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Biomedical subjects

M Edgren

Publications and source records attributed to M Edgren.

At least 19 recordsLinked to original sources
PubMed1996

Estramustine-binding protein (EMBP) in renal cell carcinoma immunohistochemistry, immunoscintigraphy and in vitro estramustine effects.

The present report shows that the human renal cell carcinoma (RCC) cell lines, A498 and CAKI-2, express the estramustine-binding protein (EMBP). The RCC cell lines investigated were highly sensitive for estramustine, with cell arrest in atypical metaphase. In vitro experiments using a fluorimetric cytotoxicity assay (FMCA) showed a pronounced cytotoxic effect mediated by estramustine. Immunohistochemical analysis of tumour specimens from patients with RCC showed positive staining for EMBP in 12/16 cases. Immunoscintigraphy was performed in an experimental system in nude mice, heterotransplanted with the CAKI-2 cell line. A radiolabelled monoclonal anti-EMBP antibody was used. The results show a specific uptake of the antibody in the RCC tumour, expressed as a percentage of the injected dose per gram tissue, which ranged from 4.03 to 6.9. The results obtained form the basis for clinical studies on the feasibility of utilizing estramustine in the management of RCC. Immunoscintigraphy using the monoclonal anti-EMBP antibody is of potential use for in vivo characterization of the malignancy and in the selection patients suitable for treatment with estramustine.

Adult↗
PubMed1993

The 'X model': a modified version of the competition theory.

In 1985, Edgren et al. proposed a modified version of the competition theory to explain the interaction of sensitizers and protectors with target molecules damaged by radiation, which was designated the 'X' model. This model incorporates concepts which have been considered previously, namely that a type of radiation damage exists which cannot be chemically repaired, and that cells may contain a naturally occurring sensitizer. The model leads to testable predictions, such as, e.g. the crossing of 'K curves' when the level of protection is varied. It can only be applied to the immediate effects of radiation, i.e. before enzymatic reactions play a part. The present paper is a summary of work carried out since 1985 to test the predictions of the 'X' model and an exposition of the related algebra.

Animals↗
PubMed1991

Comparative study of two human melanoma cell lines with different sensitivities to mustine and cisplatin.

The cytotoxic effects of the bifunctional DNA-reactive drugs cisplatin, mustine and melphalan were studied in two human melanoma cell lines, RPMI 8322 and A 375. A 375 cells were 3.0 times more sensitive to cisplatin and 1.5 times more sensitive to mustine than RPMI 8322 cells. In contrast, A 375 cells were less sensitive to melphalan than RPMI 8322 cells. The increased sensitivity of A 375 cells was parallelled by an increased induction of DNA interstrand crosslinks following exposure to cisplatin and mustine. After cisplatin exposure A 375 cells also showed higher levels of platinum-DNA intrastrand adducts than RPMI 8322 cells. The increased effect of cisplatin in A 375 cells was not due to an increased drug accumulation in these cells. The higher sensitivity of A 375 cells to cisplatin may be related to lower intranuclear levels of glutathione, compared to RPMI 8322 cell nuclei, while the sensitivity to mustine may depend on lower overall levels of glutathione than in RPMI 8322 cells.

Cell Line↗
PubMed1991

Radioprotection by dithiothreitol (DTT) at varying oxygen concentrations: predictions of a modified competition model and theory evaluation.

Cultures of Chinese hamster cells were treated with dithiothreitol (DTT) at varying concentrations, and exposed to radiation aerobically or at various oxygen tensions. The extent of radioprotection by DTT was calculated using the yield of DNA strand breaks as a measure of the radiation response. The curve of protection factors (PF) had a specific pattern, characterized by low PF values at low and high oxygen tensions with a peak at an intermediate tension. The peak value of the PF was increased and shifted to higher oxygen tensions as DTT concentrations increased. The experimentally observed pattern of the PF curves is incompatible with the Alper model of the competition hypothesis, which assumes that the entire radiation injury can be modified by sensitizers or protectors. On the other hand, the pattern is consistent with a model (X model) which is based upon a modification of the original hypothesis and assumes two types of radiation injury, only one of which is modifiable.

Animals↗
PubMed1990

Radiosensitization by oxygen and radioprotection by thiols: analysis of the combined action according to a modified competition model.

