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J Liebmann

Publications and source records attributed to J Liebmann.

At least 19 recordsLinked to original sources
PubMed1996

The effect of various nitric oxide-donor agents on hydrogen peroxide-mediated toxicity: a direct correlation between nitric oxide formation and protection.

The role that nitric oxide (NO) plays in various degenerative and disease states has remained a mystery since its discovery as a biological messenger, prompting the question, "NO, friend or foe?" Some reports have suggested that NO is cytotoxic, and yet others have shown that it possesses protective properties against reactive oxygen species (ROS). Many studies have used various NO donor complexes arriving at seemingly different conclusions. This report will address the effects of various NO donor compounds on ROS-mediated toxicity. Consistent with our previous study, the NO donor compound, DEA/NO ((C2H5)2N[N(O)NO]-Na+), afforded protection against hydrogen peroxide-mediated cytotoxicity in V79 Chinese hamster lung fibroblasts at concentrations as low as 10 microM DEA/NO. Furthermore, a survey of other NO donor complexes revealed that some either protected or potentiated hydrogen peroxide-mediated cytotoxicity. 3-Morpholinosynodiomine.HCl (SIN-1) and sodium nitroprusside (SNP) enhanced hydrogen peroxide-mediated cytotoxicity, while S-nitrosoglutathione (GSNO), and S-nitroso-N-acetylpenicillamine (SNAP) afforded protection. Electrochemical detection of NO in cell culture medium revealed that neither 1000 microM SIN-1 nor SNP yielded appreciable NO concentrations (<0.3 microM). In contrast, DEA/NO, SNAP, and GSNO yielded fluxes of NO >1.0 microM. Thus, a direct correlation between inhibition of hydrogen peroxide cytotoxicity and NO production was observed: agents that release NO during hydrogen peroxide treatment afford significant protection, whereas agents that do not release NO do not protect. Similar results were observed for NO donors studied when hypoxanthinesolidusxanthine oxidase was used as the source for ROS, although the S-nitrosothiol agents were much less protective. These results demonstrate that NO possesses properties which protect against ROS toxicity and demonstrate how the use of different NO donor compounds can lead to different conclusions about the role that NO can play in the cytotoxicity of ROS.

Animals↗
PubMed1996

Personal computer-based 3-dimensional ultrasound biomicroscopy of the anterior segment.

OBJECTIVE: To develop a practical, inexpensive system for 3-dimensional ultrasound biomicroscopic imaging of the anterior segment with a commercially available high-frequency ultrasound imager and a personal computer. METHODS: Sequential, high-frequency, ultrasound biomicroscopic images of the anterior segment were obtained with a motorized scanning control arm designed in our imaging laboratory. Images were acquired by a personal computer-based video capture device. Ultrasound slice data were then reconstructed as 3-dimensional volumetric images by a personal computer and commercially available software. RESULTS: Four 3-dimensional visualization formats were developed to enhance the clinical utility of high-frequency ultrasound. Rotational animation sequences were created that detailed the extent and anatomy of a filtering bleb, intraocular lens subluxation, focal angle closure from an iridociliary cyst, intraocular foreign bodies, and an iris tumor. CONCLUSIONS: Three-dimensional, high-frequency ultrasound of the anterior segment enhances our ability to visualize spatial relationships between adjacent anatomic structures. The low cost and ease of use of this system make widespread clinical application practical.

Adult↗
PubMed1995

Enhanced glutathione peroxidase expression protects cells from hydroperoxides but not from radiation or doxorubicin.

