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Biomedical subjects

G Medoff

Publications and source records attributed to G Medoff.

At least 73 records · Page 4Linked to original sources
PubMed1984

Potentiation by amphotericin B of the cytotoxicity of anticancer agents against MOPC-315 plasmacytoma and Lewis lung carcinoma.

The ability of amphotericin B (AmB) to potentiate the cytotoxicity of several different anticancer agents against two murine tumor models was examined. A spleen colony assay was used to quantitate the cytotoxicity of BCNU, CCNU, and L-PAM, either alone or in combination with AmB against the MOPC-315 plasmacytoma. A high level of potentiation of the effects of CCNU and L-PAM by AmB occurred, but AmB did not increase the cytotoxicity of BCNU. Tumor growth curves and calculation of cell survival demonstrated significant potentiation of the cytotoxicity of CCNU by AmB against SC Lewis lung carcinoma.

Amphotericin B↗
PubMed1984

Interaction of plasma proteins and lipoproteins with amphotericin B.

Amphotericin B (AmB) binds to the cholesterol in lipoproteins, as determined by comigration in density gradient ultracentrifugation and changes in the circular dichroic spectrum. The saturation curve and Scatchard plots obtained with circular dichroism suggest that four to 10 cholesterol molecules in low-density lipoproteins bind to one molecule of AmB. AmB interacts more rapidly with low- and very-low-density lipoproteins than with high-density lipoproteins, but the circular dichroic spectrum of the complexed species is the same in all three cases. AmB also binds to other proteins in blood, but much higher concentrations of these proteins than of lipoproteins are needed for comparable binding. Interaction with lipoproteins stabilizes the antifungal activity of AmB. Interaction with lipoproteins and with much higher concentrations of other proteins in blood can also inhibit the effects of AmB on red blood cells, which contain cholesterol in their plasma membranes, but not the effects on Candida albicans, whose membranes contain ergosterol. An appropriate inference is that, when used clinically, AmB circulates in blood bound to lipoproteins and other proteins. The toxic and therapeutic effects of AmB in clinical situations are thus contingent on competitive interactions between sterol-containing cellular membranes of the host and the parasite and components of blood, such as lipoproteins and proteins.

Amphotericin B↗
PubMed1984

Amphotericin B potentiation of the cytotoxicity of anticancer agents against both normal hematopoietic and leukemia cells in mice.

Dose-response curves in AKR or CD2F1 mice were obtained for AKR leukemia, L1210 leukemia, and hematopoietic stem cells following in vivo administration of one of the following anticancer agents alone or in combination with amphotericin B (AmB): doxorubicin, lomustine, or melphalan. AmB potentiated drug cytotoxicity of all agents against both leukemias. Potentiation of all three agents was greatest with the AKR leukemia demonstrating dose-modifying factor (DMF) values of 1.8, 3.0, and 2.7, respectively, for lomustine, melphalan, and doxorubicin. L1210 leukemia was somewhat less sensitive to drug potentiation by AmB with respective DMF values of 1.8, 1.8, and 1.3. AmB did not potentiate the action of any agent against hematopoietic stem cells. The increased life-span assays generally confirmed the clonogenic assays supporting the validity of the latter results. The specificity of AmB potentiation of anticancer agent cytotoxicity for tumor cells indicates that AmB may be a useful addition to antitumor drug combinations.

Amphotericin B↗
PubMed1984

Stimulatory, permeabilizing, and toxic effects of amphotericin B on L cells.

High concentrations of amphotericin B (AmB) killed mouse L cells, but low concentrations increased plating efficiency and stimulated the incorporation of labeled precursors into DNA and RNA. Thus, there were two disparate effects of AmB on L cells, stimulatory and toxic, and they occurred in distinct dose-related stages. AmB also affected the permeability of L cells. In dose-response studies, increases in cell membrane permeability, measured as the loss of K+ ions, occurred along with the stimulation of [3H]uridine incorporation into RNA. In contrast, stimulation of [3H]thymidine incorporation into DNA was only observed in cells recuperating from AmB-induced permeability changes. When the K+ concentration in the medium was lowered to 0.5 from 4.5 mM, or when 1 mM ouabain was added to the cultures, cell killing was potentiated, but the stimulatory and permeabilizing effects of subtoxic concentrations of AmB were unaffected. Furthermore, etruscomycin, a polyene antibiotic without any permeabilizing effects, nevertheless induced an enhancement of plating efficiency and of incorporation of [3H]uridine into RNA and [3H]thymidine into DNA. Our results suggest that the dose-related stimulatory, permeabilizing, and toxic effects of AmB most probably have distinct mechanisms of action and may be independent of one another.

