ABSTRACT
In this paper we have evaluated the ground-state properties (i.e., bulk modulus and cohesive energy) of rocksalt and zinc blende structured solids. We have presented two expressions relating the bulk modulus B (GPa) for the alkali halides, alkaline-earth chalcogenides, transition metal nitrides, rare-earth {divalent (R(2+)X) and trivalent (R(3+)X) } monochalcogenides, group IV, III-V and II-VI semiconductors and the cohesive energy E(coh) (kcal mol(-1)) for the alkali halides and alkaline-earth chalcogenides with the product of ionic charges (Z(1)Z(2)) and nearest-neighbour distance d (Å). The bulk moduli and cohesive energy of rocksalt and zinc blende type structure compounds exhibit a linear relationship when plotted on a log-log scale against the nearest-neighbour distance d (Å), but fall on different straight lines according to the ionic charge product of the compounds. We have applied the modified relation on rocksalt and zinc blende structured solids and found a better agreement with experimental data as compared to the values evaluated by earlier researchers. The results for bulk modulus differ from experimental values by the following amounts: BaO-0%, LiCl-0%, LaS-0%, SmSe-0%, ZnS-0%, CdS-0%, GaP-0%, InP-0%, MgO-0.61%, CaO-0.89%, SmS-1.7%, YbSe-1.6%, UP-1.9%, EuSe-1.9%; and the results for cohesive energy differ from experimental values by the following amounts: LiCl-0.49%, KF-0.51%, RbF-0.54%, SrO-1.2%, NaCl-1.6%, NaF-1.8%, MgSe-1.9%.
ABSTRACT
A series of title compounds has been synthesized and evaluated by the cytotoxicity assays conducted in vitro in seven human tumor cell lines, initially in MT-4 and H-9, followed by U-937, PM-1, MCF-7, Hep-3B, and K-562. These compounds were simultaneously compared with the existing clinical drug, busulfan and also with an experimental drug, hepsulfam. IC(50) values of these agents in T-cell lymphoma and leukemic cell lines indicate that two of these agents hexsulfamyl and octsulfamyl (compounds 3 and 4) were significantly more potent than busulfan and were comparable in antileukemic activity with hepsulfam. In order to determine the effect of these agents on normal proliferating cells, the toxicity of 3 and 4 was also determined in vitro against human peripheral blood mononuclear cells (PBMC) and against murine bone marrow progenitor cells. PBMC assay data indicate that these agents were generally less toxic than hepsulfam. The results of the colony forming unit-erythroid (CFU-E) and granulocyte-macrophage colony forming unit (CFU-GM) assays, however, indicate that these agents were more toxic than hepsulfam to erythroid progenitor cells than to granulocyte-macrophage progenitors. The toxicity of octsulfamyl was further assessed in vivo in normal Swiss mice by measuring drug-induced changes in hematological parameters, femoral bone marrow cellularity and splenic cellularity as well as hepatotoxicity and nephrotoxicity on day 7 and 14 following drug treatment at the dose of 1.0 mg/kg body weight from days 1 to 5. The results indicate that the compound did not adversely affect hematopoiesis. Marginal bone marrow suppression was observed on day 7, which gradually tends to reach normalcy on day 14. The other parameters were within normal limit.
Subject(s)
Alkanes/pharmacology , Antineoplastic Agents/pharmacology , Mesylates/pharmacology , Sulfones/pharmacology , Animals , Antineoplastic Agents, Alkylating/pharmacology , Bone Marrow/drug effects , Busulfan/pharmacology , Cell Survival/drug effects , Granulocytes/drug effects , Hematopoietic Stem Cells/drug effects , Humans , Inhibitory Concentration 50 , K562 Cells , Leukocytes, Mononuclear/drug effects , Macrophages/drug effects , Male , Mice , Tumor Cells, Cultured , Tumor Stem Cell AssayABSTRACT
Protein-A, 42KD cell wall glycoprotein of S. aureus Cowan I enhance mononuclear and polymorphonuclear cell counts in vivo and possesses antitoxic, antitumor, properties. In order to explain the mechanism of its function, the respiratory burst phenomenon in cell and cell free system was studied using lucigenin-dependent chemiluminescence technique. A dose dependent increase in protein A-mediated generation of superoxide radical was observed in resting and PMA stimulated neutrophils. Superoxide dismutase (SOD) was used to confirm the production of superoxide radicals (O2-). To understand the mechanism of protein-A induced O2- generation; NADPH oxidase activity was measured in cell free system using NADPH as a substrate. A significant increase in NADPH oxidase activity was observed in the membrane and post-nuclear supernatant fraction of activated human neutrophils. Cytosolic fraction showed slight enzyme activation. Protein A (SpA)-induced NADPH oxidase activation in the membrane fraction was observed even in the absence of the substrate NADPH. These data indicate that protein A attenuate the NADPH oxidase system to produce O2- radicals.
