Phase III trial of nonpegylated liposomal doxorubicin in combination with trastuzumab and paclitaxel in HER2-positive metastatic breast cancer.

Background: Nonpegylated liposomal doxorubicin liposomal doxorubicin, (Myocet™; Sopherion Therapeutics, Inc Canada, and Cephalon, Europe) (NPLD; Myocet(®)) in combination with trastuzumabHerceptin(®) (Hoffmann-La Roche) has shown promising activity and cardiac safety. We conducted a randomized phase III trial of first-line NPLD plus trastuzumab and paclitaxel (Pharmachemie B.V.

A KDR-binding peptide (ST100,059) can block angiogenesis, melanoma tumor growth and metastasis in vitro and in vivo.

A major goal of treatment strategies for cancer is the development of agents which can block primary tumor growth and development as well as the progression of tumor metastasis without any treatment associated side effects. Using mini peptide display (MPD) technology, we generated peptides that can bind to the human vascular endothelial growth factor (VEGF) receptor KDR. These peptides were evaluated for their ability to block angiogenesis, tumor growth and metastasis in vitro and in vivo.

Discovery of antitumor indolocarbazoles: rebeccamycin, NSC 655649, and fluoroindolocarbazoles.

A fermentation directed product search for potential anticancer drugs conducted by Bristol-Myers in the 1970s and early 1980s resulted in the identification of a novel indolocarbazole (IC) rebeccamycin (RBM) as a potential drug development candidate. Subsequently, an analog program designed to impart distal site in vivo antitumor activity resulted in the discovery of diethylaminoethyl analog of RBM (DEAE-RBM), which is presently undergoing clinical evaluation as NSC 655649 and BMY-27557. Strong DNA intercalation is the primary mechanism of action of DEAE-RBM resulting in the potent catalytic inhibition of both topoisomerases I and II.

The effect of space flight on the production of actinomycin D by Streptomyces plicatus.

The effect of space flight on production of the antibiotic actinomycin D by Streptomyces plicatus WC56452 was examined onboard the US Space Shuttle mission STS-80. Paired space flight and ground control samples were similarly prepared using identical hardware, media, and inoculum. The cultures were grown in defined and complex media under dark, anaerobic, thermally controlled (20 degrees C) conditions with samples fixed after 7 and 12 days in orbit, and viable residuals maintained through landing at 17 days, 15 h.

Production, isolation and structure determination of novel fluoroindolocarbazoles from Saccharothrix aerocolonigenes ATCC 39243.

Saccharothrix aerocolonigenes ATCC 39243 produces an indolocarbazole antitumor agent rebeccamycin under submerged fermentation conditions. Adding DL-6-fluorotryptophan to culture of S. aerocolonigenes ATCC 39243 induces the formation of two novel indolocarbazoles, fluoroindolocarbazoles A and B.

The effects of space flight on the production of monorden by Humicola fuscoatra WC5157 in solid-state fermentation.

The effect of space flight on the production of the antibiotic monorden on two types of agar media, T8 and PG, by Humicola fuscoatra WC5157 was examined on board the US Space Shuttle mission STS-77 in May 1996. Paired space-flight and ground control samples were prepared using identical hardware, protocol, media, and inoculum. Inoculation occurred simultaneously for both groups 2.

The effect of carbon source, temperature and aeration on the production of ascosteroside, a novel antifungal agent, by Ascotricha amphitricha.

This paper describes the optimization of production of ascosteroside, a novel antifungal agent with an alpha-linked glycoside of a lanosterone-type triterpenoid structure. Glucose, sorbose and inositol were determined to be the best carbon sources for the production of ascosteroside. Temperature affected levels of ascosteroside, with production being highest at 16 degrees C with 1% glucose, and lowest at 32 degrees C.

Pyrrolosporin A, a new antitumor antibiotic from Micromonospora sp. C39217-R109-7. I. Taxonomy of producing organism, fermentation and biological activity.

Strain C39217-R109-7 (ATCC 53791) is an actinomycete strain isolated from a soil sample collected at Puerto Viejo, Peru. It produces a new antitumor antibiotic, designated pyrrolosporin A. Taxonomic studies on its morphological, cultural and physiological characteristics identified this producing strain as Micromonospora sp.

BMS-182123, a fungal metabolite that inhibits the production of TNF-alpha by macrophages and monocytes.

A fungal metabolite, BMS-182123, which inhibited bacterial endotoxin-induced production of tumor necrosis factor (TNF-alpha) in murine macrophages and human peripheral blood monocytes (in vitro), was isolated from the culture broth of Penicillium chrysogenum strain V39673. The effective BMS-182123 concentration (IC50) resulting in 50% inhibition of lipopolysaccharide-induced TNF-alpha production in murine macrophages and human monocytes was 600 ng/ml and 4.0 microgram/ml, respectively.

Tubulin polymerization by paclitaxel (taxol) phosphate prodrugs after metabolic activation with alkaline phosphatase.

Paclitaxel (taxol) phosphate derivatives BMY46366, BMY-46489, BMS180661 and BMS180820 were used to determine the ability of alkaline phosphatase to convert these water-soluble potential prodrugs to tubulin-polymerizing metabolites (i.e., paclitaxel).

