picibanil and Body-Weight

It was reported that the symptoms of tumor patients may be alleviated markedly and even the tumor may be regressed completely after acute infection. Bacterin OK-432 has notable inhibitory effect on the growth of various tumors in animals. At present, OK-432 has been used in clinical immunotherapy for tumors with no other adverse events besides fever and leucocytosis. This study was to investigate the effects of combined bacterin on the serum level of interleukin 12(p70)[IL-12(p70)] and the growth of sarcoma 180 (S180) in mice.. After transplantation of S180, the mice were randomized into 5 groups, and received injection of Staphylococcus aureus, Salmonella typhimurium, Mycobacteria phlei, and combined bacterin containing the 3 bacteria strains, respectively, or received no treatment (blank control). The weight of S180 xenografts, the thymus, and the spleen in mice was measured. The serum level of IL-12(p70) was detected by ELISA.. The mean weight of S180 tumors was 1.39 g in Staphylococcus aureus group, 1.50 g in Salmonella typhimurium group, 1.36 g in Mycobacteria phlei group, 0.62 g in combined bacterin group, and 2.40 g in blank control group; the differences among the 5 groups were significant (F=66.73, P<0.001). The mean weight of S180 tumors was significantly lower in the 4 bacterin groups than in control group, and significantly lower in combined bacterin group than in the 3 single bacterin groups (q test, P<0.001). The weights of the thymus and the spleen among the 5 groups had no significant difference (F=2.36, P>0.05; F=1.89, P>0.05). The inhibition rate of tumor growth was significantly higher in combined bacterin group than in Staphylococcus aureus, Salmonella typhimurium, and Mycobacteria phlei groups (74.17% vs. 42.08%, 37.50%, and 43.33%, P<0.01). The mean serum level of IL-12(p70) was 19.44 pg/ml in combined bacterin group, 12.41 pg/ml in Staphylococcus aureus group, 10.35 pg/ml in Salmonella typhimurium group, 11.68 pg/ml in Mycobacteria phlei group, and 4.45 pg/ml in control group; the difference among the 5 groups was significant (F=15.76, P<0.0001), but the difference among the 3 single bacterin groups was not significant (q test, P>0.05), while the differences between other groups were significant (q test, P<0.01).. The chosen bacterins in this study can induce the mice to produce IL-12(p70) and suppress the growth of S180. The effect of the combined bacterin is much better than the single bacterins.

Topics: Animals; Bacterial Vaccines; Body Weight; Cell Proliferation; Female; Interleukin-12; Male; Mice; Mycobacterium phlei; Neoplasm Transplantation; Organ Size; Picibanil; Random Allocation; Salmonella typhimurium; Sarcoma 180; Spleen; Staphylococcus aureus; Thymus Gland

Effects of stimulation of the maternal immune system on abnormal pregnancy induced with 5-azacytidine (5ACDR) administration at embryonic day 7.5 (E7.5) were examined in mice treated with recombinant interleukin 1beta (IL-1beta) at E6.5 (5ACDR + IL-1 at E6.5) or E9.5 (5ACDR + IL-1 at E9.5), OK432 (5ACDR + OK432) at E7.5 or PSK (5ACDR + PSK) at E7.5. Embryos from these dams were examined at E13.5. The frequency of dead and malformed embryos and number of malformations on each embryo increased in the 5ACDR + IL-1 at E6.5 groups compared with the 5ACDR-alone group. Adverse pregnancy outcomes in the 5ACDR + OK432 and 5ACDR + PSK groups were less frequent than in the 5ACDR-alone group. The frequency of exencephaly, facial cleft, eye anomalies (micro- or anophthalmos), and micrognathia significantly increased in the 5ACDR + IL-1 groups, in contrast, that of exencephaly decreased in the 5ACDR + OK432 and 5ACDR + PSK groups compared with the 5ACDR-alone group. The phagocytes on the exencephalic surface drastically increased in the 5ACDR + IL-1 groups, and they often appeared to ingest the migrating neuroepithelial cells. Such findings, however, were rarely observed in the 5ACDR-alone, 5ACDR + OK432 and 5ACDR + PSK groups. Thus, administration of IL-1beta to the abnormal pregnant dams increased the mortality and severity of the malformations in the embryos caused by 5ACDR, whereas PSK or OK432 decreased them. These results suggest that the different modes of activation of the maternal immune system may exert alternative or opposite effects on teratogenic pregnancy.

