TNFα promotes osteosarcoma progression by maintaining tumor cells in an undifferentiated state.

Chronic inflammation is frequently associated with tumorigenesis in elderly people. By contrast, young people without chronic inflammation often develop tumors considered independent of chronic inflammation but driven instead by mutations. Thus, whether inflammation has a significant role in tumor progression in tumors driven by mutations remains largely unknown. Here we show that TNFα is required for the tumorigenesis of osteosarcoma, the most common tumor in children and adolescents. We show that transplantation of AX osteosarcoma cells, which harbor mutations driving c-Myc overexpression and Ink4a-deficiency, in wild-type mice promotes lethal tumorigenesis accompanied by ectopic bone formation and multiple metastases, phenotypes seen in osteosarcoma patients. Such tumorigenesis was completely abrogated in TNFα-deficient mice. AX cells have the capacity to undergo osteoblastic differentiation; however, that activity was significantly inhibited by TNFα treatment, suggesting that TNFα maintains AX cells in an undifferentiated state. TNFα inhibition of AX cell osteoblastic differentiation occurred through ERK activation, and a pharmacological TNFα inhibitor effectively inhibited both AX cell tumorigenesis and increased osteoblastic gene expression and increased survival of tumor-bearing mice. Lethal tumorigenesis of AX cells was also abrogated in IL-1α/IL-1ß doubly deficient mice. We found that both TNFα and IL-1 maintained AX cells in an undifferentiated state via ERK activation. Thus, inflammatory cytokines are required to promote tumorigenesis even in mutation-induced tumors, and TNFα/IL-1 and ERK may represent therapeutic targets for osteosarcoma.

FR901469, a novel antifungal antibiotic from an unidentified fungus No. 11243. III. Structure determination.

A novel antifungal antibiotic, FR901469, was isolated from an unidentified fungus No. 11243. It is a water-soluble 40-membered macrocyclic lipopeptidolactone, consisting of D-Ala, L-Tyr, L-Val, trans-4OH-L-Pro, trans-3OH-L-Pro, threo-3OH-L-Gln, Gly, L-Orn, L-Thr, three residues of D-alloThr and a (3R)-hydroxypalmitic acid. Its structure, including absolute configurations, was unequivocally determined as 1 based on chemical and spectroscopic evidence.

FR131535, a novel water-soluble echinocandin-like lipopeptide: synthesis and biological properties.

The synthesis and biological properties of a novel water-soluble echinocandin-like lipopeptide, FR131535, are described. This compound displayed potent in vitro and in vivo antifungal activities. The hemolytic activity of FR901379 was reduced by replacing the acyl side chain. This compound showed good water-solubility, comparable to the natural product FR901379.

Chemical diversity in lipopeptide antifungal antibiotics.

In the course of screening for antifungal antibiotics, we have discovered a novel series of lipopeptide compounds structurally related to, but highly superior to, echinocandin B in terms of their water solubility due to the presence of a sulfate residue. These compounds, WF11899s, WF738s, WF14573s, WF16616 and WF22210, and their derivatives have diversity in their nuclear structures and acyl side chains. The producing strains were classified into two groups, the Coleomycetes group and the Hyphomycetes group. Compound FK463, a derivative of WF11899A, is currently in Phase 3 clinical development as a novel antifungal antibiotic.

FR901469, a novel antifungal antibiotic from an unidentified fungus No.11243. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological properties.

FR901469 is a novel antifungal antibiotic produced by an unidentified fungus No.11243. This compound was isolated from the culture broth by solvent extraction, HP-20 and YMC ODS gel column chromatography, and lyophilization. FR901469 is a white powder which melts at 182 approximately 187 degrees C and possesses the molecular formula C71H116N14O23. This compound has good water solubility. FR901469 inhibited the activity of 1,3-beta-glucan synthase from Candida albicans with an IC50 value of 0.05 microg/ml, and displayed greater inhibitory activity than other 1,3-beta-glucan synthase inhibitors such as, WF11899A, echinocandin B, aculeacin A, and papulacandin B.

FR901469, a novel antifungal antibiotic from an unidentified fungus No.11243. II. In vitro and in vivo activities.

FR901469 is a water-soluble macrocyclic lipopeptidolactone (C71H116N14O23) that has inhibitory activity against 1,3-beta-glucan synthase and exhibits in vitro and in vivo antifungal activity against both Candida albicans and Aspergillus fumigatus. The MICs of FR901469 against Candida albicans FP633 and Aspergillus fumigatus FP1305 in a micro-broth dilution test were 0.63 and 0.16 microg/ml, respectively. FR901469 showed excellent efficacy by subcutaneous injection against both Candida albicans and Aspergillus fumigatus in a murine systemic infection mode, with ED50s of 0.32 and 0.2 mg/kg, respectively. This compound also showed potent anti-Pneumocystis activity in the nude mice model with experimental Pneumocystis pneumonia. The hemolytic activity of FR901469 towards mouse red blood cells, is about 30-fold weaker than that of amphotericin B.

Defect in cell wall integrity of the yeast saccharomyces cerevisiae caused by a mutation of the GDP-mannose pyrophosphorylase gene VIG9.