Korkormicins, novel depsipeptide antitumor antibiotics from Micromonospora sp C39500: fermentation, precursor directed biosynthesis and biological activities.

Micromonospora sp C39500, isolated in our laboratory from a soil sample, produced a complex of seven novel depsipeptide antitumor antibiotics, designated korkormicins. The major component of the complex, korkormicin A, has a MW of 1452 and a molecular formula of C66H84N16O22. Korkormicin A exhibits potent in vivo antitumor activity against P388 leukemia and M109 lung carcinoma implanted intraperitoneally (ip) in mice, with effective doses of 0.

Inhibition of antibacterial activity of himastatin, a new antitumor antibiotic from Streptomyces hygroscopicus, by fatty acid sodium salts.

Himastatin, a cyclohexadepsipeptide antibiotic, had in vivo antitumor activity against localized P388 leukemia and B16 melanoma but had no distal site antitumor activity. An in vitro Bacillus subtilis well-agar diffusion assay was employed to test the hypothesis that himastatin was enzymatically inactivated. The activity of himastatin against B.

Large scale production and semi-purification of kedarcidin in a 1000-L fermentor.

Actinomycete strain ATCC 53650 was grown in a 1000-L fermentor containing 680 L of medium and the production of kedarcidin was monitored by HPLC. The titers of kedarcidin in the fermentor cultures were 0.49-0.

The effect of cerulenin on the production of esperamicin A1 by Actinomadura verrucosospora.

Addition of cerulenin (0.25-1.0 mM) to cultures of Acinomadura verrucosospora before the onset of esperamicin synthesis inhibited the production of esperamicin A1 by the microorganism.

Improved processes for the production and isolation of dynemicin A and large-scale fermentation in a 10,000-liter fermentor.

Supplementing the culture of Micromonospora chersina sp. nov. No.

Isolation of a bromo analog of rebeccamycin from Saccharothrix aerocolonigenes.

When grown in a defined medium containing 0.05% KBr, Saccharothrix aerocolonigenes ATCC 39243 produces a novel bromo analog of rebeccamycin. This new analog, designated bromorebeccamycin, has been isolated from the culture broth and purified by vacuum liquid chromatography and column chromatography.

Kedarcidin, a new chromoprotein antitumor antibiotic. I. Taxonomy of producing organism, fermentation and biological activity.

Strain L585-6 (ATCC 53650) is an actinomycete isolated from a soil sample collected in Maharastra State, India. It produces a new chromoprotein antitumor antibiotic, designated kedarcidin. Taxonomic studies demonstrated that strain L585-6 is an unidentified and unknown actinomycete.

Maduropeptin, a complex of new macromolecular antitumor antibiotics.

Maduropeptin, a complex of new macromolecular antitumor antibiotics, is a metabolite of Actinomadura madurae H710-49. The active components maduropeptins A1, A2 and B are acidic chromopeptides with MW of around 22,500 and composed of 14 types of amino acids and an unstable chromophore. The antibiotics are active in vitro against Gram-positive bacteria and highly cytotoxic to tumor cells.

Identification of indolepyruvic acid as an intermediate of rebeccamycin biosynthesis.

Experimental evidence is presented to demonstrate that indolepyruvic acid is an intermediate in the rebeccamycin biosynthetic pathway. [3-14C]Indolepyruvic acid was prepared and efficiently incorporated (8%) into rebeccamycin by Saccharothrix aerocolonigenes.

Himastatin, a new antitumor antibiotic from Streptomyces hygroscopicus. I. Taxonomy of producing organism, fermentation and biological activity.

Strain C39108-P210-51 (ATCC 53653), an actinomycete isolated from a soil sample collected in India, was found to produce a new antitumor antibiotic, designated himastatin. Taxonomic studies on its morphological, cultural and physiological characteristics identified this producing strain as Streptomyces hygroscopicus C39108-P210-51. Himastatin shows antimicrobial activity against Gram-positive bacteria but it is inactive against Gram-negative bacteria.

Induction of the SOS response in Escherichia coli by azidothymidine and dideoxynucleosides.

A number of nucleosides with anti-human immunodeficiency virus (HIV) activity were evaluated in two colorimetric (beta-galactosidase) assays for induction of the SOS response in Escherichia coli. 3'-Azido-3'-deoxythymidine (azidothymidine; AZT), 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxyguanosine (ddG), and 2',3'-dideoxyinosine (ddI) induced cell filamentation (sulA) and prophage lambda in well-agar diffusion and liquid microsuspension assays. AZT was approximately 100 times more potent than the dideoxypurine nucleosides, inducing sulA at less than 100 ng/ml.

Biosynthesis of elsamicin A, a novel antitumor antibiotic.

The 1H noise-decoupled 13C-nmr spectrum of elsamicin A [1] prepared from the cultures of an unknown actinomycete species (ATCC 39417) supplemented with [1-13C]acetate and [2-13C]acetate showed enrichment of all 19-carbons in the aglycone. In addition, L-[methyl-13C]methionine- and D-[1-13C]glucose-supplemented cultures enriched the carbons of the two methyl groups on the disaccharide moiety and the C-1 carbons of the disaccharide, respectively. The results demonstrated that the aglycone of elsamicin A is derived entirely from acetate and the disaccharide portion is biosynthesized from two units of glucose and methionine.