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Biomedical subjects

G Bittner

Publications and source records attributed to G Bittner.

16 recordsLinked to original sources
PubMed1992

Tumor necrosis factor, but not other hematopoietic growth factors, prolongs the survival of hairy cell leukemia cells.

In order to determine the growth factor requirements of hairy cell leukemia (HCL) cells, we studied the in vitro effects of tumor necrosis factor (TNF), interleukin (IL) 1 alpha, IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, B-cell growth factor (BCGF), GM-CSF, PHA-stimulated lymphocyte-conditioned media (CM), and 5637 bladder carcinoma CM on HCL cells obtained from spleens of patients with HCL. Mononuclear cells from a normal donor, obtained at post-traumatic splenectomy, served as a control. TNF prolonged the survival of HCL cells obtained from five different HCL patients when compared to cells cultured in control media alone, although cell proliferation could be demonstrated in only two of the five. HCL cells stained negative for the Epstein-Barr nuclear antigen (EBNA) both before and after 4 weeks in culture. BCGF, 5637 CM, and PHA-stimulated lymphocyte CM also prolonged the survival of HC25 and HC56 cells, although not to the same degree as TNF. Cells cultured in BCGF, however, stained positive for EBNA. None of the other recombinantly produced or purified cytokines prolonged the survival of the leukemic cells. With the exception of IL-2, none of the growth factors studied prolonged the survival of purified normal spleen (NS) cells over a 4-week period of time when compared to NS cells incubated in media alone. TNF prolonged the survival of HC25 cells in a dose-dependent manner, and a highly purified antibody to TNF abrogated the effects of TNF. HC25 cells incubated in the presence of control media alone did not constitutively produce TNF mRNA; however, incubation of the cells in the presence of TNF for 48 h induced the cells to express TNF message. We conclude that TNF is important in prolonging the survival of HCL cells, and thus may be important in the pathogenesis of this disease.

Cell Survival↗
PubMed1992

[The body--a symbol of the unconscious?].

Based on Lacan's differentiation between the real, the imaginary and the symbolic it is shown that Moser's connection between psychoanalysis and therapy is almost exclusively concentrated on the body in the sphere of the imaginary. According to Bittner, when the body is regarded symbolically, it represents a highly emotional "transcription" of the unconscious.

Body Image↗
PubMed1991

[Gonalgia: treatment with therapeutic local anesthesia. Results of a controlled comparative study versus diclofenac].

The effectiveness and tolerance of therapeutic local anesthesia (TLA) with lidocaine was compared with those of oral diclofenac in a controlled, open, randomized study involving 76 patients with gonalgia due to gonarthrosis or patellar chondropathy. During the course of the three-week (maximum) treatment, the summed score of pain at rest, pain on movement, and restricted mobility, taken as the target parameter of effectiveness, decreased significantly more markedly (p = 0.008) under TLA, than under diclofenac. Side effects involving mainly the gastrointestinal tract occurred significantly more frequently in the diclofenac group (p = 0.012). The results of this study indicate that in the treatment of localized joint pain of degenerative genesis, TLA with lidocaine is superior to NSAID treatment in terms of effectiveness and tolerance.

Adult↗
PubMed1991

Establishment and characterization of an Epstein-Barr virus spontaneously transformed lymphocytic cell line derived from a hairy cell leukemia patient.

Hairy cell leukemia is a rare, B-cell malignancy uniquely sensitive to the antitumor effects of alpha and beta interferons (IFN). In order to further study the effects of IFN in this disease, we derived a cell line (HC1) from the peripheral blood mononuclear cells of a patient with hairy cell leukemia (HCL). Cells exhibited the typical morphological features of HCL, including the characteristic cytoplasmic projections by light, transmission, and scanning electron microscopy. HC1 cells were of B-cell lineage, as evidenced by immunophenotypic analysis. Although originally TRAP positive, HC1 cells lost this biochemical marker following 3 months in culture. Monoclonality of the cell line was confirmed by a clonal karyotypic abnormality characteristic of B-cell malignancies, and the presence of a single, distinctive fused terminal EBV fragment. The cells formed colonies in soft agar and were tumorigenic in irradiated nude mice. HC1 cells were sensitive to the antiproliferative effects of IFN-a and IFN-beta, but only moderately sensitive to the growth inhibitory effects of IFN-gamma. Incubating the cells in the presence of Type 1 IFN resulted in stabilization of cell numbers, without cellular proliferation or loss. Cell cycle analysis revealed that IFN-alpha resulted in a build-up of cells in the S phase of the cell cycle, suggesting a cytostatic effect of IFN on the growth of these cells. The HC1 cell line provides a model system which will be useful for in vitro studies of the biology and treatment of this disease.