Cultures of Chinese hamster fibroblasts were treated with dithiothreitol (DTT) and irradiated under aerobic or hypoxic conditions. Protection factors (PF) and oxygen enhancement ratios (OER) were calculated with DNA breakage as the criterion of the radiation effects, and related to the intracellular concentration of non-protein-bound thiols (NPSH). When the increment of the cellular NPSH was in a low concentration range, the PF values were smaller for aerobically than for hypoxically irradiated cells. In contrast, in the case of cells with a large increase in NPSH concentration, the PF values for the hypoxically irradiated cells were smaller. As a consequence the PF curve of the hypoxically and aerobically exposed cells crossed, and OER values followed a bell-shaped curve with respect to increasing cellular NPSH concentrations. The observations could be explained by assuming a competition between the damage-restituting and damage-fixing reactants, and postulating that only a certain proportion of the damaged targets is reparable.

Animals↗
PubMed1989

Cellular glutathione content and K values. II.

After exposure to radiation in the presence of different oxygen concentrations, the OER values were determined for human fibroblasts cell strains with differing intrinsic GSH content, and cells depleted of GSH to different extent by treatment with BSO. The yield of DNA single-strand breaks was used as the measure of radiosensitivity. The K values were found to be related specifically to the GSH concentration in the cell nuclei. A good agreement was found between the experimental observations and the prediction of a variant of the competition model in which a second type of damage, not influenced by oxygen, was included.

DNA Damage↗
PubMed1988

Effect of D,L-buthionine-S,R-sulfoximine on cytotoxicity and DNA cross-linking induced by bifunctional DNA-reactive cytostatic drugs in human melanoma cells.

The effects of D,L-buthionine-S,R-sulfoximine (BSO) on cytotoxicity and DNA cross-linking induced by bifunctional DNA-reactive cytostatic agents in a human melanoma cell line (RPMI 8322) were investigated. RPMI 8322 cells were exposed to 0.01 mM BSO for 24 h, which resulted in a decrease in cellular glutathione to 14% without any reduction of cell proliferation or plating efficiency. BSO pretreatment significantly enhanced cytotoxicity of melphalan with a dose modification factor (DMF) of 3.4 and nitrogen mustard (HN2) (DMF 3.3). The increased cytotoxicity was paralleled by similar increases in DNA cross-linking (melphalan: DMF 2.2, HN2: DNF 2.5). A small but significant potentiation by BSO of cis-diamminedichloroplatinum(II) toxicity was seen (DMF 1.5), with a corresponding minor but significant increase in DNA cross-linking (DMF 1.1). Similarly, the potentiation of bis-chloroethylnitrosurea toxicity was small but significant (DMF 1.1), with no significant increase in DNA cross-linking (DMF 1.0). No effect of BSO pretreatment on the rate of removal of HN2-induced DNA cross-links was observed. Thus, the observed sensitization of RPMI 8322 cells to melphalan, HN2, cis-diamminedichloroplatinum(II), and bis-chloroethylnitrosourea was correlated to similar changes in drug-induced DNA cross-linking. Despite the increased cytotoxicity and DNA cross-linking BSO did not significantly increase the intracellular concentration of intact melphalan. These findings support the hypothesis that the potentiation of the cytotoxicity of bifunctional alkylating agents by BSO is due to an increased DNA cross-linking caused by a reduced intracellular conjugation of drug with glutathione, which results in an increased binding of drug to DNA targets.

Antineoplastic Agents↗
PubMed1987

Cellular glutathione content and K values.

The K values for two cell strains with differing intrinsic GSH concentrations have been measured with the yield of DNA breaks as end-point of the radiation effect. The K value of the strain with reduced GSH content was decreased (1.59 microM O2) in comparison to the K value (3.01 microM O2) for the strain with a normal GSH content. The significance of the observation is discussed in relation to competition models. All variants of the competition model agree in predicting a reduction of K, if GSH is reduced.

Cells↗
PubMed1986

Chemical competition in target radical reactions: numerical simulation of the theory and comparison with measured oxygen effect on DNA damage in cells.