Topics: Abnormalities, Multiple; Adjuvants, Immunologic; Animals; Antimetabolites, Antineoplastic; Antineoplastic Agents; Azacitidine; Body Weight; Brain; Congenital Abnormalities; Female; Interleukin-1; Mice; Mice, Inbred ICR; Microscopy, Electron, Scanning; Phagocytes; Picibanil; Placenta; Pregnancy; Pregnancy, Animal; Proteoglycans; Teratogens; Time Factors

We investigated the therapeutic effects of OK432 (picibanil; CAS39325-1-4), an immunomodulator that is derived from the Su strain of Streptococcus pyogenes. This agent was administered alone or combined with human interferon-alpha in a murine model of insulin-dependent diabetes mellitus. Interferon-alpha inhibits viral replication, reducing the incidence of virus-induced IDDM. Groups of DBA/2 mice (N = 25 per group) received an intraperitoneal injection of OK432 and interferon-alpha daily for 16 d beginning 1 d after inoculation with 500 plaque-forming units of encephalomyocarditis virus (EMCV). The dose of OK432 was one clinical unit (corresponding to 0.1 mg dried cells) per mouse, and that of interferon-alpha was 1 x 10(4) u/g. The animals were killed at random at 3 or 7 d after inoculation with EMCV. The survival rate of mice treated with the combination of OK432 and with interferon-alpha was significantly greater than that of the non-treated infected control animals (P < 0.01). Fasting levels of blood glucose were significantly lower in the mice administered the combination, than in the controls, both on day 3 (68 +/- 21 mg/dl vs. 270 +/- 135 mg/dl, P < 0.01) and on day 7 (101 +/- 29 mg/dl vs. 219 +/- 112 mg/dl, P < 0.01). Serum levels of insulin were significantly higher in the treated mice than in the controls (65 +/- 5 vs. 55 +/- 1 microU/ml, P < 0.05). However, in the mice treated with OK432 or interferon-alpha alone, the survival rate and the blood level of glucose and insulin did not differ from those of infected controls. Natural killer (NK) cell activity was significantly higher in the mice treated with the drug combination than in the controls on both days evaluated: day 3, 65 +/- 5 vs. 55 +/- 1%, n = 3, P < 0.05; day 7, 44 +/- 3 vs. 22 +/- 8%, n = 3, P < 0.05). Serum levels of murine interferon in the treated mice exceeded those in controls on both days evaluated (day 3, 671 U/ml vs. 442 U/ml; day 7, 57 U/ml vs. 43 U/ml). There were no significant differences in NK cell activity or in the interferon level in mice treated with either OK432 or interferon-alpha alone as compared with the infected, non-treated controls. Results suggest that the combination of OK432 and interferon-alpha protects against virally induced IDDM by increasing the activity of NK cells as well as the plasma level of interferon.

Topics: Animals; Blood Glucose; Body Weight; Cardiovirus Infections; Cell Survival; Diabetes Mellitus, Experimental; Encephalomyocarditis virus; Insulin; Interferon Type I; Interferons; Killer Cells, Natural; Male; Mice; Mice, Inbred DBA; Pancreas; Picibanil; Recombinant Proteins; Survival Analysis

We investigated the effects of OK432, recombinant human interferon alpha A/D (rIFN alpha A/D) and a combination of these drugs on murine acute myocarditis due to encephalomyocarditis virus. Mice were administered 1 KE of OK432 and 10(4)U/g of rIFN alpha A/D starting 24 hr after viral inoculation for 14 days. The survival rate of mice having the combination therapy was significantly higher than that of untreated mice on day 21 (15 of 20 vs. 6 of 20, P less than .001), whereas the viral titer in the heart, the heart weight/body weight ratio and the scores for myocardial inflammation and necrosis were significantly lower. On the other hand, therapy with OK432 or rIFN alpha A/D individually improved neither the survival rate nor the extent of myocardial damage. The natural killer cell activity in the combination therapy mice on day 3 after infection was significantly increased in comparison with untreated mice (46.2 +/- 5.5 vs. 37.7 +/- 2.8%, P less than .01), and the cytotoxicity of peritoneal macrophages was increased (45.0 vs. 26.7%). Thus, the combination therapy of OK432 and rIFN alpha A/D was more effective than the therapy with OK432 alone or rIFN alpha A/D alone against acute viral myocarditis when the treatment was started early after infection, and the stimulation of host immunologic response by OK432 may be important for this combination therapy.

