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Biomedical subjects

J L Phillips

Publications and source records attributed to J L Phillips.

At least 73 records · Page 4Linked to original sources
PubMed1987

Iron-transferrin-induced increase in protein kinase C activity in CCRF-CEM cells.

Iron transferrin has been found to induce a mean 10-fold increase in the activity of protein kinase C in CCRF-CEM cells. This increase was not detectable up to 45 min after treatment of cells with iron transferrin, although after 60 min, a maximal increase in enzyme activity was observed. Similarly, iron transferrin at concentrations of 0.1-0.5 microgram/ml did not alter protein kinase C activity, while concentrations of iron transferrin of 1-100 micrograms/ml induced a maximal increase in enzyme activity. Apotransferrin and iron in the form of ferric citrate, as well as complexes of transferrin with copper, nickel, zinc, manganese, and cobalt did not increase protein kinase C activity. Additionally, CCRF-CEM cells pretreated with either actinomycin D or cycloheximide and then incubated with iron transferrin did not exhibit increased enzyme activity. Treatment with iron transferrin was found to have no effect on protein kinase C activity in normal human peripheral blood lymphocytes and in HL60, Daudi, and U937 cells. However, normal lymphocytes stimulated with phytohemagglutinin for 48 hr exhibited a 2-fold increase in protein kinase C activity following treatment with iron transferrin. These results indicate a specific effect of iron transferrin on protein kinase C activity in CCRF-CEM cells and in mitogen-stimulated human lymphocytes that may occur through increased synthesis of the enzyme.

Cell Line↗
PubMed1987

Metastasis from squamous cell carcinomas of SENCAR mouse skin produced by complete carcinogenesis.

The incidence of metastasis was evaluated in female SENCAR mice after induction of squamous cell carcinomas by repetitive applications of either benzo [a] pyrene (B [a] P) or N-methyl-N'-nitro-N-nitrosogaunidine (MNNG). Between 41 and 50 weeks 50% of the animals with carcinomas in the B [a] P group had metastases, whereas 20% had metastases in the MNNG group. Very few metastases were observed before 40 weeks of treatment. The major site of metastasis was the lungs; however, metastatic tumors were also found in lymph nodes, adrenal glands and kidneys.

Animals↗
PubMed1986

Transferrin receptors and natural killer cell lysis. A study using Colo 205 cells exposed to 60 Hz electromagnetic fields.

The role of target cell transferrin receptors (TfR) in natural killer (NK) cell-induced cytolysis has been studied using Colo 205 cells in which prior exposure to 60 Hz electromagnetic fields produced constitutive expression of maximum numbers of TfR. It was found that NK cell cytolysis was decreased in those cells expressing the highest levels of TfR, while cells expressing the lowest level of TfR were lysed to the greatest extent. Furthermore, pretreatment of target cells with, and the continued presence in the assay medium of, iron transferrin produced, in general, only a slight decrease in cytolysis. Incubation of cells with apotransferrin also produced only a slight decrease in cytolysis, while incubation with zinc transferrin produced a greater decrease in cytolysis. This latter effect was particularly dramatic for cells that had been exposed previously to either a 60 Hz magnetic field alone (1.0 gauss) or to a combined electric + magnetic field (current density 300 mA/m2, 1.0 gauss). In addition to indicating a discordance between TfR expression on target cells and their sensitivity to NK cell cytolysis, the data presented provide a further indication of cellular membrane changes produced by exposure to 60 Hz electromagnetic fields.

Adenocarcinoma↗
PubMed1986

Phorbol diesters and transferrin modulate lymphoblastoid cell transferrin receptor expression by two different mechanisms.

