Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Early passaged bovine pulmonary artery endothelial cells exposed to 0.1-2.0 ng/ml transforming growth factor-beta 1 (TGF-beta 1) showed concentration-dependent growth inhibition, as assessed by [3H]thymidine labeling and cell counts, over a 96-h interval. Most of the inhibition of [3H]thymidine labeling measured at 96 h persisted when the medium was replaced with TGF-beta 1-free medium after 24 h, but the inhibition of labeling was prevented by the presence of anti-TGF-beta 1 antibody in the replacement medium. Additions of 2 mM cysteine, 1 mM cystine, or 2 mM N-acetylcysteine at the time of the initial addition of TGF-beta 1 blocked the inhibitory effect of TGF-beta 1 on [3H]-thymidine labeling when this was assessed after 72-96 h, but not at earlier times. Prevention of the inhibitory effect on cellular proliferation produced by cysteine, cystine and N-acetylcysteine was associated with elevation of cellular glutathione that was present at 48-96 h. There was no evidence for direct inactivation of TGF-beta 1 by the thiol-amino acids. Conditioned medium from TGF-beta 1-treated endothelial cells inhibited proliferation of mink lung carcinoma (CCL64) cells, supporting a previously reported concept of autocrine production of TGF-beta 1 by the endothelial cells. The inhibitory action of the conditioned medium was partially prevented when 1 mM cysteine was added during conditioning. Thus, TGF-beta 1 treatment of endothelial cells appears to set off autocrine production by these cells of TGF-beta 1 that perpetuates the inhibition of cellular proliferation. Replenishment of cellular glutathione with thiol-amino acids counteracts the growth-inhibitory effect of TGF-beta 1 through a currently undefined mechanism.
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PMID:Modulation of transforming growth factor-beta 1 antiproliferative effects on endothelial cells by cysteine, cystine, and N-acetylcysteine. 143 Jan 95

As an adjunct to cancer chemotherapy, we had succeeded in creating the methionine depletion in vivo, using the technique of total parenteral nutrition (TPN) by infusing an amino acid solution devoid of methionine and cysteine, as sole nitrogen source (Met-deplet. TPN). In Experiment 1, we demonstrated that the marked depletion of thiol was induced both in the liver and tumor tissues by Met-deplet. TPN in Sato lung carcinoma (SLC)-bearing rats. Then in Experiment 2, we also confirmed the presence of the enhancing effect on nimustine hydrochloride (ACNU) in Met-deplet. TPN to SLC. The tumor proliferation was inhibited significantly by Met-deplet. TPN even in conjunction with a small dose of ACNU, which showed no anti-tumor effect on the rats treated with methionine-containing amino acid solution, without apparent increase of the side effects in comparison with those in the control groups. On the other hand, to determine the carcinostatic effect on tumor-bearing animals, not only the size of the tumor but also its components, especially the percentage of necrotic tumor tissue (necrotic index), were considered to be important.
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PMID:Thiol depletion and chemosensitization on nimustine hydrochloride by methionine-depleting total parenteral nutrition. 212 63

The activity of the thiol-dependent enzyme glyceraldehyde-3-phosphate dehydrogenase (GPD), in vertebrate cells, was modulated by a change in the intracellular thiol:disulfide redox status. Human lung carcinoma cells (A549) were incubated with 1-120 mM H2O2, 1-120 mM t-butyl hydroperoxide, 1-6 mM ethacrynic acid, or 0.1-10 mM N-ethylmaleimide for 5 min. Loss of reduced protein thiols, as measured by binding of the thiol reagent iodoacetic acid to GPD, and loss of GPD enzymatic activity occurred in a dose-dependent manner. Incubation of the cells, following oxidative treatment, in saline for 30 min or with 20 mM dithiothreitol (DTT) partially reversed both changes in GPD. The enzymatic recovery of GPD activity was observed either without addition of thiols to the medium or by incubation of a sonicated cell mixture with 2 mM cysteine, cystine, cysteamine, or glutathione (GSH); GSSG had no effect. Treatment of cells with buthionine sulfoximine (BSO) to decrease cellular GSH by varying amounts caused a dose-related increase in sensitivity of GPD activity to inactivation by H2O2 and decreased cellular ability for subsequent recovery. GPD responded in a similar fashion with oxidative treatment of another lung carcinoma cell line (A427) as well as normal lung tissue from human and rat. These findings indicate that the cellular thiol redox status can be important in determining GPD enzymatic activity.
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PMID:Cellular recovery of glyceraldehyde-3-phosphate dehydrogenase activity and thiol status after exposure to hydroperoxides. 229 24