Subject(s)
NADPH Oxidases/metabolism , Neutrophils/drug effects , Neutrophils/enzymology , Staphylococcal Protein A/pharmacology , Acridines , Cell Membrane/enzymology , Cell Separation , Cell-Free System , Enzyme Activation/drug effects , Humans , Luminescent Measurements , Neutrophil Activation/drug effects , Neutrophils/metabolism , Respiratory Burst/drug effects , Superoxides/metabolismABSTRACT
It has been well documented in the literature that the removal of circulatory immune complexes (CICs) from the host circulation leads to the immunopotentiation as well as generation of antitumor responses in a variety of tumors in rats, cats, dogs and human patients. CICs are the major immunosuppressive factors in tumor bearing host. Protein A (PA) has been extensively used for the removal of these CICs from the sera/plasma of tumor bearers, because PA has the ability to bind with the Fc portion of mammalian immunoglobulins. Previously, we reported for the first time a potent antitumor response by the inoculation of cell free Ehrlich's ascites fluid adsorbed in vitro over PA containing Staphylococcus aureus Cowan I (SAC) in Ehrlich's ascites tumor model. However, there was toxicity associated with this form of therapy in terms of early death of treated animals and the depletion of hepatic glutathione pool as well as phase I biotransformation enzyme and increase in glutathione-S-transferase (GST) activities. In the present investigation, tumor bearing animals were treated intraperitoneally (i.p.) on alternate days for 15 days with adsorbed ascites fluid (ad-ASF) (0.1 ml) and glutathione (GSH) (250 mg/kg body weight) separately. We found that GSH supplementation increases mean survival time of GSH and ad-ASF treated mice up to 37.2 days in comparison with 19.9 days for only ad-ASF treated animals, while percent increase in body weight was found to be not affected by the GSH substitution, which remains significantly lower (P < 0.01) in comparison to the tumor control animals. GSH supplementation causes a significant decrease (P < 0.05) of glutathione-S-transferase and restoration of aniline hydroxylase activity (P < 0.05) and aminopyrine-N-demethylase activity. We have also observed that GSH supplementation does not alter the tumor cell viability and tumor cell counts in ad-ASF treated animals in comparison to only ad-ASF treated animals, which indicates that GSH supplementation does not alter the antitumor effect of the therapy. Treatment of Ehrlich's ascites tumor bearing mice with ad-ASF and glutathione increased their survival, but did not reduce the mortality of animals because of tumor.
Subject(s)
Carcinoma, Ehrlich Tumor/therapy , Glutathione/therapeutic use , Staphylococcal Protein A/toxicity , Adsorption , Aniline Hydroxylase/metabolism , Animals , Antigen-Antibody Complex , Carcinoma, Ehrlich Tumor/pathology , Glutathione/analysis , Male , Mice , Staphylococcal Protein A/therapeutic useABSTRACT
Our earlier studies have shown that removal of various blocking factors from the sera of tumor-bearing animals and humans by adsorption over heat-attenuated and formalin-fixed-Staphylococcus aureus Cowan I (SAC) containing Protein A (PA) causes antitumor immune response. It was also shown that this procedure caused regression of a wide variety of established animal and human tumors. In the present investigation, the therapeutic potential of inoculation of ascites fluid adsorbed in vitro over non-viable SAC containing PA has been demonstrated in Ehrlich' s ascites tumor (EAT) in mouse. The antitumor effect was evident by a significant decrease in body weight (p<0.001) as well as significant reduction in viability of ascites tumor cells (p<0.001) in peritoneal cavity. However, some of the responding animals died earlier than controls, this may be due to the toxicity associated with therapy. The toxic effects were evident in decreased contents of glutathione, and increased activity of glutathione-S-transferase, decreased activity of microsomal enzymes and also in an early death of some of tumor regressed animals. The probable causes of toxicity of the therapy and prospects of reversing these toxic effects are discussed.