Animals↗
PubMed1990

Anti-proliferative effects of tumor necrosis factor, gamma interferon and 5-fluorouracil on human colorectal carcinoma cell lines.

We have previously utilized a bank of diverse human colorectal carcinoma cell lines to assess the synergistic antiproliferative effect of tumor necrosis factor (TNF) and IFN-gamma (IFN-gamma) in combination. In this study, we used 3 of these cell lines (HCT 116, SKO1 and VACO 9P) to study the growth-inhibitory effects of TNF and IFN-gamma (TNF/IFN-gamma) on these cells when administered in conjunction with 5-fluorouracil (5-FU). All 3 cell lines were sensitive to suprapharmacologic concentrations of 5-FU. However, the 3 lines varied in their sensitivities to clinically achievable concentrations of 5-FU. Concentrations of 0.1 microgram/ml of 5-FU administered for 96 hr, and 50 micrograms/ml administered for 1 hr, inhibited the growth of HCT 116 cells by 20% and 77%, that of SKCO1 cells by 25% and 66%, and that of VACO 9P cells by 25% and 55%, respectively. All 3 cell lines were sensitive to the anti-proliferative effects of TNF/IFN-gamma in a dose-dependent and duration-dependent fashion. TNF/IFN-gamma was administered for 1 hr every other day on days 1, 3 and 5 to the 3 cell lines. Cells were also exposed to 5-FU, administered either concomitantly for 96 hr, or for 1 hr on day 1. The addition of TNF/IFN-gamma to clinically achievable concentrations of 5-FU in both schedules resulted in additive cytotoxicity. For example, the addition of 10 ng/ml of both TNF and IFN-gamma to 96 hr of 0.1 microgram/ml 5-FU resulted in 10%, 5%, and 20% of control growth for the HCT 116 cell line, SKCO1 cell line, and VACO 9P cell line, respectively. The addition of 10 ng/ml of both TNF and IFN-gamma to 1 hr of 50 micrograms/ml of 5-FU inhibited all cell growth in all 3 cell lines. We conclude that TNF/IFN-gamma and 5-FU can be combined to achieve higher anti-tumor activity than either 5-FU or TNF/IFN-gamma alone in this in vitro model, that the 3-drug combination has potent growth-inhibitory effects at pharmacologic concentrations which are not schedule-dependent, and that this combination warrants further study in clinical trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Characterization of the synergistic antiproliferative effects of interferon-gamma and tumor necrosis factor on human colon carcinoma cell lines.

We employed a tumor-type-specific tissue culture model utilizing three human colon carcinoma cell lines to (i) assess the effects of schedule, sequence, dose, and duration of exposure on the antiproliferative activity of combinations of tumor necrosis factor (TNF) and interferon-gamma (IFN-gamma) and to (ii) determine the effects of this combination on the production of a TNF-inducible protein, IFN-beta 2, and an IFN-inducible protein, p78. A statistical model was developed to ascertain the effects of each of three of the variables (sequence, dose, and duration) on the other two. With minor exceptions, the maximal antiproliferative effect in all three cell lines was observed when IFN-gamma and TNF were administered simultaneously, regardless of the doses of each agent and duration of exposure. Exposing the cells to TNF before IFN-gamma resulted in the least inhibition in cell growth. In all three cell lines, the antiproliferative effects of each treatment group were related directly to the duration of exposure. In two of the three cell lines, an intermittent schedule was as effective as a 24-h exposure. No p78 induction was observed in the HCT 116 cell line with IFN-gamma alone, TNF alone, or the combination; p78 was slightly induced in the SKC01 and VACO 9P cell lines with IFN-gamma alone, and was synergistically induced by the combination of TNF and IFN-gamma. Treatment with a neutralizing antibody to IFN-beta did not reverse the antiproliferative effect of any of the three treatment groups in HCT 116 cells. We conclude that the maximum antiproliferative effect in human colon carcinoma can be achieved by the prolonged simultaneous administration of high concentrations of each drug. If clinical toxicity prohibits this schedule, an intermittent schedule of administration may be effective. The mechanism of the synergistic effect is not due to the induction of IFN-beta or the p78 protein.

