Toshiaki Yamashita

USEFULNESS OF GLYCOSYLATED RECOMBINANT HUMAN LYMPHOTOXIN FOR GROWTH INHIBITION OF HUMAN AND MURINE SOLID TUMORS AND EXPERIMENTAL METASTASIS IN MICE

Summary We have examined the antitumor and antimetastatic effects of native- type, glycosylated recombinant lymphotoxin (LT) on human and murine tumors transplanted in mice. The results reported here are as follows: (a) The in vivo antitumor spectrum of LT is not coincident with the in vitro study, and it has a wide antitumor spectrum and substantially inhibits the growth of human solid tumors, (b) When both syngeneic and nude mice are transplanted with Meth A tumor, the significant growth-inhibitory effect of LT is obtained in syngeneic mice, but the effect is quite small in nude mice regardless of the routes; LT attains the same degree of effectiveness as that in syngeneic mice, but at an 8 to 16 times higher dose. Furthermore, the pretreatment with antiasialo- GMl antibody inhibits the antitumor effects of LT in syngeneic mice, (c) In the pulmonary metastasis model induced by i.v. injection of Meth A cells, a high preventive effect of LT is obtained by systemic administration in syngeneic mice, but not in nude mice. In addition, the pretreatment with antiasialo- GMl antibody completely prevents the antimetastatic effect of LT, but also blocks that effect of control mice without LT treatment. In conclusion, LT appears to be a potent cytokine against tumor growth and metastasis in vivo. The differences between nude and syngeneic mice suggest the involvement of host immunity in the expression of LT function.

Analgesic and anti-inflammatory activities in rats of α-(3,5-di-t-butyl-4-hydroxybenzylidene)-γ-butyrolactone (KME-4), and its intestinal damage

α‐(3,5‐Di‐t‐butyl‐4‐hydroxybenzylidene)‐γ‐butyrolactone (KME‐4), an anti‐inflammatory drug, possesses analgesic activity in rat models. In the acetic acid‐induced writhing test, the oral ED50 values for KME‐4, indomethacin, naproxen and ibuprofen were 5.2, 3.8,7.0 and 18.6 mg kg−1, respectively, and the relative order of potency of these drugs correlated with their inhibitory effect on acetic acid‐induced vascular permeability in rats. KME‐4 also had analgesic activity in the tests of Randall‐Selitto and adjuvant arthritic flexion, but the dose required was greater than that needed in the writhing test. KME‐4 (10 mg kg−1 day−1 orally) has a preventive effect against adjuvant‐induced arthritis in rats, and its efficacy was more potent than indomethacin (2 mg kg−1 day−1) as judged from various parameters determined. When administered orally to rats once daily for 12 days, KME‐4 caused perforating ulceration of the small intestine but this action was less potent than the effect of indomethacin, naproxen and ibuprofen.

The effect of α-(3,5-di-t-butyl-4-hydroxybenzylidene)-γ-butyrolactone (KME-4), a new anti-inflammatory drug, on leucocyte migration in rat carrageenan pleurisy

KME‐4, α‐(3,5‐di‐t‐butyl‐4‐hydroxybenzylidene)‐γ‐butyrolactone was found to reduce the accumulation of leucocytes and exudate volume in the rat carrageenan pleurisy model. When administered orally 1 h before carrageenan, KME‐4 (3–10 mg kg−1) induced a degree of inhibition of leucocyte migration almost equal to that of indomethacin (3–10 mg kg−1) in both 5 n and 24 h pleurisies. Furthermore, KME‐4, when administered orally 5 h after the carrageenan, inhibited both monocyte numbers and exudate volume in a 24 h pleurisy and was more effective than indomethacin and BW755c which inhibited only monocyte migration. These results suggest that KME‐4 has a differential anti‐inflammatory activity. Dexamethasone (0.25 mg kg−1) showed strong inhibition of total cell numbers and exudate volume.