Kazutaka Hayashi

Wf-536 prevents tumor metastasis by inhibiting both tumor motility and angiogenic actions.

The signaling pathway of Rho and Rho-associated coiled-coil forming protein kinase (ROCK) is involved in tumor metastasis. In the present study, we investigated the suppressive effect of a novel inhibitor of ROCK, Wf-536 [(+)-(R)-4-(1-Aminoethyl)-N-(4-pyridyl) benzamide monohydrochloride], on spontaneous tumor metastasis in vivo and analyzed its action on tumor cell motility and angiogenesis to clarify its action mechanism. Wf-536 (0.3-3 mg/kg/day) was found to inhibit Lewis lung carcinoma (LLC) metastasis and LLC-induced angiogenesis in orally treated mice; in vitro, it inhibited both invasion and migration by LLC cells and invasion, migration, and formation of capillary-like tubes on Matrigel by endothelial cells, without cytotoxicity or anti-proliferative action in either cell type. We conclude that Wf-536 has tumor anti-metastatic activity which may depend on inhibition of tumor motility and angiogenesis. The findings support its further clinical development as an anti-metastatic agent.

WF-536 INHIBITS METASTATIC INVASION BY ENHANCING THE HOST CELL BARRIER and INHIBITING TUMOUR CELL MOTILITY

1. Rho‐associated coiled‐coil forming protein serine/threonine kinase (ROCK) is involved in the development of tumour metastasis. Wf‐536, (+)‐(R)‐4‐(1‐Aminoethyl)‐N‐(4‐pyridyl) benzamide monohydrochloride, a novel inhibitor of ROCK, inhibits tumour metastasis in some animal models. To metastasise, tumour cells have to disturb the tight intercellular junctions and the basement membrane matrix of the host tissue, which, respectively, create an intercellular barrier and the extracellular membrane. To clarify the mechanism of Wf‐536 in inhibition of tumour metastasis, we analysed the effect of Wf‐536 on the transition of tumour cells through the host cell layer and the basement membrane in in vitro systems.

Vatanidipine hydrochloride: a new long-lasting antihypertensive agent

Vatanidipine is a novel dihydropyridine (DHP)-type calcium channel blocker with slow-onset pharmacological actions, which are probably due to both its slow uptake into vascular tissues and resistance in its approach to the calcium channel binding site. Vatanidipine once incorporated into vascular tissues is not easily released, even by repeated washing, thus resulting in a long-lasting action of the agent. A slow-onset and long-lasting hypotensive action was observed in various experimental hypertensive models. Clinical trials using human subjects with essential hypertension indicated that vatanidipine exerts an antihypertensive effect with a slow onset and long duration. In spite of its potent hypotensive effect, the incidence of adverse effects by vatanidipine administration has been reported to be lower than that in cases of nitrendipine. In addition to its vasodilatory effects, vatanidipine efficiently suppressed noradrenaline release from sympathetic nerve endings, thus suggesting this agent exhibits a beneficial effect in the treatment of hypertensive patients, in which the reflex activation of peripheral sympathetic nerves is unfavourable to antihypertensive therapy. In a double-blind study, vatanidipine did not show reflex tachycardia, despite producing a potent and long-lasting hypotensive effect, in contrast to the administration of nitrendipine. In an animal study, vatanidipine exhibited a protective effect against cerebrovascular lesions, through a mechanism independent of its hypotensive effect. In addition, a renoprotective effect was also observed in experimental hypertensive models. In cholesterol-fed rabbits, vatanidipine exerted an anti-atherosclerotic action, which is probably attributable to the inhibitory action of the agent on low-density lipoprotein oxidation. In essential hypertensive patients, the plasma levels of cholesterol and triglyceride decreased after vatanidipine treatment, thus suggesting that this agent may have a therapeutic potential in preventing such vascular diseases as atherosclerosis. Taken together, vatanidipine appears to be a novel and useful antihypertensive agent, which can both prevent target-organ damage and reduce cardiovascular morbidity and mortality.

A high power X-band klystron

It is noted that the size and weight of industrial and medical electron linear accelerator systems can be significantly reduced by the use of an X-band source in place of the S-band source currently used. A description is given of a 4-MW (average 4-kW), 4- mu s, 9.3-GHz klystron developed specifically for industrial and medical accelerator applications. The peak output power achieved was 4.6 MW for beam voltage at 151 kV and beam current at 60 A. The duty was initially limited by a ghost mode in the RF window. This mode was suppressed by introducing a window, and the duty was increased to achieve 4.2-kW average output power at 5- mu s operation. The experimental results obtained with prototype klystrons as well as the design of a production model are presented.<<ETX>>