Cell Division↗
PubMed1990

Effects of combinations of interferon-beta ser and interferon-gamma on interferon-inducible proteins and on the cell cycle.

SKCO 1 human colon carcinoma cells have been shown to be synergistically inhibited in their growth by the combinations of alpha-interferon (IFN-alpha) or beta-interferon (IFN-beta ser) and gamma-interferon (IFN-gamma). To determine if a correlation could be established between this synergistic antiproliferative effect and a synergistic induction in IFN-inducible proteins, or a unique perturbation in the cell cycle, we studied the effects of IFN-beta ser and IFN-gamma, alone and in combination, on 2',5'-oligoadenylate (2-5A) synthetase, indoleamine-2,3-dioxygenase (IDO), a human analogue of the murine Mx protein (p78), and the phases of cell cycle. 2-5A synthetase was maximally induced after a 24-h exposure to both IFN-beta and IFN-gamma. A synergistic enhancement of 2-5A synthetase activity was observed only with low concentrations of each IFN (0.05 ng/ml). IDO activity was induced by IFN-gamma and the combination of IFN-beta ser and IFN-gamma, but not IFN-beta ser alone. The differences in IDO activity between IFN-gamma and the combination, however, were not statistically significant. The p78 protein was induced in a dose-dependent manner by IFN-alpha and IFN-beta ser. IFN-gamma enhanced the expression of p78 induction by IFN-alpha or IFN-beta ser, even at concentrations of IFN-gamma that did not induce the protein when administered as a single agent. The combination of IFN-alpha and IFN-beta ser, which results in an antagonistic antiproliferative effect, also resulted in an antagonistic induction of p78. No changes in the cell cycle were observed following exposure to IFN-beta ser, IFN-gamma, or the combination, and treatment with IFN-gamma did not inhibit the accumulation of cells in G2M caused by colchicine. Thus, the synergistic antiproliferative effect produced by IFN-beta ser and IFN-gamma in SKCO 1 cells could not be correlated with a synergistic enhancement in 2-5A synthetase or IDO activity, or with a perturbation in the cell cycle. In contrast, the combination of IFN-gamma and IFN-alpha or IFN-beta ser synergistically enhanced the expression of p78 protein in these cells.

2',5'-Oligoadenylate Synthetase↗
PubMed1988

Phase II trial of a combination of interferon-beta ser and interferon-gamma in patients with advanced malignant melanoma.

Based upon the in vitro synergistic activity of interferon-beta (IFN-beta) and interferon-gamma (IFN-gamma) observed in melanoma cells, we initiated a Phase II trial using the combination to determine the clinical antitumor efficacy in patients with advanced disease. Fifteen patients with metastatic malignant melanoma were given 2,000 micrograms of recombinant IFN-gamma (rIFN-gamma) (Biogen) intravenously (i.v.) over 10 min, followed by a 10 min i.v. injection of 30 million units of recombinant IFN-beta (rIFN-beta ser) (Triton) 3 x/week. Six patients had skin, soft tissue, nodal, or subcutaneous metastases, 6 had visceral disease only, and 3 had both. Seven patients had received prior treatment, including chemotherapy (6), radiotherapy (3), and/or immunotherapy (3). Side effects included typical IFN constitutional symptoms such as anorexia, fatigue, nausea, and myalgias, but were not dose limiting. The mean drop in the white blood cell count (WBC) following 1 month of therapy, compared to baseline, was 3.3 x 10(3)/mm2 (p = 0.002); the mean increase in SGOT was 24.1 U/l (p less than 0.001). One patient had a dose reduction for Grade III anorexia and fatigue which did not resolve with repeated treatment. One patient with liver metastases had radiographical and clinical stabilization of his disease for 1 year. No responses were seen. The median time to progression was 6 weeks. Two patients' tumors were evaluable in the human tumor colony forming assay (HTCFA) and were markedly sensitive to the antiproliferative effects of IFN combinations. Both patients, however, failed to respond clinically.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Synergistic antitumor effects of tumor necrosis factor and gamma-interferon on human colon carcinoma cell lines.