Expression of transferrin receptors (TfR) by activated lymphocytes is necessary for lymphocyte DNA synthesis and proliferation. Regulation of TfR expression, therefore, is a mechanism by which the lymphocyte's proliferative potential may be directed and controlled. We studied mechanisms by which lymphoblastoid cells modulate TfR expression during treatment with phorbol diesters or iron transferrin (FeTf), agents which cause downregulation of cell surface TfR. Phorbol diester-induced TfR downregulation occurred rapidly, being detectable at 2 min and reaching maximal decreases of 50% by 15 min. It was inhibited by cold but not by agents that destabilize cytoskeletal elements. Furthermore, this downregulation was reversed rapidly by washing or by treatment with the membrane interactive agent, chlorpromazine. In contrast, FeTf-induced TfR downregulation occurred slowly. Decreased expression of TfR was detectable only after 15 min and maximal downregulation was achieved after 60 min. Although FeTf-induced downregulation also was inhibited by cold, it was inhibited in addition by a group of microtubule destabilizing agents (colchicine, vinblastine, podophyllotoxin) or cytochalasin B, a microfilament inhibitor. Furthermore, FeTf-induced downregulation was not reversed readily by washing or by treatment with chlorpromazine. The inactive colchicine analogues, beta- and gamma-lumicolchicine, did not inhibit FeTf-induced TfR downregulation. Similarly, when cells were pretreated with taxol to stabilize microtubules, colchicine no longer inhibited FeTf-induced downregulation. Therefore, FeTf causes TfR downregulation in lymphoblastoid cells by a cytoskeleton-dependent mechanism. Phorbol diesters cause TfR downregulation by a cytoskeleton-independent mechanism. In other experiments, treatment of cells with both a phorbol diester and FeTf, either simultaneously or sequentially, produced additive effects on TfR expression. These data indicate that TfR expression is regulated by two independent mechanisms in lymphoblastoid cells, and they provide the possibility that downregulation of TfR by different mechanisms may result in different effects in these cells.

Cell Line↗
PubMed1986

Pharmacokinetic study of fludarabine phosphate (NSC 312887).

Characterization of the pharmacokinetics of 2-FLAA has been completed in seven patients receiving 18 or 25 mg/m2 daily X 5 of 2-FLAMP over 30 min. Assuming 2-FLAMP was instantaneously converted to 2-FLAA, the plasma levels of 2-FLAA declined in a biexponential fashion. Computer fitting of the plasma concentration-time curves yielded an average distribution half-life (t1/2 alpha) of 0.60 h and a terminal half-life (t1/2 beta) of 9.3 h. The estimated plasma clearance was 9.07 +/- 3.77 l/h per m2 and the steady state volume of distribution, 96.2 +/- 26.0 l/m2. There was a significant inverse correlation between the area under the curve (AUC) and absolute granulocyte count (r = -0.94, P less than 0.02). A relationship between creatinine clearance and total body clearance was noted, but was not statistically significant (r = 0.828; P less than 0.1). Approximately 24% +/- 3% of 2-FLAA was excreted renally over the 5-day course of drug administration.

Agranulocytosis↗
PubMed1986

In vitro exposure to electromagnetic fields: changes in tumour cell properties.

Two human colon cancer cell lines, Colo 205 and Colo 320 DM, have been studied for their responses to 60 Hz-generated electromagnetic fields (EMF) using soft agar cloning and monoclonal antibody binding assays to assess exposure-induced changes. Cellular responses have been studied after 24 h continuous exposure of cells concurrently to four experimental conditions; i.e. no EMF (E-M-), magnetic field only (M+, 1.0 G rms), electric field only (E+, 300 mA/m2 rms), and combined electric plus magnetic fields at these intensities (E+M+). Under these conditions, both cell lines demonstrated significantly increased colony formation in soft agar and increased expression of tumor associated antigens after exposure to E+M+ and to M+ as compared to unexposed controls.

Animals↗
PubMed1986

Pharmacologic analysis of the ip administration of fludarabine phosphate in the swine.

