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Biomedical subjects

J Malec

Publications and source records attributed to J Malec.

At least 19 recordsLinked to original sources
PubMed1991

Comparison of the effect of hydroxyurea and methotrexate on DNA fragmentation at various reaction conditions.

Using the changes in DNA breakage as a marker of DNA damage, the direct action of hydroxyurea (HU) and methotrexate (MTX) on DNA was examined. The experimental design was to expose isolated DNA to HU and MTX alone or HU and MTX with accelerators of free radical reaction (H2O2, Fe..) and to determine DNA fragmentation assessed by electrophoresis. The results indicated that HU can damage DNA, but to demonstrate this ability it needs H2O2, Fe.. or prolonged incubation in solution. Unlike HU, MTX with H2O2 was ineffective; MTX with Fe.. at certain degree protected DNA against lesions induced by Fe.. alone. It is concluded that despite several common features of HU- and MTX-induced toxic side-effects in the cells suggesting interference of these drugs with free radical reactions, their direct effect on DNA under oxidizing conditions is quite different at least at the concentrations used by us.

DNA↗
PubMed1989

Enhancement of methotrexate-induced growth inhibition, cell killing and DNA lesions in cultured L5178Y cells by the reduction of DNA repair efficiency.

Acute treatment of L5178Y cells by methotrexate (MTX) caused concentration-dependent post-treatment growth inhibition and cell killing. The effects were potentiated in the presence of caffeine (CAF). At the same experimental conditions the CAF-dependent increase in mature and newly formed DNA lesions was found. The results suggest that even short MTX treatment can cause DNA lesions which are normally, at least partially, repaired. By the reduction of DNA repair efficiency with CAF, these lesions can be expressed what finds its reflection in the enhancement of MTX cytotoxicity.

Animals↗
PubMed1989

Hydroxyurea-induced toxic side-effects in animals and an attempt at reducing them with vitamins E and C.

Using the changes in several blood parameters and in the histological picture of the liver as markers of toxicity, the effect of hydroxyurea (HU) in healthy rabbits or mice was examined during two weeks after a single administration of this drug. In rabbits a transient significant decrease in blood erythrocyte count with a gradual increase in their osmotic resistance, a suppression of granulocyte phagocytic capacity, and an elevation of acid phosphatase activity in the serum were found. An increase in the proportion of lymphocytes without detectable lysosomes as tested by supravital staining also appeared. No significant difference was observed in the white cell count and lipoperoxide levels after HU administration. Histological picture of the liver, excised from HU-treated mice, indicated a marked hepatotoxicity of the drug. Some of the toxic effects were reduced in animals supplemented with vitamins E and C.

Acid Phosphatase↗
PubMed1988

Millon Clinical Multiaxial Inventory (MCMI) findings among breast clinic patients after initial evaluation and at 4- or 8-month follow-up.

Twenty-seven patients who subsequently underwent benign biopsy and 41 patients diagnosed to have breast cancer completed the Millon Clinical Multiaxial Inventory (MCMI) after initial examination in a breast problem clinic and again after 4 months or, for CA patients who were completing a course of chemo/radio-therapy, after 8 months. At initial testing, the trend toward fewer moderate-severe disorders among the benign biopsy (BB) group did not reach statistical significance. However, at follow-up, the difference was significant; the BB group showed fewer moderate-severe disorders (7.5%) than the cancer (CA) group (29%). Concordance of two-point peak elevations on scales 1-8, S, C, and P was examined. For the BB group, 56% had the same two high points on both testings, compared to only 27% of the CA group. Test-retest correlations on personality scales were generally lower for the CA group than for the BB group. We concluded that (1) approximately 30% of breast CA patients showed a disruption of psychological adjustment clearly severe enough to merit consideration of a mental health referral; (2) despite the frequency of significant distress, major affective and thought disorders were infrequent among this group; (3) distress associated with breast CA may interfere with the reliable assessment of long-standing personality traits.

Adaptation, Psychological↗
PubMed1988

Inhibition of leucocyte migration by cancer chemotherapeutic agents and its prevention by free radical scavengers and thiols.

The exposure of human blood in vitro to a range of concentrations of adriblastine, hydroxyurea, methotrexate, 5-fluorouracil, 6-mercaptopurine, cytosine arabinoside and nitrogen mustard induced reduction in leucocyte migration rate in all drug dilutions under study. The reduction was dose-dependent. This effect was used to examine the protection of alfa tocopherol, acetylosalicylic acid and thiourea against drug-induced cytotoxicity. It has been found that at the suitable concentration of the protecting agent, a preventive effect of tocopherol against toxicity of all drugs, except nitrogen mustard, can be achieved. Acetylosalicylic acid protected the cells against adriblastine, cytosine arabinoside, hydroxyurea and methotrexate toxicity. Thiourea prevented the toxic effect of adriblastine, fluorouracil, hydroxyurea, methotrexate and nitrogen mustard.