We assessed the antiproliferative effects of tumor necrosis factor (TNF-alpha) and gamma-interferon (IFN-gamma) alone and in combination, on nine human colon carcinoma cell lines. All were resistant (less than 30% inhibition) to TNF-alpha alone. Four cell lines were resistant to IFN-gamma alone, two exhibited a minimal degree of sensitivity (30-50% inhibition), one was moderately sensitive, and two were inhibited 70% or greater. A synergistic antiproliferative effect occurred in eight of the nine cell lines treated with a combination of TNF-alpha and IFN-gamma. In seven of these eight, the combination of cytokines resulted in 30-40% more growth inhibition than predicted had an additive interaction occurred (P less than 0.005). In two cell lines with an induced resistance to mitomycin C, an increase in resistance to combined TNF-alpha and IFN-gamma treatment correlated with an increasing resistance to mitomycin C. The data were further analyzed to determine if combination treatment altered the sensitivity of the cells to one or both agents in addition to synergistically potentiating growth inhibitory effects. Combinations of TNF-alpha/IFN-gamma enhanced the dose response activity of TNF-alpha in three cell lines (P less than or equal to 0.09) and decreased the dose response activity of IFN-gamma in another three (P less than or equal to 0.02). Colony forming experiments on HCT 116 cells demonstrated a reduction in the number of 250-micron colonies in the IFN-gamma/TNF-alpha treatment groups when compared to controls, indicating that combined treatment had a cytotoxic effect. We conclude that combination TNF-alpha/IFN-gamma treatment has a synergistic cytotoxic effect on human colon carcinoma cells. IFN-gamma may enhance the effectiveness of TNF-alpha in some cell lines, but not conversely. These results may have therapeutic implications.

Cell Cycle↗
PubMed1986

Antiproliferative effects of interferons on human melanoma cells in the human tumor colony-forming assay.

The human tumor colony-forming assay (HTCFA) is an in vitro test that has been used to predict the activity of anticancer drugs against a patient's tumor. We utilized the assay to analyze the antiproliferative effects of seven interferons (IFNs) against 40 human melanomas to determine which IFN had the greatest antiproliferative activity in this drug-resistant tumor. IFNs studied included recombinant IFN-alpha 2; human lymphoblastoid IFN; IFN-alpha Cantell; native beta RPMI; two recombinant IFNs-beta; and recombinant IFN-gamma. Growth was sufficient [greater than 30 tumor colony-forming units (TCFU)/well] for assessing the antiproliferative effects of at least one IFN in 25 tumors (63%). A dose-response relationship was demonstrated by all IFNs in tumors in which some activity was observed (p less than or equal to 0.01). Individual melanomas differed in their sensitivities to the various IFNs. Overall, however, none of the IFNs was markedly more effective in antiproliferative effects than any other, although there was a trend toward IFN-beta ser having more potent antiproliferative properties when compared to IFN-alpha 2 (p = 0.055). Twelve of 13 tumors exposed to combinations of IFN-beta ser and IFN-gamma demonstrated a synergistic antiproliferative effect. In all but two of these, low concentrations of each IFN (less than or equal to 50 U/ml), when combined, resulted in 85-95% inhibition. As prolonged exposure to high concentrations of IFN are often not clinically tolerable, these data suggest that IFN combinations may be one way of achieving more clinically meaningful IFN doses, schedules, and regimens, provided antiproliferative effects are of importance in vivo.

Antineoplastic Agents↗
PubMed1985

Thallium-201 scintigraphy in the diagnosis of pheochromocytoma.

6 patients were studied by 201Tl scintigraphy; 1 of them suffered from a benign, and another from a malignant adrenal pheochromocytoma. 1 patient had a hormonal inactive adrenal tumor, 3 others multiple organ metastases of malignant pheochromocytomas. At the same time, 3 of the patients were studied by 131I-metaiodobenzylguanidine (131I-MIBG) scintigraphy. Using different techniques like kinetic studies, whole-body scan or a 201Tl-99m-Tc difference scan, benign and malignant pheochromocytoma tissues could be localized by 201Tl scintigraphy. Benign and malignant pheochromocytomas showed different kinetics of 201Tl. In 2 patients with multiple organ metastases of malignant pheochromocytomas, the metastases were partly imaged by 131I-MIBG, the others by 201Tl.

3-Iodobenzylguanidine↗