The Saccharomyces cerevisiae VIG9 gene encodes GDP-mannose pyrophosphorylase, which synthesizes GDP-mannose from GTP and mannose-1-phosphate. Although the null mutant was lethal, the vig9 mutants so far obtained showed no growth defect but immature protein glycosylation and drug hypersensitivity. During our search for cell-wall mutants, we found a novel temperature-sensitive mutant, JS30, which required an osmotic stabilizer for viability. JS30 excreted cell surface proteins in the medium without any indication of cell lysis. Although conventional genetic analysis using mating was impossible, by detailed characterization of JS30 including an in vitro enzyme assay and nucleotide sequencing, we found the defect of JS30 was due to a mutation in the VIG9 gene. These results indicated a critical role of GDP-mannose in maintenance of cell-wall integrity.

Therapeutic effects of water-soluble echinocandin compounds on Pneumocystis pneumonia in mice.

The therapeutic effectiveness of water-soluble echinocandin compounds obtained from Coleophoma empetri F-11899, which has a strong inhibitory effect on the growth of fungi, was examined in nude mice with experimental Pneumocystis pneumonia. The studies demonstrated the potential usefulness of the compounds.

WF11899A, B and C, novel antifungal lipopeptides. I. Taxonomy, fermentation, isolation and physico-chemical properties.

WF11899A, B and C, novel antifungal lipopeptide antibiotics were isolated from the culture broth of Coleophoma empetri F-11899. These compounds belong to the echinocandin type of lipopeptides. Of these compounds, WF11899A showed good solubility in water. These three antibiotics possess potent in vitro antifungal activities against Candida spp.

WF11899A, B and C, novel antifungal lipopeptides. II. Biological properties.

WF11899A, B and C, novel water-soluble lipopeptides related to the echinocandins, possess potent anti-Candida activities. The IC50s of the compounds against four clinical isolates of Candida albicans ranged from 0.004 to 0.03 microgram/ml by microbroth dilution assay. These compounds mildly suppressed the growth of Aspergillus fumigatus and A. niger. WF11899A, B and C showed a potent in vivo anti-Candida activity. Particularly, WF11899A was superior to cilofungin, and equal to fluconazole. 1,3-beta-glucan synthase was inhibited by these compounds at the IC50s of 0.7, 0.7 and 1.8 micrograms/ml for WF11899A, B and C, respectively. However, they hemolysed mouse red blood cells in vitro at the concentration of 62 micrograms/ml.

Modulation of C2 and C3 gene expression of human peripheral blood monocytes by interleukin 1 beta, interferon gamma, tumor necrosis factor alpha and lipopolysaccharide.

The effect of interleukin 1 beta (IL-1 beta), interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF alpha) and lipopolysaccharide (LPS) on the expression of the C2 and C3 genes in human adherent monocytes was studied. Stimulation of monocytes with IFN-gamma increased both C2 and C3 mRNA. IL-1 beta also increased C2 mRNA level, whereas C3 gene expression was not enhanced. TNF alpha failed to increase either C2 or C3 mRNA. LPS increased C2 mRNA, but suppressed C3 gene expression. These results suggest that C2 and C3 production by monocytes is regulated by IL-1 beta and IFN-gamma in the local tissues.

FR112123, a new oligopeptide antibiotic from Streptomyces viridochromogenes. Taxonomy, fermentation, isolation, physico-chemical properties, structure and biological activity.

FR112123 is a new oligopeptide antibiotic produced by Streptomyces viridochromogenes No. 7587. The structure of FR112123 is elucidated as N-(N6-(N2-glycyl-L-glutaminyl)-D-lysyl)-D-alanine (1) by spectroscopic and chemical evidence. It resembles a partial structure of peptidoglycan in bacteria. The compound has a superior activity against an Escherichia coli mutant sensitive to inhibitors of cell wall synthesis, although it has a weak activity against the parent strain. These suggest that FR112123 might act on the biosynthesis of bacterial cell wall.

Studies on new dehydropeptidase inhibitors. III. Biological properties of WS1358A1.

WS1358A1, a novel inhibitor of renal dehydropeptidase (DHP), augmented the urinary recovery of a carbapenem antibiotic imipenem and improved its protective effect in experimental infections when simultaneously administered to mice with the antibiotic. WS1358A1 was a competitive DHP inhibitor with a Ki value of 1.6 x 10(-7) M.

FR109615, a new antifungal antibiotic from Streptomyces setonii. Taxonomy, fermentation, isolation, physico-chemical properties and biological activity.

FR109615, a new antibiotic active against Candida, was isolated from Streptomyces setonii No. 7562. Based on the spectroscopic data, the structure of FR109615 was elucidated as cis-2-aminocyclopentane-1-carboxylic acid (1). The compound showed the excellent in vivo efficacy in a generalized infection test of mice.

Transient partial growth hormone deficiency due to zinc deficiency.

We present here a 13-year-old boy with partial growth hormone deficiency due to chronic mild zinc deficiency. When zinc administration was started, his growth rate, growth hormone levels, and plasma zinc concentrations increased significantly. His poor dietary intake resulted in chronic mild zinc deficiency, which in turn could be the cause of a further loss of appetite and growth retardation. There was also a possibility of renal zinc wasting which may have contributed to zinc deficiency. Zinc deficiency should be carefully ruled out in patients with growth retardation.