Both radiation and anthracycline antibiotics may produce reactive oxygen species to cause cytotoxicity, and it has been suggested that some cellular antioxidant enzymes may be important for resistance to these agents. The human breast adenocarcinoma cell line MCF-7WT has a low level of glutathione peroxidase (GPX) activity. We have transfected MCF-7WT cells with a plasmid that contains the cDNA for human GPX under the transcriptional control of the human metallothionein IIA promoter. One transfected clone, MCF-GPX-6, contained multiple copies of GPX cDNA/cell and, after exposure to heavy metals, expressed a level of GPX enzyme activity that was 40-fold higher than that present in MCF-7WT cells and comparable to the GPX activity contained in the doxorubicin-resistant MCF-7DOX cell line. No differences in levels of glutathione, catalase, superoxide dismutase, glutathione S-transferase, or glutathione reductase were noted in MCF-GPX-6 cells compared to MCF-7WT cells. MCF-GPX-6 cells were relatively resistant to hydrogen peroxide and tert-butylhydroperoxide compared to MCF-7WT cells, e.g., exposure of both cell lines to 750 microM H2O2 for 1 h resulted in a relative surviving fraction of 0.07 for MCF-7WT and 0.35 for MCF-GPX-6 cells. However, no difference in sensitivity to either radiation or doxorubicin was noted between MCF-7WT and MCF-GPX-6 cells. These results suggest that GPX is not important for the development of cellular resistance to either radiation or doxorubicin.

Antibiotics, Antineoplastic↗
PubMed1995

Nitric oxide (NO) protects against cellular damage by reactive oxygen species.

Since the discovery of nitric oxide (NO) as an endogenously formed radical, its effect on numerous physiological processes has been intensively investigated. Some studies have suggested NO to be cytotoxic while others have demonstrated it protective under various biological conditions. Though NO shows minimal cytotoxicity to a variety mammalian cell cultures, it does modulate the toxicity of some agents such as reactive oxygen species. Often, NO is generated in the presence of these reactive oxygen species in response to foreign pathogens or under various pathophysiological conditions. We will show that NO can play a protective role under oxidative stress resulting from superoxide, hydrogen peroxide and alkyl peroxides. It was found by measuring the time-concentration profiles of NO released from various NO donor compounds that only microM levels of NO were required for protection against the toxicity of these reactive species. It was found that there are several chemical reactions which may account for these protective effects such as NO preventing heme oxidation, inhibition of Fenton-type oxidation of DNA, and abatement of lipid peroxidation. Taken together, NO at low concentrations clearly protects against peroxide-mediated toxicity.

Animals↗
PubMed1995

Radiation reaction recall following simvastatin therapy: a new observation.

A 60-year-old woman was treated postoperatively for carcinoma of the gall bladder with a split course of radiotherapy. The tumour dose (TD) was 61.2 Gy in 34 fractions delivered by an anterior and two lateral wedge fields with 60Co; the Dmax was 70% of TD for the anterior field and 150% of the TD at the thin edge of the wedges. She also underwent 5-FU and leucovorin chemotherapy. No skin reaction was seen during radiotherapy or in 1 year of follow-up. A year after radiotherapy she was treated for hypercholesterolaemia by simvastatin. Within 2-3 days a severe skin and subcutaneous reaction developed in the lateral radiation fields but not in the anterior field. To our knowledge, recall of skin radiation reaction after simvastatin therapy has not been previously reported.

Anticholesteremic Agents↗
PubMed1995

Combination intraventricular therapy with thiotepa and cytarabine in meningeal carcinomatosis due to breast cancer: in vitro evidence for supra-additive cytotoxicity.

Metastatic spread of tumors to the meninges is a frequent complication of many malignancies and is difficult to treat. We describe the case of a patient who developed carcinomatous involvement of the meninges from a breast adenocarcinoma. Despite intrathecal treatment with conventional and experimental agents, the patient's cerebrospinal fluid (CSF) was not cleared of malignant cells until thiotepa and cytarabine were given in combination. This clinical observation led us to assess the in vitro activity of the combination of thiotepa and cytarabine in clonogenic cell survival assays. The human breast adenocarcinoma cell line MCF-7WT and its doxorubicin-resistant variant MCF-7ADR were exposed to thiotepa and cytarabine either singly or in combination. We have found that the combination of the two drugs resulted in more than additive cytotoxicity than would have been predicted from the cytotoxicity of either drug given alone. We discuss the implications of these findings on the clinical management of patients with carcinomatous spread to the meninges.

Adenocarcinoma↗
PubMed1995

Detection of human immunodeficiency virus type 1-specific memory cytotoxic T lymphocytes in freshly donated and frozen-thawed peripheral blood mononuclear cells.