Creation of an amino acid imbalance, particularly curtailment of L-methionine, at the tumor cell level is thought to have a favorable effect on the inhibition of tumor growth. In the present study, we examined the influence of a specially-formulated amino acid mixture, avoid of sulfur-containing amino acids (L-methionine and L-cysteine), on the growth and amino acid fraction of Sato lung carcinoma (SLC) and the host metabolism in SLC-bearing rats. The rats were treated by total parenteral nutrition containing the above amino acid mixture, plus other nutrients (methionine-deprived TPN) for 10 days. Tumor growth began to decrease 4 days after the start of this treatment and the size was significantly less at the end of the treatment than in rats receiving conventional TPN with general purpose Vuj-N type amino acid solution as a protein source. The tumor-to-carcass weight ratio also showed a similar trend. In biochemistry, the albumin level and albumin-to-globulin ratio were significantly lower than in the rats receiving conventional TPN but other parameters such as total protein, glucose, GOT and GPT were not affected by the treatment. In the amino acid fraction of the tumor tissue extraction, both L-methionine and L-tyrosine were decreased and L-serine was increased significantly compared with the control group.
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PMID:Influence of L-methionine-deprived total parenteral nutrition on the tumor tissue and plasma amino acids fraction and the host metabolism: experimental study with Sato lung carcinoma-bearing rats. 249 79

When given orally in combination with L-cysteine, 5'-deoxy-5-fluorouridine (DFUR) brought about a significant reduction in the growth of adenocarcinoma 755 and a significant prolongation of life-span in mice bearing Lewis lung carcinoma without increased toxicity to the host as compared with DFUR alone, though L-cysteine alone did not show an appreciable antitumor activity. Moreover, the combination of DFUR and L-cysteine resulted in a marked retardation of growth of human colon tumor LS174T transplanted into nude mice. Thus, the potency of DFUR was increased by L-cysteine. Pharmacokinetic studies revealed that after DFUR administration, plasma DFUR and 5-fluorouracil (5-FU) levels rapidly declined, but that, in the combination with L-cysteine, the plasma clearances of DFUR and 5-FU were slowed down considerably. In the tumor, DFUR and 5-FU levels were similar to those in the plasma. Such a prolongation of DFUR and 5-FU levels in plasma and tumor may produce the enhancement of antitumor effect seen with the combination of DFUR and L-cysteine.
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PMID:Enhanced antitumor effect of 5'-deoxy-5-fluorouridine by oral administration with L-cysteine. 252 59

Glutathione (GSH) depletion sensitizes human lung carcinoma (A549-T27) cells to the cytotoxic effects of Cd++. The effects of GSH depletion on Cd++ accumulation and Cd++-induced metallothionein (MT) content were investigated to determine the possible role of these Cd++ responses in the sensitization process. Cellular GSH was depleted to 20% to 25% of control levels with buthionine sulfoximine (BSO), or diethyl maleate (DEM), respectively. Neither treatment significantly affected Cd++-induced accumulation of exogenous 35s-cysteine into intracellular MT in a dose-dependent fashion. The results indicate that neither enhanced Cd++ accumulation nor reduced MT synthesis plays a primary role in affecting enhanced Cd++ cytotoxicity in A549 cells with reduced GSH levels. Although BSO inhibition of GSH synthesis enhanced MT synthesis, it sensitized the cells to Cd++, which suggests an additive effect of GSH and MT in cadmium cytoprotection. This observation also raises the possibility that intracellular cysteine levels limit Cd++-induced MT accumulation rates.
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PMID:Enhanced cadmium cytotoxicity in A549 cells with reduced glutathione levels is due to neither enhanced cadmium accumulation nor reduced metallothionein synthesis. 259 84

Intracellular glutathione (GSH) content of human lung carcinoma cells, A549, in log phase was 25 +/- 5 nmol/10(6) cells, which is considerably higher than that reported in other tumor cells. After partial depletion of GSH with diethyl maleate (DEM), addition of cystine to the medium allowed full resynthesis of GSH in 4 hr, cysteine in the same time period led to less resynthesis, and methionine provided minimal resynthesis. Using cystine as the sole sulfur source and with buthionine sulfoximine (BSO, 5 mM) included in the medium after cells were depleted with DEM, inhibition of both cystine uptake and resynthesis of GSH occurred. BSO inhibited [35S]cystine uptake (as early as 10 min) in a concentration-dependent process, ranging from a 28% decrease for 1 microM BSO to an 85% decrease for 100 microM BSO compared to the control cells after 240 min of incubation. In addition, GSH resynthesis from [35S]cystine for 240 min was inhibited in a parallel dose-dependent manner, in that 1 microM BSO caused a 27% decrease and 100 microM BSO provided a 75% decrease from control values. BSO did not inhibit the uptake of [35S]methionine, but inhibited the low amount of resynthesis of GSH when methionine was the sole sulfur source. BSO did not inhibit the uptake of arginine, phenylalanine, and leucine. DL-, L-, and methyl ester-BSO each inhibited [35S]cystine uptake and incorporation into GSH to a similar extent. The half-life of GSH was 3.5 +/- 0.4 hr in A549 cells that were grown in complete medium with GSH synthesis occurring.
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PMID:Buthionine sulfoximine inhibition of cystine uptake and glutathione biosynthesis in human lung carcinoma cells. 397 6

