Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protective effects of intracellular glutathione (GSH) against the cytotoxicity of human recombinant tumor necrosis factor (TNF) were investigated. Three tumor cell lines (L-M, B-16, HeLa) were used as target cells. Exposure of these cells to buthionine sulfoximine (BSO) or diethyl maleate (DEM) resulted in the depletion of intracellular GSH content to 5.2-43.0% of control values and enhancement of their susceptibility to TNF cytotoxicity. The hydroxyl radical production in L-M cells stimulated by TNF was increased by treatment with BSO or DEM. These results are consistent with the suggestion that intracellular GSH exerts its protective function against the cytocidal effect of TNF by inhibiting the hydroxyl radical production stimulated by TNF.
 ...
PMID:Suppressive effects of intracellular glutathione on hydroxyl radical production induced by tumor necrosis factor. 217 72

Radiation interacts with biological systems to produce many types of molecular lesions. Much of the molecular damage is of little consequence with regard to cell killing. The lesions that are most likely to contribute to cell killing are DNA lesions produced by clusters of radicals. The formation of clusters of radicals is characteristic of ionizing radiation and accounts for its high efficiency as a cytotoxic agent. The mechanism by which these lesions kill cells is probably the formation of DNA double-strand breaks, ultimately resulting in chromosomal breaks. There is a possibility that some of the other types of molecular lesions produced by radiation may participate in more subtle mechanisms of cell damage. For instance, radiation induces a self-destructive process (apoptosis) in certain cell types, and the molecular lesions that initiate this process have not been identified. Glutathione (GSH) is a versatile protector. Several distinct mechanisms of radioprotection by GSH can be identified. These include radical scavenging, restoration of damaged molecules by hydrogen donation, reduction of peroxides and maintenance of protein thiols in the reduced state. Of these mechanisms, hydrogen donation to DNA radicals is probably the most important. Since competing reactions are very rapid, this mechanism requires a high concentration of GSH. Radioprotection by hydrogen donation to DNA radicals is not effective in oxygenated cells because the normal intracellular GSH concentration is not sufficient for effective competition with oxygen. Consequently, moderate depletion of GSH has no effect on the radiosensitivity of oxygenated cells. Under hypoxic conditions GSH becomes more competitive, and GSH depletion can markedly affect radiosensitivity. The radiosensitivity of hypoxic cells is most affected by GSH depletion in the presence of low concentrations of radiosensitizers. Since hypoxic cells are a characteristic feature of tumors, moderate depletion of GSH in combination with treatment with hypoxic cell radiosensitizers appears to be a promising strategy for selective tumor sensitization in radiation therapy. Oxidation of GSH can result in radiosensitization of both hypoxic and oxygenated cells. The mechanism of this effect appears to involve oxidation of protein thiols which are important for DNA repair. In principle, modification of DNA repair could have a greater impact on radiation therapy than modification of the number of lesions produced by radiation. However, a strategy for modification of GSH or protein thiol redox state in vivo has not yet been devised.
 ...
PMID:Role of glutathione in the radiation response of mammalian cells in vitro and in vivo. 219 53

The in vitro interaction of mercury, copper (II) and cadmium with human glutathione transferase (GST) pi was studied using reduced glutathione (GSH) and 1-chloro-2,4-dinitrobenzene as substrate. Tumor specific human GST pi was isolated from the human hepatoma derived PLC/PRF/5 cell line. The inhibition of the GST pi activity was dose dependent. Kinetic studies never revealed competitive inhibition. A parabolic inhibition was found with GSH as the variable substrate. The heavy metals are spontaneously conjugated with GSH and cysteine, but interact with GST pi by direct binding to this protein. This binding could have a protective function against heavy metals.
 ...
PMID:In vitro interaction of mercury, copper (II) and cadmium with human glutathione transferase pi. 221 73

