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Biomedical subjects

M Kawatsu

Publications and source records attributed to M Kawatsu.

13 recordsLinked to original sources
PubMed1995

Low molecular weight immunomodulators produced by microorganisms.

In order to develop a new class of low molecular weight immunomodulators for the treatment of incurable diseases involving cancer, hematologic diseases and inflammation, we have sought cytokine inducers and inhibitors of cell adhesion to the extracellular matrix among the low molecular compounds produced by microorganisms. Cytogenin, cytoblastin (a monokine inducer), conagenin (a lymphokine inducer) and delaminomycins and IC-101 (inhibitors of cell adhesion to extracellular matrices) have been recently found in our institute. In this report, we describe the principles of screening and structures, and discuss their biological activities.

Actinobacteria↗
PubMed1995

Improvement of efficacy of antitumor agents by conagenin.

The antitumor efficacy of antitumor agents at sublethal doses was investigated in combination with conagenin (CNG) against murine leukemias. Mice were inoculated with 1 x 10(3) L1210 cells i.v. and given 300 mg/kg of cyclophosphamide (CY) i.p. on days 1 and 2 or on days 1, 5 and 9 after the tumor inoculation, and 5 mg/kg of CNG daily for 10 days. The administration of CNG was effective in increasing the number of cured mice and in prolonging the survival period of mice significantly, on both schedules of CY treatment. Moreover, the antitumor effect of CY against EL-4 was enhanced by CNG in increasing the number of cured mice, in CY treatment on days 1 and 2, and on days 1, 5 and 9. The effect of CNG was examined with mitomycin C (MMC) and adriamycin (ADM) at sublethal doses against leukemias. The antitumor effects of MMC at 10 mg/kg against L1210, and ADM at 15 mg/kg against P388 administered on days 1 and 5 were enhanced by CNG. Although mice treated with ADM at 15 mg/kg died earlier than non-treated controls on days 1 and 2 against L1210, P388 and EL-4, CNG with ADM was effective in prolonging the survival period.

Adjuvants, Immunologic↗
PubMed1994

Effect of conagenin on thrombocytopenia induced by antitumor agents in mice.

The effect of conagenin (CNG) on myelosuppression induced by antitumor agents was investigated. The daily administration of CNG prevented reduction in the number of platelets (PLT) observed in peripheral blood of mice given mitomycin C (10 mg/kg) but did not prevent reduction in the number of leukocytes (WBC). The effect on PLT was also confirmed in mice given cyclophosphamide (100 mg/kg). In mice given repeated doses of 5-fluorouracil (10 mg/kg), CNG prevented the reduction of PLT as well as WBC and maintained them at normal levels. CNG prevented reduction of the production of interleukin-2, 3 and 6 in cultured supernatants of spleen cells taken from mice given 5-fluorouracil. These results suggest that CNG modulates production of lymphokines which are responsible for thrombopoiesis.

Animals↗
PubMed1993

T cell activation by conagenin in mice.

Conagenin (CNG), a low molecular immunomodulator, enhanced incorporation of [3H]thymidine into T cells activated by concanavalin A but did not to non-activated T cells. The culture supernatants of activated T cells treated with CNG enhanced incorporation of [3H]thymidine into cytokine dependent cell lines, CTLL-2 and IC-2 cells. This indicates that CNG exclusively acts on activated T cells and stimulates them to promote DNA synthesis and to produce lymphokines, which may include T cell growth factors and hematopoietic growth factors. These activities were also observed with T cells taken from mice given CNG.

Adjuvants, Immunologic↗
PubMed1993

Effect of conagenin in tumor bearing mice. Antitumor activity, generation of effector cells and cytokine production.

Antitumor effects and function of T cells in tumor bearing mice given conagenin (CNG), a low molecular immunomodulator, were investigated. The administration of CNG, once a week for 4 weeks, was the most effective schedule in inhibiting growth of IMC carcinoma, a syngeneic tumor. In this regimen, cytotoxic T lymphocytes and natural killer activities in spleens of CNG treated mice were maintained at higher levels than those of non-treated mice. Lymphokine production by splenic T cells was also enhanced in cultures, whereas monokine production by macrophages, which was increased in accordance with tumor growth, was reduced by CNG administration. The antitumor effect of CNG was not observed in mice given anti-asialo GM1 serum and in athymic mice. Results shown in this report suggest that CNG exerts its antitumor effects through activation of T cells and enhancement of generation of antitumor effector cells.

Adjuvants, Immunologic↗
PubMed1991

Usefulness of glycosylated recombinant human lymphotoxin for growth inhibition of human and murine solid tumors and experimental metastasis in mice.

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 anti-asialo-GM1 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 anti-asialo-GM1 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.

Animals↗
PubMed1990

Synergistic antitumor effect of glycosylated recombinant human lymphotoxin with human interferon-gamma on lymphotoxin-sensitive human tumor.