Loss of anti-human immunodeficiency virus type 1 (HIV-1) memory cytotoxic T-lymphocyte (CTLm) responses is associated with disease progression in HIV-1 infection. In this study, nonspecific stimulation of peripheral blood mononuclear cells (PBMC) from HIV-1-infected homosexual men with anti-CD3 monoclonal antibody (MAb) was compared with antigen-specific stimulation with inactivated, autologous B lymphoblastoid cells (B-LCL) infected with a vaccinia virus vector encoding HIV-1 IIIb Gag, Pol, and Env (VV-GPE) for activation of HIV-1-specific CTLm responses in a bulk lysis assay and by precursor frequency analysis. The results show that VV-GPE-infected B-LCL stimulated on average 10-fold greater anti-HIV-1 CTLm activity, as detected in the bulk lysis assay, and 55-fold-greater CTLm precursor frequencies specific for the three HIV-1 structural proteins than did stimulation with anti-CD3 MAb. This effect was noted with both freshly donated and frozen-thawed PBMC. The lysis was mediated by CD8+ T cells and was restricted by the major histocompatibility class I complex. These data indicate that antigen-specific stimulation with VV-GPE-infected B-LCL is a highly efficient method for detection of anti-HIV-1 CTLm responses that is applicable to noncurrent prospective studies with frozen PBMC.

Acquired Immunodeficiency Syndrome↗
PubMed1995

High levels of anti-human immunodeficiency virus type 1 (HIV-1) memory cytotoxic T-lymphocyte activity and low viral load are associated with lack of disease in HIV-1-infected long-term nonprogressors.

Lack of disease in long-term nonprogressors with human immunodeficiency virus type 1 (HIV-1) infection was strongly associated with very low copy numbers of HIV-1 DNA and RNA in peripheral blood mononuclear cells and plasma and the presence of high levels of anti-HIV-1 CD8+ memory cytotoxic T lymphocytes specific for Gag, Pol, and Env, compared with levels present in intermediate and advanced progressors. CD8+ memory cytotoxic T lymphocytes may have an important role in controlling HIV-1 replication and preventing disease in long-term nonprogressors.

Acquired Immunodeficiency Syndrome↗
PubMed1994

In vivo radiation protection by nitric oxide modulation.

Drugs that affect blood flow have been shown to be whole body radiation protectors. Using NG-nitro-L-arginine, a specific inhibitor of nitric oxide synthase, and the NO-releasing agent (C2H5)2N[N(O)NO-]Na+ (DEA/NO), we have studied the ability of NO to modulate whole body radiation toxicity in C3H mice. NG-Nitro-L-arginine given to mice between 15 and 60 min prior to radiation afforded significant protection from whole body irradiation, e.g., the estimated whole body irradiation dose required to kill 50% of mice by 30 days after radiation (LD50/30) in mice treated with NG-nitro-L-arginine 60 min before irradiation was 1051 cGy compared with a whole body radiation LD50/30 of 822 cGy in control mice (P < 0.00001). Treatment of mice with DEA/NO prior to whole body irradiation also significantly reduced toxicity; the estimated whole body radiation LD50/30 was 1063 and 945 cGy in mice treated with DEA/NO 10 or 30 min before irradiation, respectively (P < 0.00001 for radiation LD50/30 of either DEA/NO-treated group compared with control). Measurement of [14C]etanidazole binding to bone marrow demonstrated that DEA/NO and NG-nitro-L-arginine exacerbated bone marrow hypoxia. Perturbations of NO levels have profound effects on in vivo radiosensitivity of normal tissues. We hypothesize that alterations in regional blood flow may underlie the changes in radiosensitivity that we have observed.

Amino Acid Oxidoreductases↗
PubMed1994

Changes in radiation survival curve parameters in human tumor and rodent cells exposed to paclitaxel (Taxol).