Antineoplastic Agents↗
PubMed1987

Protection of L5178Y cells by vitamin E against acute hydroxyurea toxicity does not change the efficiency of ribonucleotide reductase-mediated hydroxyurea-induced cytotoxic events.

Exposure of L5178Y cells in culture to 0.2 mM hydroxyurea (HU) for up to 48 h induces inhibition of DNA synthesis, killing of about 20% of cells during the first 24 h exposure, gradual progress of cells into the state of unbalanced growth (measured as progressive increase in cell size, DNA protein ratio and acid phosphatase activity) with final death of the majority of cells. These effects were used to compare effectiveness of rapid and late HU cytotoxicity in cells treated with HU in the presence or absence of vitamin E, employed as a protective agent against non-specific toxicity of HU. It has been found that while the presence of vitamin E prevents cell killing induced by HU treatment during first 24 h, its presence does not change the progress of cells into the state of unbalanced growth and final cell killing. It is suggested that the protection exerted by vitamin E against HU-induced side toxicity does not change the effectiveness of ribonucleotide reductase-mediated DNA synthesis inhibition, leading to cell death through the state of unbalanced growth.

Animals↗
PubMed1987

Modification by caffeine of acute cytotoxic response of cultured L5178Y cells to hydroxyurea treatment.

The effect of caffeine (CAF) on acute cytotoxic response of L5178Y lymphoblasts to hydroxyurea (HU) treatment was studied. The following events were examined: abnormal cell enlargement (giant cell formation), the rate of recovery of cell reproduction and DNA synthesis after releasing the cells from the HU blockage, parental DNA breakage and cell death. The presence of CAF at nontoxic concentration prevented giant cell formation, enhanced cell growth inhibition and cell killing. The effect of CAF was variable, dependent on the duration of exposure to HU and the time of exposure to CAF. To obtain maximal effect, the continuous presence of CAF during HU treatment and posttreatment time was necessary. Hydroxyapatite chromatography assay of single strand (ss) and double strand (ds) fractions in parental DNA and the measurement of the rate of post-treatment recovery of DNA synthesis indicated that CAF enhanced HU-induced DNA lesions. It is concluded that the results give further evidence that even short HU treatment can damage not only newly formed but also parental DNA. The lesions are normally, at least partly repaired and can be expressed under the conditions of DNA repair inhibition.

Animals↗
PubMed1986

Mechanism of unbalanced growth-induced cell damage. II. A probable relationship between unbalanced growth, DNA breakage and cell death.

This study examines the relationship between unbalanced growth, DNase II activity, DNA breakage and cell survival during the exposure of L5178Y cells to hydroxyurea (HU), excess thymidine (dThR) or HU with excess of four deoxyribonucleosides (dNR). It has been found that in the cells arrested by HU or dThR, but still appearing viable with the trypan blue exclusion test, Protein/DNA imbalance and abnormal cell volume are correlated with enhancement of DNase II activity in the cells and in the medium and with moderate increase in parental DNA breakage. The incidence of DNA breaks was markedly potentiated in the presence of non-toxic concentration of caffeine (CAF), used to inhibit DNA repair. In HU+dNR arrested cells, in which unbalanced growth was abolished, enhancement of DNase II activity and of DNA breakage in the presence or absence of CAF was substantially prevented. Comparison of posttreatment cell survival in the presence or absence of CAF confirmed the differential effect of CAF: while in HU or dThR arrested cells the presence of CAF induced marked cell killing, in HU+dNR arrested cells the influence of CAF was negligible. Only a slight effect of CAF was observed in cells in which dThR-induced arrest and unbalanced growth were reversed by deoxycytidine (dCR) addition. It is suggested that the involvement of DNA nucleases in the unbalanced growth-induced overproduction of numerous hydrolytic enzymes, with their progressive leakage through the cell membranes, can lead to progressive DNA digestion. DNA breaks produced in this way are normally, at least partly, repaired. Concomitant exposure of such cells to DNA repair inhibitor can markedly enhance the level of breaks, leading to potentiation of unbalanced growth-induced cell killing.

Animals↗
PubMed1986

Mechanism of unbalanced growth-induced cell damage. I. A probable role for hydrolytic enzymes synthesis.