An intracellular radiation-chemical reaction scheme is tested in which solute and solvent radicals R. react with non-target molecules Sa (scavengers) or with target molecules (presumed to be DNA) to produce target radicals T., which may also be produced by direct ionization of DNA. The rate of target radical decomposition to become 'uncommitted damage' that the cell may repair is affected by the concentration of oxygen (O2), thiols (S) and electronaffinic sensitizers (F), which compete with one another to form, respectively, target products TO2, TS and TF. This uncommitted damage is then subject to biochemical modification, including molecular repair, by the cell. The rate equations for this competing reaction scheme were written and programmed for computer simulations of changes in oxygen, thiol and electronaffinic sensitizer concentrations. A reaction scheme that also includes some non-radical target damage was also simulated. Simulations were made using available experimental data concerning intranuclear concentrations and reaction rate constants, respectively, ko, ks and k1 for the reactions T. + O2----TO2, T. + S----TS and T. + F----TF, which produce uncommitted chemical damage. Experimental data on strand-break induction in glutathione-proficient and glutathione-deficient cells, in cells treated with thiol active agents, and in cells treated with hypoxic sensitizers, along with the computer simulations, generally agree that thiol molecules can react with target radicals to reverse T. in competition with O2 and/or electronaffinic sensitizers. Forward reaction rate constants ko, ks (dithiothreitol), ks (glutathione) and k1 (misonidazole) in the approximate ratio 10:0.3:0.02:0.4 satisfied the above reaction scheme, and approximately 5 per cent non-radical target molecule damage could be included with satisfactory agreement with experimental data.

DNA↗
PubMed1985

Glutathione requirement for the rejoining of radiation-induced DNA breaks in misonidazole-treated cells.

The role of glutathione (GSH) in the rejoining of radiation-induced single-strand DNA breaks (ssb) was studied in human fibroblast cultures sensitized to radiation by a 30 min treatment with 1 mM misonidazole (MISO). Hypoxically irradiated cells, deficient in GSH, either inherently, or due to a 16 h incubation with 1 mM buthionine sulphoximine (BSO), rejoined the breaks after MISO treatment at a lower rate and to a lesser extent than did GSH-proficient cells. Without MISO treatment, the hypoxically induced ssb were rejoined in the GSH-deficient cells as effectively as in the proficient cells. It is concluded that a large proportion of the breaks which arise after hypoxic irradiation in the presence of MISO are of a different type to those which arise in the absence of the drug, and require a particular GSH-dependent, enzymatic repair system. This requirement for rejoining in hypoxically irradiated, MISO-treated cells is similar to that seen earlier in MISO-untreated, oxically irradiated cells, and suggests that the ssb induced by radiation in the presence of MISO or oxygen are of a similar nature.

Buthionine Sulfoximine↗
PubMed1985

Combined effect of misonidazole and glutathione depletion by buthionine sulphoximine on cellular radiation response.

Chinese hamster cells (V79) and glutathione-proficient (GSH+/+) and glutathione-deficient (GSH-/-) human fibroblasts were treated with a glutathione (GSH)-depleting agent buthionine sulphoximine (BSO) and the hypoxic radiosensitizer misonidazole (MISO), separately or in combination. Subsequently, the cells were exposed to X-rays. Determination of the yield of single-strand DNA breaks (ssb) immediately after irradiation indicated no effect of BSO or MISO treatment when radiation exposure was made aerobically. Assuming that ssb determined immediately after irradiation reflects mainly the effect of radical processes, the results obtained with BSO and MISO, singly and in combination, agreed well with the predictions of a modified version of the 'competition model' using V79 and GSH+/+ cells. Some results obtained with GSH-/- cells could not be so explained.

Animals↗
PubMed1984

Glutathione-dependent yield and repair of single-strand DNA breaks in irradiated cells.

The yield and rejoining of single-strand DNA breaks (ssb) was investigated after irradiation of cells which were deficient in glutathione (GSH) either due to a genetic defect of their GSH synthetase activity, or inhibition of gamma-glutamylcysteine synthetase activity by DL-buthionine-SR-sulfoximine (BSO). The results were concordant in indicating that decreased cellular GSH content is associated with an increased yield of ssb after anoxic, but not after aerobic radiation exposures. Rejoining of ssb was delayed and incomplete during a one hour's incubation period after oxic, but not after anoxic exposure of GSH-deficient cells. The defective rejoining capacity of these cells was restituted to nearly normal by the admixture of GSH-proficient cells in the incubation medium.

Buthionine Sulfoximine↗