Effect of oligofucose derivatives on acetic acid-induced gastric ulcer in rats.

This study attempted to enhance the anti-ulcer activity of fucoidan from Cladosiphon okamuranus TOKIDA by chemical modification with a hydrophobic group. The suitable number of fucose residues in the effective compound was also clarified to obtain a compound of constant quality. Degraded fucoidans were coupled with several hydrophobic groups via Schiff bases, and their anti-ulcer activities were determined by acetic acid-induced ulcer models in rats. Size-fractionated oligofucose was also modified and assayed for anti-ulcer activity. Among the modified oligofucoses, only the oligofucose-dodecylaniline combination (OFDA) significantly promoted ulcer healing. The effective dose was 0.2 mg/kg/d. The most suitable number of fucose residues in the compound for the anti-ulcer activity was determined to be around 12. We succeeded in enhancing the anti-ulcer activity of Cladosiphon fucoidan by modification with dodecylaniline. The activity of this compound was comparable or greater than that of typical anti-ulcer agents. By determination of the optimal OF chain length for the anti-ulcer activity of OFDA, it became possible to obtain OFDA of constant quality.

Diarylheptanoids suppress expression of leukocyte adhesion molecules on human vascular endothelial cells.

Diarylheptanoids possess potent anti-inflammatory properties. However, the mechanism of their action is not fully understood. In this study, we found that three diarylheptanoids, 1-(3, 5-dimethoxy-4-hydroxyphenyl)-7-phenylhept-1-en-3-one (YPE-01), yakuchinone B and demethyl-yakuchinone B, reduced the adhesion of both human monocytic cell line U937 and human eosinophilic cell line EoL-1 cells to tumor necrosis factor-alpha (TNF-alpha)-treated human umbilical vein endothelial cells. In addition, they suppressed interleukin-1beta- or TNF-alpha-induced expression of E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) on the surface of the endothelial cells. Since YPE-01 reduced both VCAM-1 and ICAM-1 mRNA induction in TNF-alpha-stimulated endothelial cells, diarylheptanoids appeared to suppress adhesion molecule expression at the transcriptional level. Furthermore, YPE-01 suppressed both VCAM-1 and ICAM-1 mRNA induction as well as edema in 12-O-tetradecanoylphorbol 13-acetate (TPA)-inflamed mice ears in vivo. These results suggest that the anti-inflammatory action of diarylheptanoids is, at least in part, due to their suppressive effect on the surface expression of inducible adhesion molecules in endothelial cells, and subsequent leukocyte adhesion.

Facilitation of passive avoidance response by newly synthesized cationized arginine vasopressin fragment 4-9 in rats.

The effects of a newly synthesized cationized arginine vasopressin fragment 4-9 analogue (C-AVP-(4-9)) on learning and memory in rats were studied by the passive avoidance test. C-AVP-(4-9) and its parent peptide, arginine vasopressin fragment 4-9 (AVP-(4-9)), a well known potent neuropeptide, were subcutaneously injected 1.5 hr prior to the retention test. The most effective doses of C-AVP-(4-9) and AVP-(4-9) were 8.6 x 10(-2) and 1.3 nmol/kg, respectively. To evaluate the distribution of C-AVP-(4-9) in the control nervous system (CNS), apparent tissue-plasma concentration rations (Kp.app) of intravenously administered radioiodinated C-AVP-(4-9) (125I-C-AVP-(4-9)) in the CNS in mice were determined. At the apparent steady state of plasma concentration of 125I-C-AVP-(4-9), the Kp.app values of the 125I-C-AVP-(4-9) in the cerebrum, cerebellum and spinal cord were over 12 times higher than that of the vascular space marker which slightly penetrates the BBB. Moreover, the rat cerebral homogenate converted C-AVP-(4-9) into its parent peptide AVP-(4-9). These results suggest that the potent effects of C-AVP-(4-9) on learning and memory may be due to AVP-(4-9) generated as a result of distribution and metabolism of peripherally administered C-AVP-(4-9) in the CNS.

Synthesis and antitumor activity of 20(S)-camptothecin derivatives. A-ring-substituted 7-ethylcamptothecins and their E-ring-modified water-soluble derivatives.

Twenty-six novel A-ring-modified 7-ethylcamptothecins (6) were synthesized by Friedländer's condensation of the chiral tricyclic ketone (5) with aminopropiophenones (4). The compounds substituted with fluorine at the 11 position showed strong cytotoxicity to KB and L1210 cells. The 11-fluoro derivatives also exhibited strong inhibitory activity on DNA topoisomerase I. Nine compounds 6 with four to ten times stronger cytotoxicity than that of camptothecin were selected and converted into water-soluble 17-O-acyl amide derivatives (8). Compounds 8e (10-Me, O-COCH2CH2SCH3) and 8f (11-F, O-COC2H5) showed activity towards Meth A in mice that was comparable to that of CPT-11, at lower doses than CPT-11.

