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)

The correct classification of carcinoma of the lung is not only of therapeutic and prognostic importance but is also considered to have epidemiological and aetiological significance. Histological tests for mucin are essential in the classification of lung tumours but there is little information available about the influence of the method of detection used on the results of classification. Five established staining techniques were tested using paraffin blocks from surgical specimens of 81 human lung tumours diagnosed as adenocarcinoma, i.e. tumours of WHO Type III. Mowry's alcian blue-periodic acid-Schiff (AB-PAS) technique gave the highest proportion of positives (93%) slightly fewer (90%) being obtained by the PAS technique alone. Both these methods were influenced by the presence of cytoplasmic hyaline globules, structures which cannot be regarded as mucin. The stain recommended by the World Health Organization was also influenced by the presence of hyaline globules, was less frequently positive than the PAS techniques and was considered to have no special advantages. The aldehyde fuchsin-alcian blue sequence was positive in only 83% of cases but provided some information about the type of mucin present. Southgate's mucicarmine also detected mucin in only 83% of cases. It was concluded that the apparent incidence of adenocarcinomas may be influenced by staining methods used. Some standardization of technique is desirable and the AB-PAS combination appears to be the most satisfactory.
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PMID:A comparison of different methods of detecting mucin in adenocarcinomas of the lung. 4 91

Bovine serum albumin nanospheres (BSA-NS), prepared with glutaraldehyde cross-linking and ultrasonication, were coated with antibodies by covalent linkage (Schiff's base formation) of aldehyde groups at the surface of the nanospheres with amino groups of the antibody. The coating was confirmed using Fluorescein isothiocyanate which conjugates with antibodies and also by the antigen-antibody interaction using Sepharose beads. Rapid in vitro degradation of BSA-NS was first confirmed by incubating a radioactive nanosphere suspension at 37 degrees C in 0.25 M sucrose solution with 1% liver or lung extract. The radioactive compound conjugated BSA-NS suspension was then administered to mice intravenously, and tissue distribution of BSA-NS was examined using whole body autoradiography; the BSA-NS were found to be localized mainly in the liver, the lungs and the kidneys and 4 hr and 24 hr after injection, almost all radioactivity had disappeared except for that in the kidneys. The binding ratio of monoclonal antibodies to tumor cells in vitro was found to be 2-2.5 times greater than that of control antibodies (mouse IgG) by means of a gamma ray counter. An in vivo binding test showed that monoclonal antibodies might recognize the target organ (Lewis lung carcinoma). Applying these findings, BSA-NS coated with monoclonal antibodies were found to be trapped in the tumoral tissue of Lewis lung carcinoma-bearing mice more than in controls (BSA-NS coated with mouse IgG) at 24 hr after the injection. Thus, BSA-NS offer potential as useful drug carriers enabling concentration of drugs at specific target sites. Furthermore, their rapid elimination from the body and their degradability suggest that side effects due to long-lasting accumulation in several organs may be avoided.
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PMID:Preparation and evaluation of bovine serum albumin nanospheres coated with monoclonal antibodies. 325 26

Bronchitis, asthma, and cystic fibrosis, marked by inflammation and mucus hypersecretion, can be caused or exacerbated by airway pathogens or irritants including acrolein, an aldehyde present in tobacco smoke. To determine whether acrolein and inflammatory mediators alter mucin gene expression, steady-state mRNA levels of two airway mucins, MUC5AC and MUC5B, were measured (by RT-PCR) in human lung carcinoma cells (NCI-H292). MUC5AC mRNA levels increased after >/=0.01 nM acrolein, 10 microM prostaglandin E2 or 15-hydroxyeicosatetraenoic acid, 1.0 nM tumor necrosis factor-alpha (TNF-alpha), or 10 nM phorbol 12-myristate 13-acetate (a protein kinase C activator). In contrast, MUC5B mRNA levels, although easily detected, were unaffected by these agonists, suggesting that irritants and associated inflammatory mediators increase mucin biosynthesis by inducing MUC5AC message levels, whereas MUC5B is constitutively expressed. When transcription was inhibited, TNF-alpha exposure increased MUC5AC message half-life compared with control level, suggesting that transcript stabilization is a major mechanism controlling increased MUC5AC message levels. Together, these findings imply that irritants like acrolein can directly and indirectly (via inflammatory mediators) increase airway mucin transcripts in epithelial cells.
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PMID:Regulation of human airway mucins by acrolein and inflammatory mediators. 1019 52

