ABSTRACT
A novel series of rapamycin derivatives with modifications in the C(22)-C(27) region has been prepared. These compounds are evaluated for their ability to prevent ring fragmentation while still retaining immunosuppressive capabilities.
Subject(s)
Sirolimus/analogs & derivatives , Sirolimus/chemistry , Chromatography, High Pressure Liquid , Humans , Immunosuppressive Agents/chemistry , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Survival , TemperatureABSTRACT
Aminophenyl mercuric acetate (APMA)-activated collagenase (C) (60 U/ml) obtained from in vitro cultures of human skin fibroblasts or recombinant interleukin-1 beta (IL-1 beta) (200 U/ml) was infused continuously for 7 days into the rabbit knee synovial space by means of an implanted Alzet osmotic pump. In stability studies in vitro, activated C or IL-1 incubated for 7 days at 37 degrees C, showed no significant loss of biological activity. Alterations in knee cartilage morphology and proteoglycan (PG) content were determined histologically, and the incidence of cartilage damage calculated. C or IL-1 vehicles infused for 7 days, caused no damage. Incidences of damage for C or IL-1 (n = 8-9), respectively, were as follows: loss PG: 88% and 100%; chondrocyte disorganization and loss, 50% and 78%, fissures and or fraying, 25% and 78%; and convergence of inflammatory cells, 25% and 66%. These results confirm the important role of C and IL-1 in cartilage damage.
Subject(s)
Interleukin-1 , Microbial Collagenase , Osteoarthritis/chemically induced , Animals , Cartilage, Articular/pathology , Disease Models, Animal , Hindlimb , Humans , Injections, Intra-Articular , Interleukin-1/administration & dosage , Microbial Collagenase/administration & dosage , Osteoarthritis/pathology , Rabbits , Recombinant ProteinsABSTRACT
Rapamycin exhibits activity against several ascites and solid transplantable tumors; it is slightly active to inactive against leukemias. On a weight basis, rapamycin was less active than 5-fluorouracil, cyclophosphamide and adriamycin, but rapamycin's maximal activity against Colon 38 tumor was similar to that of 5-fluorouracil and cyclophosphamide. Its activity was such that it significantly inhibited tumor growth at any stage of development. In the active dose range, rapamycin appeared less toxic than the other drugs. In the Colon 38 tumor model, rapamycin at a given dose exhibited the same activity when administered ip, iv, im and sc; upon oral administration, its activity was reduced but not abolished. Rapamycin was compatible with 5-fluorouracil and cyclophosphamide. The sequential treatment 5-fluorouracil-rapamycin-cyclophosphamide was superior to the sequence 5-fluorouracil-adriamycin-cyclophosphamide in protecting Colon 38 tumor-bearing mice. 29-Demethoxyrapamycin exerted only marginal activity against P388 lymphocytic leukemia; it was inactive against B16 melanocarcinoma and Colon 38 solid tumor.
Subject(s)
Antibiotics, Antineoplastic/therapeutic use , Neoplasms, Experimental/drug therapy , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colonic Neoplasms/drug therapy , Male , Mice , Mice, Inbred Strains , Polyenes/administration & dosage , Polyenes/therapeutic use , SirolimusABSTRACT
Demethoxyrapamycin is a new antifungal antibiotic which is co-produced with rapamycin by Streptomyces hygroscopicus. It was isolated as a minor component during recovery of rapamycin. Its antifungal and antitumor activity is compared with that of rapamycin.
Subject(s)
Antifungal Agents/isolation & purification , Animals , Antifungal Agents/pharmacology , Candida albicans/drug effects , Fermentation , Neoplasms, Experimental/drug therapy , Polyenes/isolation & purification , Polyenes/pharmacology , Sirolimus , Streptomyces/metabolismABSTRACT
The responses of lymphocytes to stimulation by three common plant mitogens (PHA, Con A, and PWM) have been studied prior to irradiation treatment in 65 patients with bronchogenic carcinoma. The lymphocyte mitogen stimulation (LMS) responses of these patients were determined to be normal or abnormal based on data obtained from similar studies in healthy volunteers. The data for the patients with lung cancer were analyzed for correlations between the lymphocyte responses and (1) the stage of disease, (2) prognostic significance, and (3) period of survival. Statistically significant correlations were observed between the responses of lymphocytes and the stage of disease and the period of survival. However, this study indicates that these correlated responses will be of limited prognostic clinical value for individual patients.
