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R D Issels

Publications and source records attributed to R D Issels.

46 records · Page 3Linked to original sources
PubMed1987

Influence of oxidative stress induced by cysteamine upon the induction and development of thermotolerance in Chinese hamster ovary cells.

Chinese hamster ovary cells exposed to the sulfhydryl compound cysteamine combined with heat treatment at 44 degrees C developed thermotolerance within 8 h. After initial treatment either with 15 min cysteamine (0.4 mM) at 37 degrees C immediately followed by 15 min heat at 44 degrees C or with 15 min cysteamine (0.4 mM) at 44 degrees C, the magnitude of thermotolerance developed was identical. The D0 of the subsequent 44 degrees C heat survival curves increased by factors of 8.9 and 7.9, respectively. The kinetics of thermotolerance induction and the time to reach the maximum of thermotolerance expression after combined cysteamine treatment at 44 degrees C for 15 min was found to be comparable to the effects of 44 degrees C treatment alone for 30 min. The synergistic effect of cysteamine with the conditioning heat treatment at 44 degrees C was blocked by catalase (50 micrograms/ml). Following initial treatment with cysteamine at 37 degrees C, cells became thermotolerant within 2 h. The D0 of the survival curves for 44 degrees C heat treatments increased with duration (t1 = min, 37 degrees C) of the cysteamine (0.4 mM) exposure; e.g., the D0 increased by factors of 1.5, 1.6, 2.2, and 2.6 for t1 = 30, 60, 90, and 120 min. The induction of thermotolerance by cysteamine at 37 degrees C was completely blocked by the addition of catalase (50 micrograms/ml), present during the initial period of drug treatment. Combined cysteamine and heat treatment at 44 degrees C, but also cysteamine exposure at 37 degrees C, enhanced synthesis of heat shock proteins. The data suggest that oxidative stress by cysteamine can be synergistic with the conditioning heat treatment at 44 degrees C which induces thermotolerance. At 37 degrees C, cysteamine itself induces thermotolerance and the enhanced synthesis of heat shock proteins under these conditions.

Adaptation, Physiological↗
PubMed1986

Effects of hyperthermic conditions on the reactivity of oxygen radicals.

Generation and reactivity of superoxide (O2.-) and hydroxyl (OH.) radicals in enzymatic and radiolytic systems were investigated over the temperature range from 20 degrees-50 degrees C. The generation rate and reaction kinetics of both enzymatically and radiolytically produced superoxide radicals were determined by a cytochrome c reduction assay. For OH. radical reaction studies the degradation of hyaluronic acid was assayed. An increase in temperature leads to a greater reactivity of both radicals, but in the case of an enzymatic source a disproportionate increase in the rate of generation is observed. In the pulse radiolysis system, the reactivity of superoxide radicals was found to be stimulated 15-fold over the temperature range from 20 degrees C to 60 degrees C, although the activity of superoxide dismutase was only minimally increased (about 1.6-fold). The results are discussed with respect to the possible importance of active oxygen species to the biological effects of hyperthermia.

Cytochrome c Group↗
PubMed1985

Temperature-dependent influence of thiols upon glutathione levels in Chinese hamster ovary cells at cytotoxic concentrations.

Chinese hamster ovary cells were exposed to the sulfhydryl compound cysteamine at different temperatures (5 degrees C, 37 degrees C, 44 degrees C) at concentrations known to generate activated oxygen species. At 37 degrees C, the cellular glutathione (GSH) content increased linearly over the time of drug exposure (2 h) as compared to untreated cells or to cells kept at 5 degrees C during drug treatment. The 2-4-fold increase in GSH induced by cysteamine was more rapid at 44 degrees C than at 37 degrees C and showed a saturation effect at the higher temperature. The elevation of GSH could be completely blocked by DL-buthionine-S,R-sulfoximine, an inhibitor of gamma-glutamylcysteine synthetase, or by incubation in a cystine-free medium during the period of drug treatment. The increased cellular GSH content induced by cysteamine alone at 37 degrees C or combined with heat at 44 degrees C decreased to the range of control values within 22 h after either treatment. Other thiols like cysteamine, namely cysteine, N-acetylcysteine, and dithiothreitol, were found to be similar in their potential to induce GSH elevation in Chinese hamster ovary cells. Cytotoxic effects of these sulfhydryl compounds were observed in the same concentration range as that for cysteamine (0-2 mM), but only if cells were plated at low densities (10(2)-10(4) cells/flask), and were completely blocked by the addition of catalase (50 micrograms/ml). In contrast, the elevation of GSH after thiol treatment (0.8 mM) was not modified by catalase. The data suggest that thiol treatment combined with hyperthermia leads to a rapid increase of GSH biosynthesis in Chinese hamster ovary cells which seems to be independent of the simultaneous generation of activated oxygen species by thiol autoxidation.