Fludarabine phosphate, an investigational water-soluble adenosine analog, was administered ip to five miniature swine at doses of 10, 16, and 25 mg/m2. Blood and peritoneal fluid samples were collected for 4 hours following drug administration and were submitted to high-performance liquid chromatographic analysis for the concentrations of the dephosphorylated derivative, 2-fluoro-ara-A. Peak peritoneal fluid concentrations of 2-fluoro-ara-A ranged from 7.72 to 18.01 micrograms/ml at the doses tested; peritoneal fluid areas-under-the-curve (AUCs) ranged from 19.23 to 47.33 micrograms X hour/ml. The peak serum concentrations of 2-fluoro-ara-A ranged from 0.15 to 0.46 micrograms/ml; serum AUCs ranged from 0.51 to 1.2 micrograms X hour/ml. The ip administration of fludarabine phosphate results in a 28-62-fold peak peritoneal concentration advantage over peak serum concentrations and a 20-53-fold advantage for peritoneal over serum AUCs. Comparison of data generated in this swine study to data from pilot studies of the ip administration of fludarabine phosphate in humans will be of interest.

Animals↗
PubMed1986

Transferrin binding to two human colon carcinoma cell lines: characterization and effect of 60-Hz electromagnetic fields.

125I-Labeled human transferrin was used to study the binding of transferrin to Colo 320 DM and Colo 205 human cell lines derived from adenocarcinomas of the colon. Although transferrin uptake was greater in both cases at 37 degrees than at 4 degrees it was found that slightly greater than two-thirds of the transferrin associated with the cells at 37 degrees was not bound to surface receptors but rather had been internalized by the cells. Subsequent analysis of true surface binding at 4 degrees by Scatchard analysis allowed determination of the number of transferrin receptors as well as association constants for the interaction. The number of transferrin receptors per cell was found to be inversely related to the cell density of the cultures from which cells were removed for study. Association constants were unaffected by cell density, with average values of 1.2 and 5.4 X 10(8) M-1 obtained for Colo 320 DM and Colo 205, respectively. Additionally, maximum theoretical numbers of receptors of 1.05 X 10(5)/cell for Colo 320 DM and 1.39 X 10(5)/cell for Colo 205 were determined. Furthermore, exposure of Colo 205 cells to three different experimental situations, i.e., 60 Hz-generated electric field only (E+, 300 mA/m2rms), magnetic field only (M+, 1.0 gauss rms), and combined electric + magnetic fields at these intensities (E+M+), altered the expression of transferrin receptors as compared to a concurrently run unexposed control population of cells (E-M-). In three separate experiments the number of transferrin receptors quantitated on both M+ and E+M+ cells was independent of cell culture density and was close to or exceeded the maximum theoretical number of receptors determined for this cell line. In contrast, E+ cells expressed fewer transferrin receptors than was predicted on the basis of cell culture density.

Adenocarcinoma↗
PubMed1985

Stimulation of spermatogenesis by gonadotropins in men with hypogonadotropic hypogonadism.

We evaluated the efficacy of gonadotropin treatment in stimulating spermatogenesis in men with hypogonadotropic hypogonadism. When 21 men with hypogonadotropic hypogonadism were treated with human chorionic gonadotropin, the sperm count increased to within the normal range in the 6 in whom hypogonadism had begun after puberty, but in only 1 of the 15 in whom it had begun before puberty (P less than 0.002). When the remaining 14 men with prepubertal hypogonadism were treated with human menopausal gonadotropin in addition to human chorionic gonadotropin, the sperm count increased to normal in 5 of the 7 who had not had cryptorchidism, but in only 1 of the 7 who had (P less than 0.05). The need for human menopausal gonadotropin as a replacement for follicle-stimulating hormone could not be predicted by pretreatment serum and urinary levels of follicle-stimulating hormone. We conclude that gonadotropin treatment will usually increase the sperm count to normal in men with hypogonadotropic hypogonadism, unless cryptorchidism has occurred. The need for human menopausal gonadotropin treatment appears to depend on the time of onset of hypogonadism.

Adult↗
PubMed1985

Comparison of hormonal secretory behavior of gonadotroph cell adenomas in vivo and in culture.

