRCTs.

Antitumor activity of 4-phenyl-1-arylsulfonylimidazolidinone, DW2143.

We examined the ability of sulfonylurea derivative, DW2143 (4-phenyl-1-[1-(4-aminobenzoyl)-indoline-5-sulfonyl]-4,5-dihydro-2-imida zolone hydrochloride), to inhibit the growth of tumor cells in vitro and in vivo. When its anti-proliferative activities were tested on five murine tumor (B 16, Colon26, E1-4, 3LL and P388) and nine human tumor (BxPC-3, HepG2, Lovo, MCF-7, NCI-H69, SW480, WiDR, KB and KBV20C) cells of diverse tissue origins, the in vitro antitumor activities of DW2143 were comparable to those of doxorubicin against all tumor cell lines. In addition, the anti-proliferative activities of DW2143 against KBV20C, a vincristine-resistant cell line, are similar or superior to those of doxorubicin. When the in vivo antitumor activities using three murine tumor cells were tested after oral administration of DW2143, a wide range of tumor growth inhibition was observed. Tumor growth inhibition against 3LL at doses of 50 and 100 mg/kg DW2143 was 84.3% and 47.2%, respectively, which was comparable or superior to those of doxorubicin (5 mg/kg). Tumor growth inhibition of B16 at a dose of 100 mg/kg in the DW2143-treated group was 42% as compared to 54% for doxorubicin (5 mg/kg). When mice implanted with Colon26 were tested, tumor growth inhibition at a dose of 80 mg/kg DW2143 was 36% as compared with 37% for doxorubicin (5 mg/kg). Taken together, these results indicate that the novel sulfonylurea derivative, DW2143, is an attractive candidate for further development as a useful oral anticancer drug.

Characterization of the anticancer activity of DW2282, a new anticancer agent.

DW2282 [(S)-(+)-4-phenyl-1-[N-(4-aminobenzoyl) indoline-5-sulfonyl]-4,5-dihydro-2-imidazolone].hydrochloride] was derived from diarylsulfonylurea and was identified as a prominent new anticancer agent. We examined the characteristics of DW2282 activity on the proliferation of human lung carcinoma cells, A549 and human leukemic cells, K562. DW2282 effectively inhibited cancer cell proliferation in vitro. Colony forming assay and viability tests demonstrated that DW2282 is a cytotoxic agent rather than a cytostatic agent. The isotope uptake test exhibited that DW2282 inhibited or inactivated protein synthesis. Also, under conditions which cause RNA or protein synthesis inhibition, by co-treatment with actinomycin D or cycloheximide, reduced the anticancer effects of DW2282. This means that the cytotoxicity of DW2282 depends partially on RNA or protein synthesis and proteins affected by DW2282 may inactivate or alter the process of the synthesis of another protein. DW2282 activity was highly diminished in the presence of colcemid, a metaphase spindle blocker. This result suggests that DW2282 may be related to the cell cycle. After exposure to DW2282, morphologically apoptotic cells appeared in A549 cells and fragmented DNA was detected in K562 cells. It demonstrated that apoptosis is one of the mechanisms by which DW2282 inhibits the proliferation of A549 and K562 cells.

Momordins inhibit both AP-1 function and cell proliferation.

The activation of Jun/Fos is a crucial factor in transmitting the tumor promoting signal from the extracellular environment to nuclear transcription machinery. One of the final steps in signal transduction is the binding of Jun/Fos to the AP-1 site in order to express gene transcription. Utilizing this concept, we screened about 100 extracts of natural plants to search for a Jun-Fos function inhibitor. The methanol extract of Ampelopsis radix reduced Jun/Foc retardation remarkably. The active principles of the extract were isolated and purified by repeated column chromatography and their structures were identified as oleanolic acid glycosides known as momordin I, Id, and Ie. These compounds reduced the Jun/Fos-DNA interaction and their activities were quantitated with liquid scintillation counting of corresponding bands. Among them, momordin I had the strongest inhibitory activity, with an IC50 value of 22.8 micrograms/ml. The methanol extract and momordin I, Id and Ie also showed cell cytotoxicity against human cancer cell lines. As expected from a gel shift assay, momordin I showed the strongest cytotoxicity and its IC50 value was from 7.280 micrograms/ml to 16.05 micrograms/ml depending on the cell line. With these data, it may be concluded that the mechanism of anticancer activity of momordin I comes from its inhibitory effect on the protein-DNA interaction. The in vivo test was done only with the methanol extract. The extract showed measurable anticancer activity against murine colon cancer. The wet tumor weight reduction rate was 17.73% at 90 mg/kg dose. We suggest that the Jun/Fos-DNA interaction results in cell cytotoxicity.

Synthesis and antitumor activity of 4-phenyl-1-arylsulfonyl imidazolidinones.

Novel 1-(1-benzoylindoline-5-sulfonyl)-4-phenyl-4,5-dihydroimidazolon es 3 synthesized show highly potent and broad cytotoxicities. Among them compound 3b (DW2143) exhibits much more potent cytotoxicities than doxorubicin and highly effective antitumor activities against murine (3LL, Colon 26) and human xenograft (NCI-H23, SW620) tumor models.