Subject(s)
Carcinoma, Ehrlich Tumor/chemistry , Carcinoma, Ehrlich Tumor/metabolism , Staphylococcal Protein A/metabolism , Staphylococcus aureus/chemistry , Albinism , Animals , Carcinoma, Ehrlich Tumor/drug therapy , Carcinoma, Ehrlich Tumor/mortality , Cell Survival/drug effects , Glutathione/metabolism , Glutathione Transferase/metabolism , Liver/drug effects , Liver/enzymology , Male , Mice , Microsomes/drug effects , Microsomes/enzymology , Mixed Function Oxygenases/metabolism , Neoplasm Proteins/analysis , Neoplasm Proteins/therapeutic use , Neoplasm Proteins/toxicity , Staphylococcus aureus/growth & developmentABSTRACT
Protein A (PA) is an immunostimulating glycoprotein (mol. wt. 43,000 kDa) obtained from Staphylococcus aureus cowan I. The antitumour property of PA is well documented in the literature in various transplantable tumours of rats and mice. In the present set of investigations, the antitumour property of PA was tested in Swiss albino mice in a two-stage initiation-promotion mouse skin carcinogenesis model. The animals were initiated topically with a single subcarcinogenic dose (52 microgram) of 7,12-dimethylbenzanthracene (DMBA). PA was administered intraperitoneally (1 microgram/animal), twice weekly for 2 weeks. Promotion was performed by twice weekly applications of 12-O- tetradecanoyl phorbol-13-acetate (TPA) at a dose of 5 microgram/animal for 32 weeks. The result showed that the treatment schedule can effectively check the onset of tumorigenesis, the cumulative number of tumours and the average number of tumours per mouse. In the PA administered group, 30% of the animals remained tumour free until the termination of the experiments (i.e. 32 weeks of promotion). Thus the present study proves that protein A can effectively inhibit DMBA initiated and TPA promoted mouse skin carcinogenesis.
Subject(s)
Anticarcinogenic Agents/therapeutic use , Skin Neoplasms/prevention & control , Staphylococcal Protein A/therapeutic use , 9,10-Dimethyl-1,2-benzanthracene , Acetone , Animals , Carcinogens , Female , Mice , Skin Neoplasms/chemically induced , Skin Neoplasms/pathology , Staphylococcus aureus , Survival Analysis , Tetradecanoylphorbol Acetate , Time FactorsABSTRACT
Aflatoxins are suspected human carcinogens and are also known to possess diverse toxicological activities. In the present communication an attempt has been made to evaluate the effects of aflatoxin B1 (AFB1) on hepatic microsomal drug metabolizing enzymes in growing rats. The weanling rats were exposed to 60, 300 or 600 micrograms AFB1/kg body weight, per os, on alternate days for 4 weeks, in 0.2 ml corn oil. A significant depression in the activities of aryl hydrocarbon hydroxylase (AHH), aniline hydroxylase (AH) and aminopyrene-N-demethylase (AND) was observed at 300 micrograms and 600 micrograms doses of AFB1. However, no significant change was recorded in glutathione-S-transferase (GST) activity and total sulphydryl (SH) content upon AFB1 exposure in weanling rats. Thus, AFB1 appears to have more pronounced effect on the phase I, rather than phase II, biotransformation enzyme system in weanling rats. The depression of drug metabolizing enzymes together with suppression of immunity by AFB1, as reported earlier by us, may increase the susceptibility of the host to toxic chemicals, drugs and infectious agents, particularly during the post-natal period.
Subject(s)
Aflatoxin B1/pharmacology , Microsomes, Liver/enzymology , Aging/metabolism , Alanine Transaminase/blood , Animals , Aspartate Aminotransferases/blood , Biotransformation , Male , Microsomes, Liver/drug effects , Rats , Rats, WistarABSTRACT
Protein A of S. aureus Cowan I has been shown to stimulate macrophage mediated phagocytosis. The present study was undertaken to understand the mechanism involved in the enhancement of phagocytosis of peritoneal macrophages by protein A. The lucigenin and luminol-dependent chemiluminescence (CL) of rat peritoneal macrophages, after incubation with various concentrations of protein A, flow-cytometric studies using DCFH-DA as a fluorescent compound and phagocytosis of sheep red blood cells (SRBCs) by rat peritoneal macrophages were studied. A significant increase in lucigenin dependent CL due to formation of superoxide anions (O2-.) and in luminol dependent CL due to formation of hydrogen peroxide (H2O2) was observed in protein A treated macrophages. A significant increase in intracellular hydrogen peroxide (H2O2) was also observed along with an increase in phagocytosis of SRBCs by protein A treated macrophages. The present findings indicate that protein A helps to increase phagocytosis and triggers respiratory burst of macrophages. Thus, both increased phagocytic response and respiratory burst of macrophages in protein A treated animals may be contributing to the antitumor property of protein A reported earlier.