Amphotericin B↗
PubMed1984

Potentiation of cytotoxicity of anticancer agents by several different polyene antibiotics.

The ability of several different polyenes to potentiate the cytotoxicity of carmustine, lomustine (LOM), and doxorubicin (DX) against AKR mouse leukemia was quantitated. All polyenes could potentiate the cytotoxicity of the anticancer agents; however, the methyl ester derivatives of the heptaenes amphotericin B and candicidin and the triene trienine were most effective with potentiations in the order of ten thousandfold for DX and LOM. A steep dose-response relationship for the polyenes was also noted. Neither the toxicity of the polyenes nor their level of potentiation could be correlated with structure or class.

Animals↗
PubMed1983

Sulfhydryl induced respiratory "shunt" pathways and their role in morphogenesis in the fungus, Histoplasma capsulatum.

When the mycelial to yeast transition of the dimorphic fungus Histoplasma capsulatum is induced by a temperature shift from 25 to 37 degrees C, the activities of the cytochrome system and the alternate oxidase decrease in parallel over the first 24 to 40 h (stage 1 of the transition). The decrease in activity of the cytochrome system is correlated with extensive decreases in the amounts of cytochromes b, c, and aa3, assayed spectrophotometrically. After 40 h, the cells enter a dormant phase (stage 2 of the transition) and cysteine or other sulfhydryl-containing compounds are required to reactivate mitochondrial respiration. This reactivation is due to the establishment of shunt pathways which bypass blocked segments of the electron transport system. The "shunt" pathways operate normally in mycelia grown at 25 degrees C, but are shut down during the transition, possibly because of depletion of intracellular cysteine. The longstanding observation that cysteine is required to progress beyond the initial stages of the morphological transition may be due, at least in part, to the reactivation of these "shunt" pathways.

Cytochromes↗
PubMed1983

Possible relationship of morphogenesis in pathogenic fungus, Histoplasma capsulatum, to heat shock response.

Histoplasma capsulatum, like many other fungal pathogens, is dimorphic: it exists as mycelia in the soil and yeast in animal hosts. Because only the yeast phase is parasitic, factors which affect morphogenesis have been of interest for understanding and controlling pathogenicity. In culture, the mycelial to yeast transition of H. capsulatum is induced by a temperature shift from 25 to 37 degrees C (ref. 1). The transition occurs over several days and is accompanied by marked changes in metabolic processes, including respiration and cysteine metabolism. Here, we show that the triggering event for these morphological and biochemical changes is a rapid decline in intracellular ATP levels that follows uncoupling of oxidative phosphorylation when mycelia are shifted from 25 to 37 degrees C. We also show that respiration in the yeast phase is coupled at 37 degrees C and thus that the morphological transition may be viewed as a heat shock followed by cellular adaptation to higher temperature.

Adaptation, Physiological↗
PubMed1983

Purification and characterization of a cysteine dioxygenase from the yeast phase of Histoplasma capsulatum.

A cysteine dioxygenase, cysteine oxidase (EC 1.13.11.20), has been purified from the cytosolic fraction of yeast phase cells of the dimorphic fungus Histoplasma capsulatum. The cysteine oxidase is an iron-containing dioxygenase with a molecular weight of 10500 (+/- 1500) and is present only in the yeast phase of the fungus. The enzyme is highly specific for L-cysteine, with a Km of 2 X 10(-5) M in vitro. The product of cysteine oxidation is cysteinesulfinic acid, as analyzed by thin-layer chromatography and mass spectroscopy. To our knowledge, this is the first cysteine oxidase isolated from a fungus, and it probably plays an important role in the mycelial to yeast phase transition of H. capsulatum during which redox potential and cysteine levels are crucial factors.

Cysteine Dioxygenase↗
PubMed1983

Antifungal chemotherapy.