Tyrosinase inhibitors from crude drugs.

Various crude drugs were examined for their tyrosinase inhibitory activity. Marked activity was observed in Chouji and Yakuchi extracts and the active substances in these extracts were identified as eugenol and yakuchinone A, respectively. Other vanillyl compounds such as ferulic acid, curcumin and yakuchinone B also had higher activities than eugenol or yakuchinone A and inhibited the enzyme competitively. The presence of the hydroxyl group at the 4 position of the aromatic ring of the cinnamoyl moiety and the alpha,beta-unsaturated carbonyl conjugated with an aromatic ring in these substances may play important roles in the competitive inhibition of tyrosinase.

Prevention of indigenous infection of mice with Escherichia coli by nonspecific immunostimulation.

We have previously reported that the lethal toxicity of 5-fluorouracil (5-FU) in specific-pathogen-free mice is due to an intestinal infection with indigenous Escherichia coli induced by the drug (K. Nomoto, T. Yokokura, Y. Yoshikai, M. Mitsuyama, and K. Nomoto, Can J. Microbiol. 37:244-247, 1991). In the present study we demonstrate that nonspecific immunostimulation is effective in the protection of mice from the lethal indigenous infection induced by 5-FU. Intravenous or subcutaneous injection of a preparation of heat-killed Lactobacillus casei YIT 9018, a potent nonspecific immunostimulant, into BALB/c mice reduced the lethal toxicity of 5-FU at doses ranging from 338 to 800 mg/kg of body weight if YIT 9018 was injected 7 to 40 days before administration of 5-FU. Systemic infection with E. coli developed in all of the 5-FU-treated control mice 7 days or more after administration of 5-FU in large doses and was accompanied by overgrowth of the bacteria in the intestinal tract. Pretreatment of mice with YIT 9018 resulted in a decreased occurrence of systemic infection with E. coli to levels of 0 to 20% and no significant changes in the population levels of E. coli in the intestinal tract during the 14 days after administration of 5-FU. The levels of leukopenia in the spleen and peripheral blood were lower, and recovery of granulocyte-macrophage precursor cells in the spleen and femur began earlier in the treated animals than in the 5-FU-treated controls. Intravenous transfusion of syngeneic normal bone marrow cells or spleen cells into the mice at an early period after administration of 5-FU diminished markedly the occurrence of the lethal indigenous infection, suggestion that an earlier recovery from chemotherapy-induced myelosuppression is important in the mechanisms of protection of the host from the infection.

Antitumor activity of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothec in, a novel water-soluble derivative of camptothecin, against murine tumors.

The search for new water-soluble analogues of camptothecin (CPT) with higher activity and less toxicity has led to the development of a novel compound, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11), which showed significant antitumor activity against a broad spectrum of experimental tumor models by i.p., i.v., or oral administration. When its activity against L1210 was compared with that of CPT and known derivatives, CPT-11 was most effective, giving the highest maximum increase in life span (ILS) and showing good activity over a wide dose range. The antitumor activity of CPT-11 was shown against tumors not only in the ascites form but also in the solid form. Included among the more susceptible murine tumors are S180, Meth A fibrosarcoma, Lewis lung carcinoma, Ehrlich carcinoma, MH134 hepatoma, mammary carcinoma of C3H/HeN mice, L1210, and P388 leukemia. Probable cures of these tumors were induced frequently by CPT-11. The antitumor activity of CPT-11 against i.p.-implanted L1210 was superior to that of Adriamycin in maximum ILS, the number of cured mice, and the therapeutic ratio. CPT-11 at a dose of 100 mg/kg produced an ILS in excess of 300% with five of six mice surviving tumor free, and effected 100% tumor regression at 200 mg/kg, whereas the optimum dose of Adriamycin, 12.5-25 mg/kg, brought about 114-129% ILS with one of six mice surviving. The acute toxicity of CPT-11 was extremely low, particularly in the case of oral administration. CPT-11 is expected to be clinically useful.

[Antitumor activity of chlorella extract, PCM-4, by oral administration].

The antitumor activity of a water-soluble substance extracted from Chlorella regulararis S-50, PCM-4, against murine transplanted tumors was investigated. PCM-4 is composed of sugar (25.7%), protein (51.5%) and nucleic acid (18.7%). By oral administration of PCM-4, both the growth of Sarcoma 180 and Meth A, subcutaneously implanted into mice, and ascites hepatoma AH 44 and AH 41C, intravenously implanted into rat, was inhibited. PCM-4 also showed antitumor activity against Sarcoma 180 and Meth A by intraperitoneal administration. The finding that PCM-4 has no direct growth-inhibition effect on tumor cells in vitro suggests that the antitumor activity of PCM-4 be elicited from the host-mediated response system.