PURPOSE: Late G2 and M are the most radiosensitive phases of the cell cycle. Cells exposed to paclitaxel develop a cell cycle arrest in G2/M. These studies were performed to assess the in vitro radiosensitization properties of paclitaxel in human tumor and rodent cell lines. METHODS AND MATERIALS: The effect of paclitaxel on the radiation sensitivity of human breast (MCF-7), lung (A549), ovary (OVG-1) adenocarcinoma and Chinese hamster lung fibroblast V79 cells was determined with clonogenic assays. DNA flow cytometry studies were performed to define the cell cycle characteristics of the cells during irradiation. Survival curve parameters for all cell lines were determined with the use of a computer program which represents cell survival after radiation by a linear-quadratic model. RESULTS: All cell lines developed a G2/M block after exposure to paclitaxel for 24 h. However, the degree of radiosensitization produced by paclitaxel varied among the cell lines. The maximal sensitizer enhancement ratio (SER) of paclitaxel was 1.8 in MCF-7 cells, 1.6 in OVG-1 cells, and 1.7 in V79 cells. However, no concentration of paclitaxel was able to enhance the radiation sensitivity of A549 cells. Paclitaxel increased the linear (alpha) component of the radiation survival curves in all cell lines. The quadratic (beta) component was unaffected by paclitaxel in the rodent cells. High concentrations of paclitaxel (> or = 1000 nM) increased beta slightly in the human cell lines but there was considerable variation in the effect of paclitaxel on beta. The cells which were sensitized to radiation by paclitaxel had a relatively small baseline alpha component, while A549 cells had a large alpha component. CONCLUSION: We conclude that paclitaxel is a modest radiosensitizer in some, but not all, human tumor cells. Paclitaxel appears to cause radiosensitization mainly by increasing the alpha component of radiation survival curves. Cells that normally have a relatively small alpha component should exhibit the most radiosensitization in response to paclitaxel while cells with a large alpha component should show little or no radiosensitization after paclitaxel treatment. Because the greatest effect of paclitaxel is on the linear component of radiation survival curves, these results indicate that paclitaxel may be an effective radiation sensitizer in many human tumors treated at clinically relevant radiation doses of 2 Gy or less.

Animals↗
PubMed1994

In vitro studies of Taxol as a radiation sensitizer in human tumor cells.

BACKGROUND: Cells exposed to paclitaxel (Taxol) develop a cell cycle arrest in G2/M. It has long been recognized that late G2 and M are the most radiosensitive phases of the cell cycle. PURPOSE: These studies were performed to assess the in vitro radiosensitization properties of paclitaxel in human tumor cell lines. METHODS: The effect of paclitaxel at concentrations ranging from 0 to 10,000 nM on the radiation sensitivity (from 0 to as much as 10 Gy in certain experiments) of human breast (MCF-7), lung (A549), ovary (OVG-1), and pancreas (PC-Sh) adenocarcinoma cells was determined using clonogenic assays. DNA flow cytometry studies were performed to define the cell cycle characteristics of populations of cells that had been treated for 6-72 hours with 0, 100, 1000, or 10,000 nM paclitaxel. RESULTS: All cell lines developed a G2/M block after exposure to 100-10,000 nM paclitaxel for 24 hours. However, the degree of radiosensitization produced by paclitaxel varied among the cell lines. The sensitizer enhancement ratio (SER) of paclitaxel at 10% survival was 1.8 in MCF-7 cells and 1.6 in OVG-1 cells. However, paclitaxel at any concentration was unable to enhance the radiation sensitivity of A549 cells. PC-Sh cells demonstrated a complex and inconsistent radiosensitization response to paclitaxel. At 10% survival, an SER of 1.5 was observed in PC-Sh cells. However, at 1% survival, no radiosensitization was observed in PC-Sh cells. Maneuvers that prevented paclitaxel from producing a G2/M block, including coincident treatment with cycloheximide or treatment of cells in plateau phase of growth, completely abrogated the radiosensitization afforded by paclitaxel in MCF-7 cells. CONCLUSIONS: Paclitaxel is a modest radiosensitizer in some, but not all, human tumor cells. The degree of radiosensitization that we have observed with paclitaxel is similar to what has been found with other chemotherapeutic agents. The absence of radiosensitization by paclitaxel in MCF-7 cells grown to plateau phase or treated with cycloheximide implies that the development of a G2/M block is a necessary condition for paclitaxel radiosensitization. However, the inability of paclitaxel to radiosensitize A549 cells despite the presence of a G2/M block in those cells demonstrates that a G2/M block is not a sufficient condition for paclitaxel radiosensitization. IMPLICATIONS: Paclitaxel can radiosensitize to a modest degree some, but not all, human cell lines by a mechanism that requires the production of a G2/M cell cycle block. Additional studies are needed to define more clearly the mechanism by which paclitaxel radiosensitizes cells.