To determine whether pituitary macroadenomas associated with supranormal serum FSH concentrations represent gonadotroph cell adenomas or nonsecreting adenomas that selectively impair LH secretion by normal gonadotroph cells, we studied the secretory behavior in dispersed cell culture of three pituitary adenomas from patients who had supranormal serum FSH concentrations. Similar comparisons were made for 11 other adenomas, which were associated with the in vivo hypersecretion of alpha-subunit (n = 4) or PRL/GH (n = 4) or with no obvious hypersecretion (n = 3). Adenomas associated with supranormal serum FSH in vivo released more FSH in culture (5.1-27.0 ng/well . 24 h) than they did other hormones (TSH, less than 0.33; GH, less than 0.10; PRL, less than 0.14 ng/well . 24 h) and more FSH than did PRL/GH-secreting (less than 0.1-0.9 ng/well . 24 h) and nonsecreting (less than or equal to 0.5 ng/well . 24 h) adenomas. Adenomas associated with supranormal serum alpha-subunit in vivo released not only more alpha-subunit in culture (7.2-22.0 ng/well . 24 h) than did other adenomas (0.1-2.4 ng/well . 24 h), but two of them also released as much FSH (12.7 and 17.0 ng/well . 24 h) as did adenomas associated with supranormal serum FSH. The close correlation between the hormonal secretory behavior in vivo and that in culture of the three pituitary macroadenomas associated with supranormal serum FSH concentrations suggests that these are indeed adenomas of gonadotroph cells that are hypersecreting FSH. The release of relatively large amounts of FSH by cultured cells of adenomas that appeared to be hypersecreting only alpha-subunit in vivo suggests that at least some alpha-subunit-secreting adenomas are also gonadotroph cell adenomas.

Adenoma↗
PubMed1983

Effect of zinc on the Stokes' radius of metallothionein.

Apothionein was prepared from rat liver metallothionein-II. To this, zinc, as zinc acetate, was re-added in a stepwise fashion to yield a series of complexes with ratios of metal to protein varying from 1:1 to 7:1. The Stokes' radius of the apoprotein and each zinc-metallothionein complex was then determined by gel filtration. A plot of atoms Zn/mol metallothionein versus Stokes' radius yielded a sigmoid curve, with values for Stokes' radius ranging from 20.8 A for the apoprotein 15.4 A for the fully saturated zinc complex.

Animals↗
PubMed1982

Structure and function of ovotransferrin. I. Production of iron-binding fragments from iron-ovotransferrin by the action of immobilized subtilisin. Purification and characterization of the fragments.

Immobilized subtilisin Novo was used for the cleavage of iron-saturated ovotransferrin (Fe2OT) into separate NH2- and CO2H-terminal iron-binding fragments, designated as FeNF and FeCF, respectively. The Mr of each fragment is 39,000. The purified fragments show major differences in the content of histidine, alanine, and methionine. Both apo-NH2- and apo-CO2H-terminal fragments are able to bind one ferric ion per molecule. FeCF is more resistant than FeNF to dissociation at acid pH and to subtilisin action. FeNF and FeCF are immunochemically distinct. However, equal mixtures of the two show immunochemical reaction indistinguishable from intact Fe2OT. The iron-binding sites of FeNF and FeCF are very similar to each other on the basis of visible absorption and CD spectra. The major difference in the backbone conformations between FeNF and FeCF is in the alpha-helical content of FeCF which is twice that of FeNF. Individually, fragments show quantitative differences in the electron paramagnetic resonance spectra; however, equal mixture of the two fragments produce EPR spectra very similar to that of the intact Fe2OT. These studies indicate that subtilitic cleavage of Fe2OT does not produce significant change in the iron-binding capacity or the conformation of the separated iron-binding domains.

Amino Acids↗
PubMed1981

Acute heroin abstinence in man: IV. Sleep--waking state contingencies.