Subject(s)
Macrophages/immunology , Phagocytosis/immunology , Staphylococcal Protein A/immunology , Acridines/metabolism , Animals , Fluorescent Dyes , Hydrogen Peroxide/metabolism , Luminescent Measurements , Luminol/metabolism , Macrophage Activation/immunology , Peritoneal Cavity , Rats , Respiratory Burst/immunology , SheepABSTRACT
Protein A is an immunostimulating glycoprotein obtained from Staphylococcus aureus Cowan I. Its antitumour activity is proven in various tumour models. Its ability to provide protection against tumour initiation by the chemical carcinogen 7,12-dimethylbenzanthracene (DMBA) has been investigated in the present study using a mouse skin model of two-stage carcinogenesis. Protein A was administered intraperitoneally (1 microgram/animal 20 g body wt.) twice a week for 2 weeks, prior to initiation by DMBA. The promotion was performed by twice weekly applications of 12-O-tetradecanoyl phorbol-13-acetate (TPA) (3 or 5 micrograms/animal in 100 microliters acetone). Protein A provided significant protection to animals from DMBA-induced tumour initiation as was observed by the decrease in cumulative number of tumours, percent of animals developing tumours, number of tumours per animal and rate of tumour growth. Our data indicate that protein A has anticarcinogenic properties.
Subject(s)
Antineoplastic Agents , Skin Neoplasms/prevention & control , Staphylococcal Protein A/administration & dosage , 9,10-Dimethyl-1,2-benzanthracene , Animals , Female , Mice , Skin Neoplasms/chemically induced , Survival AnalysisABSTRACT
In a transplantable solid tissue Dalton's lymphoma tumor model in mice we have studied the mode of antitumor action of protein A, a well known biological response modifier. Protein A (15 ug) was administered intravenously in normal and solid tissue Dalton's lymphoma tumor bearing mice on day 3 and 7 after tumor inoculation. Incidence of mortality was more in untreated tumor bearing group than that in PA treated tumor bearers. There was a significant decrease (p less than 0.001) in tumor diameter in PA treated group compared to untreated group. Protein A treatment significantly enhanced the delayed type hypersensitivity (p less than 0.01), T-cell number in spleens (p less than 0.001) and lymph nodes (p less than 0.05) as well as phagocytosis (p less than 0.001) of opsonized SRBC by peritoneal macrophages of tumor bearing animals. Apart from the nonspecific immunopotentiation, Protein A also activates natural Killer (NK) cell activity and also splenic lymphocytes mediated killing of autologous tumor targets in a significant (p less than 0.001) manner. These results suggest that PA treatment activates cellular arc of the immune system in general, and macrophage, T cells and NK cells specifically. In the present communication, we have attempted to provide the information that these immune activations appear to be related to antitumor response induced by Protein A.
Subject(s)
Graft Rejection/drug effects , Lymphoma/immunology , Staphylococcal Protein A , Animals , Hypersensitivity, Delayed , Killer Cells, Natural/drug effects , Lymphoma/mortality , Macrophage Activation/drug effects , Male , Mice , Neoplasm Transplantation , Nitroblue Tetrazolium/metabolism , Phagocytosis/drug effects , T-Lymphocytes/drug effectsSubject(s)
Furaldehyde/toxicity , Lung/drug effects , Administration, Inhalation , Alkaline Phosphatase/drug effects , Alkaline Phosphatase/metabolism , Animals , Eye/drug effects , Furaldehyde/administration & dosage , Kinetics , Lung/enzymology , Lung/pathology , Male , Nasal Mucosa/drug effects , Rats , Respiration Disorders/chemically induced , Tears/drug effects , Tears/metabolismSubject(s)
Aminopyrine N-Demethylase/drug effects , Aniline Hydroxylase/drug effects , Cyanates/poisoning , Glutathione Transferase/drug effects , Inactivation, Metabolic/physiology , Isocyanates , Lung/enzymology , Microsomes/enzymology , Aminopyrine N-Demethylase/metabolism , Aniline Hydroxylase/metabolism , Animals , Glutathione Transferase/metabolism , Male , Membranes/enzymology , Microsomes/ultrastructure , Rats , Sulfhydryl Compounds/metabolismABSTRACT
Changes in hepatic microsomal mixed-function oxidase enzyme levels (aniline hydroxylase, aminopyrine demethylase, glutathione S-transferase), glutathione content, total sulphydryl content, and plasma enzyme levels of aspartate transaminase, alanine transaminase and alkaline phosphatase were studied in male Swiss albino mice exposed to Salmonella typhimurium endotoxin (50-150 micrograms per mouse, LC50 141.82 micrograms). Animals exposed to the same dose of endotoxin but pretreated with protein A of Staphylococcus aureus (5 micrograms/per mouse) protected the animals from both mortality and depletion of biotransformation enzymes.