After twenty years, understanding the mechanisms of tumor cells kill by anthracyclines still remains an active area of research. Of many mechanisms described for this class of drugs, efforts in the last year have focused on defining the role of free radical formation, topoisomerase II-induced DNA breakage, and P-170-dependent cellular accumulation of anthracyclines in tumor cell kill and resistance. First, in a number of tumor cell lines, the formation of free radical species from anthracyclines has been implicated in the cell killing. Modulation of detoxification pathways in a drug-resistant cell line e.g depletion of GSH, a substrate for peroxidase and transferase, enhanced both the formation of oxy-radicals and adriamycin cytotoxicity. It should be noted, however, that these findings are not true for every cell line examined, and free radical-mediated tumor kill may be cell- or tissue-specific. Second, anthracyclines-mediated topo II-dependent DNA cleavage was observed in most cell lines and reduced breaks were found in resistant cells. The decrease in single-strand breaks, however, neither correlated with the degree of resistance nor with differences in the relative topo II activity, which was in most cases only two-fold less in resistant cells than in sensitive cells. Finally, the reduced accumulation of the drug does not appear to be the only contributing factor in multidrug resistant cells and P-170 is not the only protein overexpressed in certain cells, e.g., an 85,000 Da protein may also be linked to adriamycin resistance. Although GST protein is overexpressed in most adriamycin resistant cells along with mdr1 gene, current evidence suggests that this protein may not be directly involved in adriamycin resistance. Taken together, both the mechanism of action and resistance to this class of drug likely vary among cell lines. Clinical studies in the past year have brought about interesting refinements in anthracycline-containing chemotherapy; ICRF-187 (by itself also cytotoxic) seems to offer protection against cardiac toxicity, while implicating iron in the mediation of cardiac damage. Out of a large number of newer anthracycline derivatives, clinical evidence indicates only a modest increase in therapeutic index with a few analogs, perhaps idarubicin and epirubicin. It is not yet clear that being able to receive more milligrams (or more cycles) of anthracycline eventually translates into a significantly better response rate or in a survival advantage. Much less clear is whether patients refractory to adriamycin may derive any benefit from newer anthracyclines.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Anthracyclines. 222 2

The effect of glutathione (GSH) depletion on the interaction of hyperthermia (HT) and single-dose external-beam radiation delivered at conventional dose rates (RT) and low-dose-rate brachytherapy (BT) was examined in a murine mammary adenocarcinoma (MTG-B). Tumour volume growth delay from the day of treatment to double the treatment volume (GDDV) was used as the experimental end-point. The growth delay for radiation alone was greater when combined with GSH depletion, while this level of GSH depletion produced no effect on the BT alone or HT alone response. The synergism ratio (SR) was calculated for all HT and RT or HT and BT protocols at each dose. Although depletion did not increase the SR for external-beam treatments, the SR for HT and BT treatments was increased with GSH depletion.
 ...
PMID:The effect of in vivo GSH depletion on thermosensitivity, radiosensitivity and thermal radiosensitization. 225 Jan 20

Several halogenated alkenes are nephrotoxic; some others induce renal tubular adenocarcinomas in rodents after lifelong administration. A bioactivation mechanism accounting for the organ-selective tumor induction has been elucidated: conjugation of the parent compounds with glutathione (GSH), catalyzed by hepatic GSH S-transferases, results in the formation of haloalkyl and halovinyl glutathione S-conjugates. Formation of S-conjugates (identified by NMR and mass spectrometry) could be demonstrated with trichloroethene, tetrachloroethene, hexachlorobutadiene, perfluoropropene, trichlorotrifluoropropene, and dichloroacetylene in incubations with rat liver microsomes and in the isolated perfused rat liver. The GSH conjugates formed are eliminated from the rat liver with the bile and may be translocated to the kidney, intact or after metabolism to the corresponding cysteine S-conjugates that are metabolized in the kidney by renal tubular cysteine conjugate beta-lyase (beta-lyase) to reactive intermediates, most likely thioacylchlorides and thioketenes. Interaction of these potent electrophiles with DNA [demonstrated for intermediates formed from S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine] causes mutagenicity in bacteria, genotoxicity in cultured renal cells, and cytotoxicity in kidney cells. As an alternative to beta-lyase-catalyzed cleavage, the cysteine S-conjugates may be acetylated to the corresponding mercapturic acids, which have been identified in urine. The ability of the kidney to concentrate GSH and cysteine S-conjugates and the intensive metabolism of GSH S-conjugates to cysteine S-conjugates in this organ are evidently responsible for the organotropic carcinogenicity.
 ...
PMID:A mechanism of haloalkene-induced renal carcinogenesis. 227 3

Though various chemotherapy protocols lead to considerable response rates in squamous cell head and neck cancer (SCHNC), the overgrowth of a tumor cell phenotype which no longer responds to clinically achievable drug concentrations regularly impairs definite tumor control. In order to investigate mechanisms of drug resistance towards one of the most active agents in SCHNC we established four Cisplatin (CDDP)-resistant sublines (DDP1-DDP4) of the recloned human SCHNC cell line HLac 79. The 50% inhibitory drug concentration (IC50) of CDDP as determined by the colorimetric MTT-assay was increased by the factors 2.7 (DDP1), 3.3 (DDP2), 5.1 (DDP3), and 6.4 (DDP4) in the respective sublines. Three subpopulations contained significantly elevated glutathione (GSH) levels by the factors 1.4 (DDP3), 1.7 (DDP2), and 2.4 (DDP4) compared to the maternal line (50.2 nM/mg protein). DDP4 showed increased activity of gamma-glutamyl-transpeptidase (1.83 vs. 1.21 mU/mg protein), and DDP2 and DDP4 showed increased activity of GSH-S-transferase (35.6 and 51.9 vs. 25.1 mU/mg protein). Concerning both GSH-peroxidase and GSH-reductase no significant differences between the HLac 79 subpopulations were observed. Intracellular CDDP accumulation determined by neutron activation analysis revealed reduced drug uptake in DDP3 and DDP4 (60% and 76% of control value).
 ...
PMID:Establishment and characterization of cisplatin-resistant sublines of the human squamous carcinoma cell line HLac 79. 228 22