When the decision to treat a fungal infection is made, there are several antifungal agents available for use. AmB remains the first-line drug in the treatment of most systemic fungal infections. Miconazole should be used to treat patients who cannot tolerate AmB or who are infected with AmB-resistant organisms. Ketoconazole has a distinct advantage in that it is a relatively nontoxic oral agent and may prove very effective in treating non-life-threatening chronic fungal infections. Clinical experience with miconazole and ketoconazole is too limited at present to recommend them as first-line therapeutic agents, except in a limited number of clinical situations. 5-FC should only be used in combination with AmB to treat yeast infections.

Amphotericin B↗
PubMed1983

Treatment of systemic mycoses with ketoconazole: emphasis on toxicity and clinical response in 52 patients. National Institute of Allergy and Infectious Diseases collaborative antifungal study.

The pharmacology, in vitro mycologic activity, toxicity, and efficacy of ketoconazole were studied in a Phase-II evaluation by the National Institutes of Health and National Institute of Allergy and Infectious Disease Mycoses Study Group. This report emphasizes the toxicity and clinical response data in 52 patients with the following systemic mycoses: blastomycosis in 16 patients; nonmeningeal coccidioidomycosis in 13; histoplasmosis in 8; nonmeningeal cryptococcosis in 7; sporotrichosis in 7; and both blastomycosis and nonmeningeal coccidioidomycosis in 1. Maximum daily doses of ketoconazole were 100 mg in 1 patient; 200 mg in 23; 400 mg in 12; and 600 mg in 16. In 52% of the patients, duration of therapy ranged from less than 1 to 6 months, whereas in 35%, duration ranged from 7 to 12 months, and in 13%, from 12 to 22 months. In 35 patients (67%), evidence of toxicity was not seen. Nausea, anorexia, or vomiting occurred in 21%. Cure or marked improvement was shown in 27 patients (52%), whereas failure of the primary course was seen in 14 (27%) and relapse after ketoconazole was discontinued in 11 (21%). Although this evaluation did not provide clear-cut clinical response data, our results indicate that ketoconazole, in the dosage regimens used, was more effective in patients with histoplasmosis and nonmeningeal cryptococcosis than in patients with blastomycosis and nonmeningeal coccidioidomycosis, and least effective in patients with sporotrichosis.

Adolescent↗
PubMed1982

Antifungal action of amphotericin B in combination with other polyene or imidazole antibiotics.

We compared the in vitro antifungal action of amphotericin B (AmB) used alone or in combination with a second polyene antibiotic or with miconazole or ketoconazole. When AmB was used in combination with either filipin or Etruscomycin (Farmitalia, Milan, Italy), antagonism or potentiation of the antifungal effect against Candida albicans resulted. Addition of AmB to Etruscomycin- or filipin-treated cultures resulted in antagonism. In contrast, potentiation occurred when Etruscomycin or filipin was added to cultures treated with AmB. The outcome of incubating C. albicans with combinations of AmB and either miconazole or ketoconazole depended on the duration of exposure of the cells to the drugs. Short-term incubations resulted in antagonism, whereas potentiation of antifungal effects occurred after prolonged exposure of cells to the antibiotics. In addition, supplementation of cultures with serum protein-potentiated AmB induced k+ leakage at low protein concentrations and inhibited K+ leakage at high protein concentrations.

Amphotericin B↗
PubMed1982

Relative avidity of etruscomycin to cholesterol and ergosterol.

Two methods, biological and spectroscopic, were used to determine the avidity of the polyene antibiotic Etruscomycin for cholesterol and ergosterol. The biological method consisted of measuring the inhibitory potency of both sterols on the Etruscomycin-induced damage to erythrocytes and fungi. The spectroscopic method consisted of recording of series of differential spectra in a number of solvents of different composition. The results obtained showed that cholesterol protected erythrocytes and candida albicans against the damaging action of Etruscomycin more efficiently than ergosterol did and that Etruscomycin-cholesterol complexes were more resistant to interruption by organic solvents than Etruscomycin-ergosterol complexes. These results and their comparison with the results obtained with other polyene antibiotics indicate that Etruscomycin resembles filipin in that it binds more avidly to cholesterol than to ergosterol. This implies that the length of the hydrophobic chain rather than the presence of the amino sugar determines sterol preference. The spectral method that we used can have general application for the quantitative measurement of complex formation between polyenes and sterols.