Animals↗
PubMed1984

Enhancement of cysteamine cytotoxicity by hyperthermia and its modification by catalase and superoxide dismutase in Chinese hamster ovary cells.

Chinese hamster ovary cells were exposed to the sulfhydryl compound cysteamine at concentrations ranging from 0 to 8 mM for 120 min. No toxicity was found in cells maintained at 5 degrees during treatment; however, at 37 degrees and 44 degrees a paradoxical toxicity was observed, i.e., substantial toxicity was observed at cysteamine concentrations of 0.2 to 1 mM but decreased at higher drug concentrations. When drug-treated cells were exposed to a 30-min 44 degrees -heat treatment (surviving fraction, 0.15 in the absence of drug) toxicity was markedly enhanced. At 0.4 mM cysteamine, the surviving fraction was approximately 0.6 at 5 degrees, 0.01 at 37 degrees, and 0.00008 when the 44 degrees -heat treatment was also used. Cysteamine toxicity was not modified by the addition of superoxide dismutase (10 micrograms/ml) but was completely blocked by the addition of catalase (50 micrograms/ml) over the drug concentration range of 0.2 to 2.0 mM. Cysteamine autoxidation as measured by O2 uptake at 0.4 mM proceeds through hydrogen peroxide (H2O2) production as evidenced by the regeneration of O2 upon the addition of catalase. In contrast, at 4.0 mM cysteamine, O2 regeneration was not pronounced. The data suggest that the production of H2O2 is the first reaction step in the mechanism of cysteamine toxicity. The subsequent production of highly reactive oxygen species like hydroxyl radicals (.OH) from H2O2 in the presence of reduced metal (Fenton chemistry) probably leads to the observed cellular toxicity.

Animals↗
PubMedDate not supplied

Hyperthermia in oncology.

The purpose of this article is to provide an overview on the current clinical application of hyperthermia combined with conventional treatment modalities (e.g. ionizing radiation, chemotherapy) in the treatment of malignant disease. The clinical application of hyperthermia with increase of tissue temperatures (range 40-44 degrees C) has been integrated in multimodal anti-cancer strategies. This review describes selected phase I or II (n = 17) and phase III trials (n = 16) investigating the effect of hyperthermia combined with radiotherapy (n = 10 trials), chemotherapy (n = 15 trials), or both (n = 8 trials) in a total of more than 2200 patients. The trials were performed in a variety of solid tumours (e.g. melanoma, head and neck cancer, breast cancer, cancer of the gastrointestinal or urogenital tract, glioblastoma, sarcoma) in paediatric or adult patients. Profound research has produced a scientific basis for the simultaneous application of hyperthermia in combination with ionizing radiation and/or systemic chemotherapy. Hyperthermia is becoming more accepted clinically, due to the substantial technical improvements made in achieving selected increase of temperatures in superficial and deep-seated tumours. At present, the combination of hyperthermia and chemotherapy or radiochemotherapy is further tested within clinical protocols (phase II/III) in order to improve local tumour control and relapse-free survival in patients with high-risk or advanced tumours of different entities.

Body Temperature↗
PubMedDate not supplied

Heat shock protein 70: role in antigen presentation and immune stimulation.

Heat shock proteins (HSP) when released into the extracellular milieu can act simultaneously as a source of antigen due to their ability to chaperone peptides and as a maturation signal for dendritic cells, thereby inducing DCs to cross-present antigens to CD8+ T-cells. HSP can also act independently from associated peptides, stimulating the innate immune system. Previous results regarding the activation of NK cells by HSP70 cell surface expression on tumour cells and soluble HSP70 will be further covered elsewhere within this issue. For cross-presentation, HSP70-peptide complexes (HSP70-PC) were used from two human melanoma cell lines that differ in the expression of the tumour-associated antigen tyrosinase. Purified HSP70-PC consists of both the constitutively expressed HSC70 and the inducible HSP70. HSP70-peptide complexes purified from tyrosinase positive (HSP70-PC/tyr+) human melanoma cells, incubated with immature DCs, results in the activation of HLA-*A0201-restricted tyrosinase peptide-specific T-cells. Receptor-mediated uptake of HSP70-PC by DCs and intracellular transport are required for efficient MHC class I restricted cross-presentation of chaperoned peptides. Demonstration of HSP70-PC mediated cross-presentation of such non-mutated naturally expressed tumour antigens is of special clinical interest with regard to hyperthermia. Tumour regression and improved local control have been shown within clinical phase II/III trials integrating regional hyperthermia combined with radiation and/or chemotherapy in multimodal treatment strategies. According to the proposed concept, local necrosis induced by hyperthermic treatment induces the release of HSPs, followed by uptake, processing and presentation of associated peptides by DCs. By acting as chaperone and a signal for DC maturation, HSP70-PC might efficiently prime circulating T-cells. Therefore, upregulating HSP70 and causing local necrosis in tumour tissue by hyperthermia offers great potential as a new approach to directly activate the immune system.