This study examines the relationship between cell progress into the state of unbalanced growth, hydrolytic enzyme activities and cell survival during the exposure of L5178Y cells to hydroxyurea (HU), excess thymidine (dThR), hydroxyurea with excess of four deoxyribonucleosides (dNR) or excess dTHR with deoxycytidine (dCR). Cell progress into the state of unbalanced growth was measured as cell size, protein/DNA ratio and protein content per cell. Activities of two lysosomal (acid phosphatase, beta-N-acetylglucosaminidase) and one cytoplasmic non-lysosomal (LDH) enzymes were determined. It has been found that in cells arrested by HU or excess dThR, a progressive cell volume increase with protein/DNA imbalance is correlated with a progressive increase in lysosomal and non-lysosomal hydrolase activities in the cells and in the medium and with a marked lethal effect. Cell volume increase, enhancement of enzyme activities and cell killing could be prevented in HU-arrested cells by concomitant addition of excess dNR (deoxyadenosine, deoxyguanosine, thymidine, deoxycytidine) leading to equal inhibition of DNA and protein synthesis. Control-like values of all parameters were achieved also in cells in which the dThR-inhibiting effect was reversed by dCR addition. It is suggested that a common pathway in the mode of action of the chemotherapeutic agents inducing cell killing through the state of unbalanced growth can be the over-production, abnormal accumulation and progressive leakage of numerous hydrolytic enzymes through the cell membranes, leading in consequence to 'lytic' cell death.

Acetylglucosaminidase↗
PubMed1986

Effect of hydroxyurea treatment on lysosomal membrane stability and enzyme latency in L5178Y cells in culture.

The stability of lysosomes prepared from hydroxyurea (HU) treated or untreated L5178Y cells and exposed to an HU-free iso- or hypoosmotic solution was compared. The data revealed that exposure of the cells to 1-10 mM HU for few hours tends to stabilize lysosomes. Partial protection against this effect could be afforded by catalase and superoxide dismutase. Under the same conditions of HU treatment lysosomal enzyme latency remained similar in HU treated and untreated cells.

Acid Phosphatase↗
PubMed1985

Amelioration of hydroxyurea-induced suppression of phagocytosis in human granulocytes by free radical scavengers.

The exposure of human circulatory white cells in vitro to 0.1-1-10 mol/l hydroxyurea (HU) for 20 h induced a progressive dose-dependent suppression of the phagocytic activity of granulocytes. The suppressing effect of 20 h exposure to 1 mol/l HU was used to examine the protection afforded by free radical scavengers against HU-induced cytotoxicity. It has been found that, in the suitable concentration of the protecting agent, a substantial protective effect of sodium benzoate, acetylosalicylic acid, alpha-tocopherol, ascorbic acid, catalase, peroxidase or superoxide dismutase can be achieved.

Antioxidants↗
PubMed1985

Giant cell formation in cultured L5178Y lymphoblasts induced by hydroxyurea treatment.

The conditions leading to hydroxyurea-induced abnormal cell enlargement (giant cell formation) were studied in L5178Y lymphoblasts in the culture. Exposure for only 1 hour to a concentration of 1 mM hydroxyurea (HU) was sufficient to produce an abnormal enlargement of about 25 percent of the cells. The maximal proportion of giant cells reached the value of about 50 percent after treatment with 1 mM HU for 5 hours and was not changed by a further prolongation of exposure time and/or by increasing the concentration of HU to 10 mM. Comparison of cell populations with various proportions of giant cells as regards their ability to reproduce, DNA synthesis and persistence in the culture suggested that at least some part of giant cells lost the ability to divide, their DNA synthesis was markedly suppressed or retarded and more than 50 percent of them disappeared earlier than 48 hours after the termination of HU exposure. It is concluded that at least at certain HU concentrations and in suitable stage of target cells the response of cells to short HU treatment can resemble that produced by X-rays or other DNA damaging agents.

Cells, Cultured↗
PubMed1984

Hydroxyurea has the capacity to induce damage to human erythrocytes which can be modified by radical scavengers.

The treatment of human erythrocytes with hydroxyurea [HU] results in the azide-dependent changes in osmotic fragility and in increased methemoglobin formation. Similar changes were induced by H2O2 treatment. However when H2O2 in the presence of azide stimulated malondialdehyde production, in the HU-treated cells no malondialdehyde was detectable. When subjected to an oxidant stress [sodium ascorbate] HU-treated erythrocytes were more fragile and revealed changes in the absorption spectrum of the TBA-reactive material in comparison with the cells treated with ascorbate alone. Partial protection by radical scavengers against certain HU-induced changes can be achieved. The results indicate that HU can damage erythrocytes and suggest the radical origin of these effects.

Ascorbic Acid↗
PubMed1983

Alteration in lysosome supravital staining as a marker of hydroxyurea-induced cytotoxicity and its modification by radical scavengers in L5178Y cells in culture.

Supravital staining of lysosomal membranes with euchrysine was employed to study hydroxyurea (HU)-induced side toxic effects in L5178Y lymphoblasts in culture. Exposure of cells to 0.1-1.0-10.0 mM HU-induced progressive increase in the proportion of cells without detectable lysosomal fluorescence. This effect preceded the occurrence of non-viable cells, determined by trypan-blue exclusion test. Addition of alpha-tocopherol, acetylsalicylic acid, sodium benzoate or ascorbic acid to the culture medium afforded a concentration-dependent modification of lysosomal response to HU treatment. It is suggested that the fluorescence technique of supravital lysosome staining can be a useful test in studies on the side toxic effects of free radical-forming drugs and their amelioration by radical scavengers.

Animals↗