Anti-Bacterial Agents↗
PubMed1981

Role of cysteine in regulating morphogenesis and mitochondrial activity in the dimorphic fungus Histoplasma capsulatum.

Three stages can be distinguished in the temperature-induced mycelial-to-yeast phase transition of Histoplasma capsulatum. Stage one is characterized by a progressive decrease in the respiration rate and in the intracellular concentrations of cysteine and other amino acids. By stage two, respiration has ceased completely and free cysteine has fallen to low levels. Exogenous cysteine is required during the second stage for activation of mitochondrial respiration (stage three) and completion of the morphological transition. Mitochondria isolated from cells in the second stage show no respiration with NADH, succinate, or other substrates unless they are first incubated with cysteine. In addition, a novel, cytosolic cysteine oxidase appears during the latter part of the second stage. In stage three, the respiration rate rises, intracellular concentrations of free cysteine and other amino acids increase to levels characteristic of yeast, and the morphological transition is completed. The results support the idea that alterations in cysteine metabolism play a key role in this differentiation process.

Cell Differentiation↗
PubMed1981

Regulation of dimorphism in Histoplasma capsulatum by cyclic adenosine 3',5'-monophosphate.

During temperature-induced transition of the dimorphic pathogenic fungus Histoplasma capsulatum from the single yeast cell form to the multicellular mycelial form, there was an increase in intracellular cyclic adenosine 3',5'-monophosphate (cAMP) levels as well as a striking accumulation of cAMP in the medium. cAMP levels also changed during the reverse mycelium-to-yeast transition.

Cyclic AMP↗
PubMed1981

Temperature- and cyclic nucleotide-induced phase transitions of Histoplasma capsulatum.

The transition from yeast to mycelia of Histoplasma capsulatum could be accomplished by shifting the temperature of incubation from 37 to 25 degrees C. It was accompanied by many changes in cellular metabolism, including changes in respiration, intracellular cyclic adenosine 3',5'-monophosphate (cAMP) levels, and activities of two enzymes specific for the yeast phase, cystine reductase (EC 1.6.4.1) and cysteine oxidase (EC 1.13.11.20). Even at 37 degrees C, the yeast to mycelial transition could be induced by cAMP and agents which raise the intracellular levels of cAMP (theophylline, acetylsalicylic acid, prostaglandin E1, and nerve growth factor). During this morphogenesis the same pattern of changes occurred as in the temperature-induced transition. Therefore, these changes were not simply dependent on a shift in temperature, but rather were part of the process of the phase transition.

Aspirin↗
PubMed1981

Cutaneous mycobacteriosis: analysis of 34 cases with a new classification of the disease.

Several points can be made from analysis of the published cases of cutaneous mycobacteriosis and those in our series: 1) mycobacterial cutaneous infections are probably more common than is reported-we collected 34 cases over a 10-year period; 2) most patients with cutaneous infections caused by nontuberculous mycobacteria have significant underlying disease; 3) there is a relative lack of classic histologic features in patients with cutaneous mycobacteriosis, and there appear to be diverse forms of clinical presentation; 4) a high index of suspicion is needed in evaluating patients with possible cutaneous mycobacteriosis, and appropriate cultures must be done to establish the diagnosis. In attempting to provide a practical classification of cutaneous mycobacteriosis which includes infection by nontuberculous mycobacteria, we propose the following grouping, which uses simple terms, avoids confusing nomenclature, and incorporates pathophysiologic descriptions and prognostic information: 1) Mycobacteriosis caused by inoculation from an exogenous source. 2) Cutaneous mycobacteriosis caused by spread from an endogenous source. Contiguous spread originates most often with osteomyelitis, but also occurs through autoinoculation of the perirectal, oral, or vaginal skin as organisms are passed or expectorated from pulmonary or genitourinary tuberculosis. 3) Cutaneous mycobacteriosis caused by hematogenous spread. This group includes lupus vulgaris, nodules and abscesses, and acute disease with hemorrhagic pustules. Some mycobacterioses will be difficult to classify when inoculation or hematogenous spread cannot be ruled out. However, the system of classification we have proposed should help clinicians understand and diagnose the diverse forms of cutaneous mycobacterial infections.

Adult↗