We examined the antitumor effect of glycosylated recombinant lymphotoxin (LT) in combination with human interferon-gamma (IFN-gamma) on human tumors transplanted into nude mice and compared it with that of tumor necrosis factor (TNF). The results were as follows: (i) The systemic administration of glycosylated LT combined with IFN-gamma produced a significant antitumor activity against HT-1080 fibrosarcoma, G-361 malignant melanoma, KB nasopharyngeal carcinoma, and ZR-75-1 breast carcinoma, all of which are relatively resistant to a single treatment with LT or IFN-gamma. The synergistic effect was also seen in LT-sensitive HeLa S3 tumors. The effect was observed after either i.v. or s.c. injection. (ii) In contrast, no synergistic or additive effect on HeLa S3 tumors was observed in the case of TNF combined with IFN-gamma. (iii) The serum half-life of glycosylated LT in tumor-bearing mice was about 22-fold longer than that of TNF. In conclusion, glycosylated LT, especially in combination with IFN-gamma, appears to be a potent cytokine against tumor growth in vivo compared with TNF. Its long serum half-life can result in a strong antitumor effect in combination with IFN-gamma in vivo.

Amino Acid Sequence↗
PubMed1990

The pharmacokinetic pattern of glycosylated human recombinant lymphotoxin (LT) in rats after intravenous administration.

We have examined the pharmacokinetics of glycosylated recombinant human lymphotoxin (LT) after intravenous bolus injection in rats and compared them with those of tumor necrosis factor (TNF) or LT species. The results are as follows. 1) The mean half-life of glycosylated LT in serum increases for each increase in dose, and the distribution volume (V) and total body clearance [(Cl (total)] tend to decrease for increase in dose. On the other hand, the half-life of TNF also increases for increase in dose, but the V tends to increase for increase in dose and Cl (total) does not change. 2) The glycosylated LT distributes to all organs so far tested except brain, and tends to accumulate to kidney more than other tissues at 6 h after the injection. 3) Nonglycosylated LT produced by E. coli and the glycosylated LT species carrying both N-type and mucin-type sugar moieties (25 kDa LT) have shorter half-lives and higher Cl (total)s than 23 kDa LT carrying N-type sugar moieties alone. The 21 kDa LT, the same species as 23 kDa LT except that it lacks 15 amino acid residues at the N-terminus, disappears much faster than 23 kDa LT and shows higher V and Cl (total). Thus, glycosylated LT shows nonlinear pharmacokinetics like TNF, but the deposition is quite different from that of TNF. The high serum concentration of glycosylated LT depends upon the presence of N-type sugar moieties, but not mucin-type sugar moieties. The N-terminal protein chain of LT also correlates with the serum concentration.

Amino Acids↗
PubMedDate not supplied

Improvement of intestinal toxicity of 5-fluorouracil by conagenin, a low molecular immunomodulator.

The effect of conagenin (CNG) on intestinal toxicity induction by 5-fluorouracil (5-Fu) was investigated. In mice given sublethal doses of 5-Fu (50mg/kg, i.v.) for 5 consecutive days, a decrease in body weight and diarrhea accompanied with hemorrhaging of the duodenum, atrophy of cecum and reduced small intestine length appeared. The administration of CNG in combination with 5-Fu inhibited thoe side effects induced by 5-Fu. Although all mice given 5-Fu alone were died within 13 days, 3 out of 10 mice treated with CNG survived for more than 21 days. The cytotoxicity of 5-Fu was not affected by CNG in vitro. The antitumor activity of 5-Fu was improved by CNG in increasing the number of surviving mice.

Adjuvants, Immunologic↗
PubMedDate not supplied

Modulation by conagenin of inflammatory mediator productions in mice given 5-fluorouracil.

The effect of conagenin (CNG) on the production of the inflammatory mediators induced by 5-fluorouracil (5-Fu) in mice was investigated. We found that the production of interleukin (IL)-1 alpha and prostaglandin E2(PGE2) in whole spleen cell cultures from mice given a sublethal dose of 5-Fu was induced in the week after treatment, and subsequently the production of IL-4 and IL-IO was induced. The administration of 5-Fu and CNG suppressed the production of IL-1 alpha and PGE2, and induced the production of IL-4 and IL-10 earlier than 5-Fu alone did. In cultures of cells from Peyer's patches, IL-1 alpha production was suppressed by CNG administration. The effect of CNG was also demonstrated in vitro. CNG at 0.001 to 1.0 microgram/ml suppressed IL-1 alpha and PGE2 production in cultures of adherent peritoneal exudate cells (PEC) and cells from Peyer's patches of mice given 5-Fu. IL-10 production in cultures of non-adherent splenic cells was enhanced by CNG. These results indicate that CNG modulates inflammatory responses induced by 5-Fu through production of anti-inflammatory cytokines such as IL-4 and IL-10.

Adjuvants, Immunologic↗