By treating a human tumor cell line with various concentrations of diamide, we explored the relationship between extent and duration of protein and nonprotein thiol oxidation, initiation of DNA double-strand break rejoining after X-rays, and the degree of radiosensitization. We also examined the relationship between protein thiol status and the non-protein thiol, glutathione (GSH). A549 cells were irradiated and incubated postirradiation with 0, 100, 300 or 500 microM diamide for 1 h. The dose of radiation required to give 10% survival decreased from 4.8 Gy to 3.2 Gy with 300 microM and to 2.7 Gy with 500 microM diamide (enhancement ratios of 1.5 and 1.8, respectively) but was not significantly affected by 100 microM diamide. The time of initiation of double-stranded DNA rejoining after X-irradiation (DNA repair) was delayed by 300 and 500 microM diamide. Furthermore, DNA rejoining began only after total cellular protein thiol content recovered to 55% of pretreatment levels for both concentrations. Intracellular GSH/GSSG ratios decreased immediately after diamide addition to less than 1. Large decreases in GSH/GSSG ratio preceded significant loss of protein thiols, but protein-glutathione mixed disulfides accounted for a minor percentage of the total protein thiol oxidized (up to 20%). We believe that diamide-induced protein thiol loss, and not GSH oxidation, is related to the cessation of DNA strand rejoining after X-irradiation, thereby affecting survival.
 ...
PMID:Diamide induced shift in protein and glutathione thiol: disulfide status delays DNA rejoining after X-irradiation of human cancer cells. 229 69

Recent studies have suggested that differences in the initial low-dose region of the radiation survival curves for human tumor cells might explain the differences in clinical response of tumors to fractionated radiation treatment. In this study, which is described in two companion papers, we investigated this hypothesis directly using animal model systems. In the present paper we determined in vitro radiation survival curves for eight murine tumor cell lines of varying histopathological type and: (a) measured survival at the 2 Gy and 8 Gy dose levels, (b) fitted parameters to the linear quadratic and two component multi-target equation models of cellular survival and (c) calculated mean inactivation doses. We found that the choice of the data fitting procedure affected the absolute value, relative ranking, and power to discriminate between the cell lines of these calculated parameters. A detailed statistical study indicated that the measured surviving fraction at 2 Gy (SF2) was the best discriminant of intrinsic radiosensitivity between the eight tumor cell lines. When these same cell lines were assayed for intracellular glutathione (GSH) levels, no correlation was found between levels of GSH and the SF2 value. Determining the SF2 value may be the method of choice to describe the low-dose region of the radiation survival curve, as it precludes the necessity of choosing a model to fit the survival data, it has excellent discriminatory powers, and it represents the survival in the radiotherapeutically relevant region of the in vitro radiation survival curve. Furthermore, as demonstrated in the companion paper, it correlates with cell survival in the tumors following 10 fractions of 2 Gy given in vivo.
 ...
PMID:Comparison between in vitro radiosensitivity and in vivo radioresponse of murine tumor cell lines. I: Parameters of in vitro radiosensitivity and endogenous cellular glutathione levels. 229 17

The success of antineoplastic chemotherapy in head and neck carcinoma is limited by the insufficient primary chemosensitivity of the tumor and/or the decrease of drug efficacy in the course of treatment. As regards cisplatin (CDDP) this phenomenon of chemoresistance may be closely associated with glutathione (GSH) metabolism since GSH is responsible for the detoxication of active CDDP hydrolysates. In the human squamous carcinoma cell line HLac 79, selective inhibition of GSH synthesis by buthionine sulfoximine (BSO) led to enhanced CDDP chemosensitivity both in vitro and in vivo. Using the colony-forming assay GSH depletion of HLac 79 tumor cells of more than 90% (Table 1) resulted in a dose modifying factor of 2 (Table 2). Combined treatment of HLac 79 tumor-bearing nude mice with BSO and CDDP brought about significant increase in mean survival time (p less than 0.001) as compared to the CDDP-treated group. The possible role of BSO as chemosensitizer is discussed.
 ...
PMID:[Increasing chemosensitivity to cisplatin by glutathione depletion with buthionine sulfoximine. In vitro and in vivo studies with a human squamous cell cancer line]. 231 Apr 56


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>