Cell Cycle↗
PubMed1994

The influence of Cremophor EL on the cell cycle effects of paclitaxel (Taxol) in human tumor cell lines.

We have performed DNA flow analysis, mitotic index studies, time-lapse photography, and paclitaxel uptake studies of human tumor cell lines exposed to paclitaxel. DNA flow analysis demonstrated that cells began accumulating in G2/M within 6 hrs of exposure to paclitaxel; by 12 hrs over 50% of cells accumulated in G2/M at all concentrations tested. After 24 hrs of exposure to 10 nM paclitaxel, cells underwent non-uniform mitotic division resulting in multinucleated cells. Of cells treated with 30 nM to 1000 nM paclitaxel, 75% to 85% remained blocked in G2/M for up to 72 hrs. Although a large proportion of cells treated with higher concentrations of paclitaxel (10,000 nM) was blocked in G2/M, a significant proportion (10% to 40%) of these cells was also in G1. Cells exposed to lower concentrations of paclitaxel (10 nM to 1000 nM) in medium containing 0.135% (v/v) Cremophor EL also had a relatively large proportion in G1. Mitotic index studies demonstrated that the paclitaxel-induced G2/M block was initially a mitotic block and that cells remained in mitosis for up to 24 hrs. With additional time of exposure to paclitaxel, mitotic index and time-lapse studies indicated that cells attempted to complete mitosis; however, cytokinesis was inhibited and cells became multinucleated. Time-lapse photography revealed that paclitaxel markedly prolonged the time in mitosis from 0.5 hr to 15 hr. High levels of Cremophor EL (0.135% v/v) markedly reduced the number of cells in mitosis but did not alter the mitotic delay induced by paclitaxel. 3H-paclitaxel uptake studies revealed that high concentrations of Cremophor EL did reduce the rate of uptake of paclitaxel into cells but had little effect on total paclitaxel accumulation. These results confirm that paclitaxel has striking effects on the cell cycle and show that high concentrations of Cremophor EL are capable of inducing a cell cycle block distinct from the mitotic block seen with paclitaxel. These results also demonstrate that cells exposed to paclitaxel for longer than 24 hours attempt to complete mitosis but the process of cytokinesis is inhibited. Together with cytotoxicity data, these results indicate that entry into and exit out of mitosis are prerequisites for paclitaxel cytotoxicity.

Adenocarcinoma↗
PubMed1994

Pharmacokinetic properties of nitroxide-labeled albumin in mice.

We have conjugated bovine serum albumin (BSA) with a pyrrolidinyl nitroxide and report on the in vivo pharmacokinetic properties of this conjugate in mice. In vivo EPR measurements of nitroxide were obtained after intravenous injection of 30 mg of labeled BSA by analysis of the nitroxide signal from the tails of mice. Following in vivo nitroxide measurements, the animals were sacrificed by exsanguination and organs were removed for determination of nitroxide levels. The level of nitroxide as determined by in vivo measurements declined exponentially with time and had a half-life (t1/2) of 7 hours. Blood nitroxide levels also declined exponentially with time with an initial t1/2 of 70 minutes and a terminal t1/2 of 10 hours. Nitroxide concentration varied among different organs; no nitroxide was detected within brain whereas lung had high concentrations of nitroxide. Liver and kidney both had relatively low levels of oxidized nitroxide, though total nitroxide (reduced plus oxidized) accumulated in the kidneys with time. Nitroxide-labeled BSA was well tolerated by the mice, is relatively stable, and is mainly confined to the intravascular space. Nitroxide-labeled albumin may be useful as a contrast agent for MRI or EPR imaging.

Animals↗