Subject(s)
Carcinoma, Bronchogenic/immunology , Lung Neoplasms/immunology , Lymphocyte Activation , Mitogens/pharmacology , Aged , Carcinoma, Bronchogenic/radiotherapy , Concanavalin A/pharmacology , Humans , Lectins/pharmacology , Lung Neoplasms/radiotherapy , PrognosisSubject(s)
Carcinoma, Bronchogenic/immunology , Immunity , Lung Neoplasms/immunology , Adult , Age Factors , Aged , Antigens, Bacterial , B-Lymphocytes/immunology , Carcinoma, Bronchogenic/pathology , Carcinoma, Bronchogenic/surgery , Female , Humans , Lung Neoplasms/pathology , Lung Neoplasms/surgery , Lymphocyte Activation , Male , Middle Aged , Skin Tests , T-Lymphocytes/immunologyABSTRACT
Proliferation was observed during in vitro cultivation of peritoneal exudate cells that had been educed from a C3H mouse with Freund's incomplete adjuvant. These cells were successfully subcultured by release with trypsin-EDTA solution and are now at passage 108 after 22 months in culture. Using this technique, 12 other rapidly growing peritoneal exudate cultures were obtained, whereas 10 cultures not educed with adjuvant did not proliferate. Characteristics of four adjuvant-induced cell lines established in culture include: rapid attachment to glass, doubling time in culture of 18 to 19 hr, phagocytosis of colloidal carbon, enhanced phagocytosis of specifically sensitized bacteria, epithelium-like morphology, and retention of C3H histocompatible specificities. These cell lines had widely varying chromosome distributions with modes from 37.3 +/- 2.4 to 82.6 +/- 2.30, but inoculation of 10(7) cultured cells into syngeneic animals did not produce tumors. Procedures described for the reproducible establishment of peritoneal exudate cell lines did not require use of conditioned media or exogenous viral infection.
Subject(s)
Ascitic Fluid/cytology , Cell Line , Cell Adhesion , Cell Division , Chromosomes/analysis , Culture Media , PhagocytosisSubject(s)
Antibodies, Neoplasm/analysis , Carcinoma, Ehrlich Tumor/immunology , Neoplasms, Experimental/immunology , Animals , Cell Line , Complement System Proteins , Cricetinae/immunology , Cross Reactions , Cytotoxicity Tests, Immunologic , Dogs/immunology , Erythrocytes/immunology , Guinea Pigs/immunology , Humans , Immune Sera , Lymphoma, Non-Hodgkin , Male , Mice , Mice, Inbred C3H , Mice, Inbred Strains/immunology , Rabbits/immunology , Rats/immunology , Sheep/immunology , Species SpecificitySubject(s)
Cell Line/immunology , Immunity , Neoplasms, Experimental/immunology , Animals , Ascites , Carcinoma, Ehrlich Tumor , Freeze Drying , Freezing , Immunization , Injections, Intramuscular , Injections, Intraperitoneal , Injections, Intravenous , Iodoacetates , Lymphoma, Non-Hodgkin , Male , Mammary Neoplasms, Experimental , Mice , Mice, Inbred Strains , Neoplasm Transplantation , Neoplasms, Experimental/prevention & control , Vibration , Virulence , Wilms TumorSubject(s)
Carbohydrates/therapeutic use , Carcinoma, Ehrlich Tumor/prevention & control , Immunization , Animals , Glucosamine/therapeutic use , Glyceraldehyde/therapeutic use , Glyceraldehyde/toxicity , Hexoses/therapeutic use , Histocytochemistry , Immunization Schedule , Immunization, Passive , Lethal Dose 50 , Male , Mannose/therapeutic use , Mice , Mice, Inbred Strains , Time FactorsSubject(s)
Carcinoma, Ehrlich Tumor/metabolism , Cryoprotective Agents/pharmacology , Nucleic Acids/metabolism , Spleen/drug effects , Animals , Centrifugation, Density Gradient , Chromatography , DNA/metabolism , Dimethyl Sulfoxide/pharmacology , Female , Hypoxanthines/metabolism , In Vitro Techniques , Inositol/pharmacology , Isotonic Solutions , Mice , Proteins/metabolism , RNA/metabolism , Sodium Chloride/pharmacology , Spectrophotometry , Xanthines/metabolismABSTRACT
Primary monolayer cultures were prepared from mouse ascites tumor cells of the Ehrlich-Lettré line and cultivated in chemically defined media containing various carbohydrates as the sole energy source. An absolute glucose requirement for culture survival was found, which could be satisfied by either the alpha or beta forms. The cultures died within 2-3 days when D-mannose, D-fructose, or D-galactose was substituted for D-glucose. Of over 50 other carbohydrates and related compounds tested, none could replace glucose. Cells of the Ehrlich and Ehrlich-Lettré lines suspended in balanced salt solutions containing various carbohydrates removed D-glucose, D-mannose, D-fructose, D-glucosamine, and 2-deoxy-D-glucose from the suspending fluid. In the presence of D-glucose, culture survival was inhibited by D-mannose, D-fructose, L-glucose, and D-galactose. D-Glucosamine and 2-deoxy-D-glucose strongly inhibited culture survival with the 50% inhibition points at 375 mg/liter and 62.5 mg/liter, respectively. The inhibition by D-glucosamine could be reversed by alpha- and beta-glucose, but not by D-mannose or D-fructose. The inhibition by 2-deoxy-D-glucose could be reversed completely by alpha- and beta-glucose, to a slight degree by D-mannose, and not at all by D-fructose.