Tsunehiko Soga

DJ-927, a novel oral taxane, overcomes P-glycoprotein-mediated multidrug resistance in vitro and in vivo.

DJ‐927 is a novel taxane, which was selected for high solubility, non‐neurotoxicity, oral bioavailability, and potent antitumor activity. In this study, we compared the in vitro and in vivo efficacy of DJ‐927 with those of paclitaxel and docetaxel. DJ‐927 exhibited stronger cytotoxicity than paclitaxel and docetaxel in various tumor cell lines, especially against P‐glycoprotein (P‐gp)‐expressing cells. The cytotoxicity of DJ‐927, unlike those of other taxanes, was not affected by the P‐gp expression level in tumor cells, or by the co‐presence of a P‐gp modulator. When intracellular accumulation of the three compounds was compared, intracellular amounts of DJ‐927 were much higher than those of paclitaxel or docetaxel, particularly in P‐gp‐positive cells. In vivo, DJ‐927 showed potent antitumor effects against two human solid tumors in male BALB/c‐nu/nu mice, and yielded significant life‐prolongation in a murine liver metastasis model with male C57BL/6 mice, in which neither paclitaxel nor docetaxel was effective. The results demonstrate the superior efficacy of orally administered DJ‐927 over intravenously administered paclitaxel or docetaxel against P‐gp‐expressing tumors, probably due to higher intracellular accumulation. A phase I clinical trials of DJ‐927 is currently ongoing in the US. (Cancer Sci 2003; 94: 459–466)

New highly active taxoids from 9β-Dihydrobaccatin-9,10-acetals. Part 4

It was shown that a new taxane analogue 3, which exhibited both in vitro antitumor activity and in vivo efficacy by both i.v. and p.o. administration, was prone to be metabolized by human liver microsomes. We identified a major metabolite, M-1, generated by human liver microsomes as 20a, a hydroxylated compound at the pyridine ring of 3. To improve the metabolic stability of 3, we designed and synthesized new taxane analogues based on the structure of M-1, and obtained some compounds that maintained excellent antitumor activity and were scarcely metabolized by human liver microsomes.

Orally active docetaxel analogue: Synthesis of 10-deoxy-10-C-morpholinoethyl docetaxel analogues

To improve cytotoxicity of 10-deoxy-10-C-morpholinoethyl docetaxel analogues against various tumor cell lines including resistant cells expressing P-glycoprotein (P-gp), we modified the 7-hydroxyl group to hydrophobic groups (methoxy, deoxy, 6,7-olefin, alpha-F, 7-beta-8-beta-methano, fluoromethoxy). Among these analogues, the 7-methoxy analogue showed the strongest cytotoxicity. This analogue showed potent activity against B16 melanoma BL6 in vivo by oral administration.

Significant antitumor effect of a synthetic lipid A analogue, DT-5461, on murine syngeneic tumor models

SummaryThe antitumor effect of a synthetic lipid A analogue, DT-5461, was investigated using syngeneic tumor models in mice. Intravenous injection of DT-5461 into mice transplanted with solid tumors of MethA fibrosarcoma, MH134 hepatoma, MM46 mammary carcinoma, Lewis lung carcinoma (3LL), and colon adenocarcinomas 26 and 38 resulted in significant reductions in the weight of all tumors except Colon 26, with marked hemorrhagic necrosis of tumor tissues. Efficacy was almost equal to that of anEscherichia coli-type synthetic lipid A (compound 506), and also to those of some chemotherapeutics including Adriamycin, mitomycin C, fluorouracil and cisplatin. Furthermore, DT-5461 was more effective than other immunotherapeutics, including picibanil (OK-432) and lentinan. However, its antitumor effects were inferior to those of Adriamycin or OK-432 against the malignant ascites caused by intraperitoneal inoculation with MethA or with MH134 cells; life span was not prolonged by either intraperitoneal or intravenous administration. In addition, although DT-5461 showed direct inhibitory effects on the in vitro growth of MethA or MH134, these were much weaker than those of Adriamycin. These findings clearly indicated that DT-5461 with systemic administration is a highly effective antitumor agent on solid tumors, and suggest that the antitumor effect of DT-5461 with potent necrotizing activity might derive from indirect mechanisms related to the activation of host immune systems and not to the weak direct cytotoxicity.

Synthesis and cytotoxic activity of novel 10-alkylated docetaxel analogs.

An alkylation method of docetaxel at the C-10 position has been established by a radical coupling reaction using a 10-xanthate derivative of 7-O-TES-10-deacetylbaccatin III and appropriate alkenes. In addition the cytotoxic activity of 10-alkylated docetaxel analogs was evaluated. Among these analogs, a derivative having a methoxycarbonyl group at the end of the alkyl moiety exhibited more potent cytotoxic activity than docetaxel.

First synthesis and cytotoxic activity of novel docetaxel analogs modified at the C18-position

Abstract To investigate the effect of the C-18 position of docetaxel in its cytotoxic activity, 18-modified docetaxel analogs were synthesized for the first time from the 18-brominated baccatin derivatives. All of these analogs were found to be less active than docetaxel in cytotoxic activity against four test cell lines.