This study investigated the effect of acute heroin withdrawal on the pattern of sleep--waking state sequences. Subjects included drug-dependent patients using pure heroin and drug-free controls. Electrophysiological data were recorded on a 24-hour per day basis for the first 5 - 7 days of withdrawal. EEG records were scored according to standard criteria. Marked increases in the sequential state changes occurred during withdrawal when progressing from awake-with-alpha, stage I, stage II and rapid eye movement (REM) sleep to the awake state. Heroin withdrawal also caused significant decreases in sequential state changes when proceeding from waking or light sleep states into deeper sleep states or into REM sleep. This study revealed that heroin withdrawal caused more abrupt transitions from quiet awake or sleeping conditions into the awake state and impeded progression into slow wave or REM sleep states.

Alpha Rhythm↗
PubMed1980

Acute heroin abstinence in man: I. Changes in behavior and sleep.

The purpose of this study was to examine overt behavioral characteristics and sleep during acute heroin abstinence in man. Both heroine-dependent patients and drug-free control subjects were observed and monitored on a 24-hour per day basis for 5 to 7 days. Observational data were analyzed for frequency of occurrence of various behaviors including the signs and symptoms of withdrawal. Electroencephalographic (EEG) data were scored into awake and sleep stages according to standard techniques. The heroin-dependent subjects generally displayed a higher number of observations across all recording days as compared to the controls. In addition, the signs and symptoms of withdrawal for these patients peaked on day 1 or day 2 and then declined over the remaining recording days. The EEG state data showed an increase in waking and decrease in both slow wave and REM sleep during acute heroin withdrawal. Total sleep was maximally suppressed on withdrawal days 2 and 3 and was still below normal control values on withdrawal days 5 - 7. REM sleep was more disrupted than slow-wave sleep during withdrawal from heroin. Results of this study indicate that heroin withdrawal produces a differential action upon central nervous system structures responsible for the various states of sleep, waking and related behaviors.

Acute Disease↗
PubMed1980

Acute heroin abstinence in man. III. Effect upon waking and slow wave sleep.

The purpose of this study was to evaluate the effects of acute heroin withdrawal on waking behavior and slow wave sleep. Data were collected from drug-dependent patients who were using pure heroin and from drug-free controls. All data were recorded on a 24-hour per day basis for 5 - 7 consecutive days. EEG records were manually scored according to standard criteria. The heroin-dependent patients during withdrawal showed approximately a 26% decrease in slow wave sleep and an 18% increase in waking behavior. The awake state in the heroin-dependent patients during withdrawal also displayed an increase in number of episodes and number of state shifts, and a decrease in duration and sleep onset latency. In addition, the slow wave sleep categories during withdrawal generally showed an increase in sleep onset latency and interstate interval and a decrease in number of episodes. These results indicate that heroin withdrawal is associated with a marked disruption of the central nervous system mechanisms responsible for maintenance of the normal sleep--waking cycle. Analyses of the pattern of this disruption will further aid in understanding the withdrawal syndrome.

Electroencephalography↗
PubMed1980

Acute heroin abstinence in man: II. Alterations in rapid eye movement (REM) sleep.

The purpose of this study was to examine the effects of withdrawal from heroin upon rapid eye movement (REM) sleep. Subjects included both heroin-dependent patients and drug-free controls. The drug users were young males who had an average daily intake of approximately 973 mg of 92 - 98% pure heroin before entering the study. All electrophysiological data were obtained via a telemetry system on a 24-hour per day basis for 5 to 7 consecutive days. EEG records were scored into the standard awake and sleep states. Results showed a marked decrease in total amount of REM sleep during heroin withdrawal. This total decrease was associated with a decrease in duration of individual REM episodes and a large decrease in the number of occurrences of REM sleep. The heroin-dependent patients during withdrawal also showed a prolonged latency from sleep onset to first REM episode and a reduced number of REM shifts per 24-hour period. No significant difference in REM sleep interval was observed between the control subjects and drug users. Some of the overt behavioral characteristics associated with heroin withdrawal may be indirectly related to the concurrent loss in REM sleep as observed in this study.

Electroencephalography↗