Topics: Animals; Body Weight; Cytotoxicity, Immunologic; Drug Therapy, Combination; Encephalomyocarditis virus; Female; Heart; Interferon Type I; Killer Cells, Natural; Macrophages; Mice; Mice, Inbred C3H; Myocarditis; Myocardium; Necrosis; Picibanil; Recombinant Proteins

OK-432 (a streptococcal preparation) has been widely used for cancer immunotherapy in Japan. It is a potent immunostimulator, activating macrophages and T lymphocytes, and increasing the production of TNF and several other cytokines in both humans and animals. In the present study, we evaluated the prophylactic effect of OK-432 on the development of autoimmune kidney disease in NZB/W F1 (BWF1) mice. The mice were given 0.5 or 2.0 KE ('klinische Einheit'; clinical unit) of OK-432 intraperitoneally every week from 21 weeks of age to the time of death. The control group received the same volume of saline (vehicle). OK-432 delayed the development of proteinuria and prolonged the survival of these mice dose dependently. At 49 weeks, 33.3% of control mice were alive, whereas 55.6% in the 0.5-KE- and 75% in the 2.0-KE-treated mice were alive. In the control group, the serum cholesterol level increased due to the development of glomerulonephritis. In contrast, mice treated with OK-432 had significantly lower levels of serum cholesterol. The serum levels of anti-DNA and anti-TNP antibodies were not affected by OK-432 administration. OK-432 induced the production of tumor necrosis factor (TNF)-alpha in the peritoneal fluid in the BWF1 mice. These results indicate that the effect of OK-432 in preventing the development of autoimmune disease in the mice may result from the stimulation of the endogenous TNF-alpha production.

Topics: Animals; Antibodies, Antinuclear; Autoantibodies; Autoimmune Diseases; Biological Products; Body Weight; Cholesterol; Crosses, Genetic; DNA; Female; Glomerulonephritis; Immunoglobulin G; Immunoglobulin M; Immunologic Factors; Immunosuppressive Agents; Mice; Mice, Inbred C3H; Mice, Inbred NZB; Picibanil; Proteinuria; Tumor Necrosis Factor-alpha

Cancer cells and macrophages produce large amounts of prostaglandin (PG) E2, which suppress cellular immune r action in tumor-bearing individuals. These findings raised a possibility that PG synthetase inhibitor can restore the immune reactivity against tumors. The anti-tumor activity of indomethacin, a potent PG synthetase inhibitor, by oral administration of 0.002% water solution as drinking water from the day 0 or 7 days after tumor transplantation was investigated in BALB/c or CDF1 (BALB/c X DBA/2) mice implanted subcutaneously with colon carcinoma 26 (10(6) cells) as a series of model studies for cancer treatment. The treatment with indomethacin substantially 1) inhibited the tumor growth, 2) prolonged the survival time, 3) caused a regression and disappearance of tumor with some cured mice and 4) reduced the levels of PGE2 and ornithine decarboxylase activity, a first rate limiting enzyme of polyamine synthesis in tumor tissue. Those anti-tumor activities were 5) reduced by a concomitant administration of PGE2 and 6) increased by a combined administration of an immunopotentiating agent, Picibanil (OK-432). The results indicate that indomethacin inhibited the synthesis of PGE2 in the tumor tissue, which suppress the non-specific cellular immune reaction against tumor cells, resulting in the regression and disappearance of tumor. PG synthetase inhibitor may be effective also against human cancer.

Topics: Administration, Oral; Animals; Body Weight; Colonic Neoplasms; Cyclooxygenase Inhibitors; Dinoprostone; Indomethacin; Male; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Picibanil; Prostaglandins E

Topics: Animals; Body Weight; Brain Neoplasms; Carboxymethylcellulose Sodium; Dose-Response Relationship, Drug; Interferons; Male; Methylcellulose; Neoplasm Transplantation; Nimustine; Nitrosourea Compounds; Peptides; Picibanil; Poly I-C; Polylysine; Rats