The homologue of the viral Kirsten ras (v-Ki-ras) gene found in the human lung carcinoma cell line, Calu-1, has an intron-exon structure similar to that of the human homologue of the viral Harvey ras (v-Ha-ras) gene. A second, potential fourth coding exon is present in the human Ki-ras gene and similar sequences are found in the Kirsten murine sarcoma virus. Cysteine is encoded at the twelfth amino acid position, suggesting that the Calu-1 Ki-ras gene has undergone a mutational activation at the same position as the human Ha-ras gene of the bladder carcinoma cell line, T24. A comparison of their predicted amino acid sequences suggests that ras proteins have a 'constant' region and a 'variable' region. Here we propose a common modular structure for ras gene products in which the variable region forms a physiologically important combining site.
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PMID:Structure of the Ki-ras gene of the human lung carcinoma cell line Calu-1. 630 65

Cellular nonprotein thiols (NPSH) consist of glutathione (GSH) and other low molecular weight species such as cysteine, cysteamine, and coenzyme A. GSH is usually less than the total cellular NPSH, and with thiol reactive agents, such as diethyl maleate (DEM), its rate of depletion is in part dependent upon the cellular capacity for its resynthesis. If resynthesis is blocked by buthionine-S,R-sulfoximine(BSO), the NPSH, including GSH, is depleted more rapidly, Cellular thiol depletion by diamide, N-ethylmaleimide, and BSO may render oxygenated cells more sensitive to radiation. These cells may or may not show a reduction in the oxygen enhancement ratio (OER). Human A549 lung carcinoma cells depleted of their NPSH either by prolonged culture or by BSO treatment do not show a reduced OER but do show increased aerobic responses to radiation. Some nitroheterocyclic radiosensitizing drugs also deplete cellular thiols under aerobic conditions. Such reactivity may be the reason that they show anomalous radiation sensitization (i.e., better than predicted on the basis of electron affinity). Other nitrocompounds, such as misonidazole, are activated under hypoxic conditions to radical intermediates. When cellular thiols are depleted peroxide is formed. Under hypoxic conditions thiols are depleted because metabolically reduced intermediates react with GSH instead of oxygen. Thiol depletion, under hypoxic conditions, may be the reason that misonidazole and other nitrocompounds show an extra enhancement ratio with hypoxic cells. Thiol depletion by DEM or BSO alters the radiation response of hypoxic cells to misonidazole. In conclusion, we propose an altered thiol model which includes a mechanism for thiol involvement in the aerobic radiation response of cells. This mechanism involves both thiol-linked hydrogen donation to oxygen radical adducts to produce hydroperoxides followed by a GSH peroxidase-catalyzed reduction of the hydroperoxides to intermediates entering into metabolic pathways to produce the original molecule.
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PMID:The role of thiols in cellular response to radiation and drugs. 668 10

6-Ethynyluracil (3) was prepared by two different synthetic procedures. In one approach, 6-formyluracil was reacted with (dibromomethylene)triphenylphosphorane to give 6-(2,2-dibromovinyl)uracil (2), which was silylated and treated with phenyllithium to yield 3. Alternatively, silylated 6-iodouracil was reacted with trimethylsilylacetylene in dry triethylamine in the presence of a palladium/copper catalyst to give 6-[(trimethylsilyl)ethynyl]uracil (5). Compound 5 was converted to 3 in refluxing methanol. At neutral pH, 3 reacted with thiols, such as glutathione, 2-mercaptoethanol, and L-cysteine, but did not react with glycine or L-lysine. This reaction was accompanied by a shift in the UV maximum of 3 from 286 nm to 321-325 nm. The reaction of 3 with 2-mercaptoethanol gave cis-6-[2[(2-hydroxyethyl)-thio]vinyl]uracil as the predominant product. Compounds 2 and 3 inhibited the growth of leukemia L1210, B-16 melanoma, and lewis lung carcinoma cells at concentrations ranging from 1 x 10(-6) to 2 x 10(-5) M. As determined with L1210 cells, the inhibition of growth caused by 2 and 3 was not prevented by the natural pyrimidines, indicating that the agents do not act as antimetabolites.
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PMID:Synthesis and biological evaluation of 6-ethynyluracil, a thiol-specific alkylating pyrimidine. 714 68


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