Animals↗
PubMedDate not supplied

Estimated number of children with cancer eligible for hyperthermia based on population- and treatment-related criteria.

Patients with recurrent, progressed or otherwise, therapy resistant malignancies, whose diseases are not amenable to standard therapies, may benefit from hyperthermia (HT). Based on the number of 1600 newly diagnosed malignancies, in patients < 15 years of age, per annum of which 70% are successfully treated on the standard treatment protocols of the German Society of Pediatric Oncology and Hematology (GPOH) and allowing for various drop-outs for reasons such as lack of established protocols, insufficient state of health and others, this means that as many as 100 children per annum can be expected to be enrolled into phase I/II trials in Germany. In view of the promising results in adults, phase I/II HT studies have also been performed in children and adolescents with recurrent or advanced malignancies including Ewing's tumours, aggressive fibromatosis, and germ cell tumours. Recent results in paediatric studies indicate the feasibility of both regional deep HT and whole body HT, and the best case analysis reveals promising response rates (CR + PR) as well as some long-term remissions. Technical modifications, due to the smaller body diameters, led to mean intratumoural temperatures in paediatric patients similar to those reported for adults in whom an improved outcome was demonstrated. The results in children and adolescents even suggest that introduction of HT into standard treatment protocols may be promising to improve tumour response and event-free survival in patients with poor risk malignancies of childhood.

Adolescent↗
PubMedDate not supplied

Association of HSP72 with the nuclear (TX-100-insoluble) fraction upon heating tolerant and non-tolerant HeLa S3 cells.

HSP72 levels in the cellular and the nuclear (TX-insoluble) fraction before and after heating of heat- and sodium arsenite-induced thermotolerant and non-tolerant HeLa S3 cells have been investigated by 1D- and 2D-electrophoresis, followed by Western blotting and immunostaining, using a newly developed monoclonal antibody that specifically detects HSP72 (Heine et al. 1991). HSP72 was constitutively expressed in HeLa S3 cells and elevated upon heat or arsenite stress. Immediate association of HSP72 with the nuclear fraction was induced by heat but not arsenite. However, at the time of maximal thermotolerance, elevated levels of HSP72 were found associated with nuclei isolated from both heat- and arsenite-induced thermotolerant cells. After (test) heat treatments (0-60 min at 45 degrees C) translocation of HSP72 to the nuclear fraction in all cells was observed, albeit with different kinetics and to different plateau values. When tolerant and non-tolerant cells were allowed to recover from a heat stress (at 37 degrees C) before isolation of the nuclei, no dissociation of HSP72 from the nuclear fraction was observed within a 5 h time period. Our data indicate that association/dissociation of HSP72 with/from the nuclear fraction is not related to the recovery from heat-induced intranuclear protein aggregation (Kampinga et al. 1992), nor to the extent of thermotolerance in the human HeLa S3 cell line.

Cell Nucleus↗
PubMedDate not supplied

Quality control of the SIGMA applicator using a lamp phantom: a four-centre comparison.

An elliptical phantom with a fat-equivalent ring and lamp matrix was developed for observing the power distribution in ring applicators used for regional hyperthermia. This phantom was used on four European BSD-2000-type therapy systems under routine conditions to test the quality of the SIGMA-60 applicator (systems in Berlin, Essen, Munich and Rotterdam). Frequency-dependent focusing imbalances were observed in all systems. At the time of the quality control test two of the systems displayed considerable errors in their settings. The system setups and possible ways of correcting errors are described in detail. Small maladjustments are caused by coupling effects between antennas and their surroundings and by interactions between the coaxial cables which supply the power. Serious distortions can be caused by phase errors and defects in cables or plugs; the latter can result in significant long-term restrictions on the ability to control the SAR (specific absorption rate) distribution in a way the user may not notice. The measurements gained from these four systems confirm the need for a practical and universal procedure for quality control in regional hyperthermia.

Europe↗