Acrolein is a highly reactive unsaturated aldehyde formed endogenously and present in the environment. Acrolein efficiently reduces glutathione-contents and is highly cytotoxic in two lung carcinoma cell lines (A-427 and SK-LU-1) and the glioblastoma cell line A-172. A-427, which has the lowest GSH content of the cell lines, is also more sensitive to growth inhibition and more depleted in GSH after acrolein exposure. A-427 is also highly sensitive to docosahexaenoic acid (22:6 n-3, DHA) and acrolein potentiates the cytotoxic effect of DHA in this cell line, but not in the DHA-resistant cell lines SK-LU-1 and A-172. Surprisingly, the cytotoxic effect of acrolein was partially reversed by vitamin E, selenite and 2-phenyl-1,2-benzisoselenazol-3(2H)-one (ebselen, a Se-glutathione peroxidase mimic) in A-427 cells, but not in SK-LU-1 and A-172 cells. Using the TUNEL assay a strong nuclear fluorescence was observed in DHA-treated A-427 cells, indicating death by apoptosis, whereas acrolein apparently did not induce apoptosis.
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PMID:Acrolein cytotoxicity and glutathione depletion in n-3 fatty acid sensitive- and resistant human tumor cells. 1022 83

A series of new 7-iminomethyl derivatives of camptothecin were obtained from camptothecin-7-aldehyde and aromatic, alicyclic and aliphatic amines. Their hydrogenation led to the corresponding amines. All the imines and the less polar amines showed a marked increase of the cytotoxic activity against H460 non-small lung carcinoma cell line, with respect to topotecan. The lipophilicity of the substituent in position 7 of camptothecin seems to play an important role for cytotoxic potency. The 7-phenyliminomethyl derivative showed efficacy comparable to topotecan in vivo against NSCLC H460 xenografted in athymic nude mice.
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PMID:Novel cytotoxic 7-iminomethyl and 7-aminomethyl derivatives of camptothecin. 1121 94

In an attempt to synthesize potential anticancer agents acting by inhibition of topoisomerase I (Topo I) a new series of oxyiminomethyl derivatives in position 7 of camptothecin (CPT) was prepared. The synthesis relied on the condensation of 20S-CPT-7-aldehyde or 20S-CPT-7-ketones with alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl O-substituted hydroxylamines. The compounds were tested for their cytotoxic activity in vitro against H460 non-small lung carcinoma cell line, the activity being for 24 out of 37 compounds in the 0.01-0.3 microM range. A QSAR analysis indicated that lipophilicity is the main parameter correlated with cytotoxicity. Investigation of the DNA-Topo I-drug cleavable complex showed a rough parallelism between cytotoxicity and inhibition of Topo I. Persistence of the DNA cleavage after NaCl-mediated disruption of the ternary complex suggests that for the most potent compounds, e.g., 15, the cytotoxicity was at least in part related to stabilization of the complex, as also supported by the persistence of the DNA-enzyme complex in drug-treated cells. The in vivo antitumor efficacy of the most potent analogue (15) was evaluated in direct comparison with topotecan using human lung tumor xenograft models. In the range of optimal doses (2-3 mg/kg), the improved efficacy of 15 was documented in terms of inhibition of tumor growth and rate of complete response.
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PMID:Novel 7-oxyiminomethyl derivatives of camptothecin with potent in vitro and in vivo antitumor activity. 1156 25

Glycation of nucleotides in DNA forms AGEs (advanced glycation end-products). Nucleotide AGEs are: the imidazopurinone derivative dG-G [3-(2'-deoxyribosyl)-6,7-dihydro-6,7-dihydroxyimidazo[2,3-b]purin-9(8)one], CMdG ( N (2)-carboxymethyldeoxyguanosine) and gdC (5-glycolyldeoxycytidine) derived from glyoxal, dG-MG [6,7-dihydro-6,7-dihydroxy-6-methylimidazo-[2,3-b]purine-9(8)one], dG-MG(2) [ N (2),7-bis-(1-hydroxy-2-oxopropyl)deoxyguanosine] and CEdG [ N (2)-(1-carboxyethyl)deoxyguanosine] derived from methylglyoxal, and dG-3DG [ N (2)-(1-oxo-2,4,5,6-tetrahydroxyhexyl)deoxyguanosine] derived from 3-deoxyglucosone and others. Glyoxal and methylglyoxal induce multi-base deletions, and base-pair substitutions - mostly occurring at G:C sites with G:C-->C:G and G:C-->T:A transversions. Suppression of nucleotide glycation by glyoxalase I and aldehyde reductases and dehydrogenases, and base excision repair, protects and recovers DNA from damaging glycation. The effects of DNA glycation may be most marked in diabetes and uraemia. Mutations arising from DNA glycation may explain the link of non-dietary carbohydrate intake to incidence of colorectal cancer. Overexpression of glyoxalase I was found in drug-resistant tumour cells and may be an example of an undesirable effect of the enzymatic protection against DNA glycation. Experimental overexpression of glyoxalase I conferred resistance to drug-induced apoptosis. Glyoxalase I-mediated drug resistance was found in human leukaemia and lung carcinoma cells. Methylglyoxal-mediated glycation of DNA may contribute to the cytotoxicity of some antitumour agents as a consequence of depletion of NAD(+) by poly(ADP-ribose) polymerase, marked increases in triosephosphate concentration and increased formation of methylglyoxal. S - p -Bromobenzylglutathione cyclopentyl diester is a cell-permeable glyoxalase I inhibitor. It countered drug resistance and was a potent antitumour agent against lung and prostate carcinoma. Glyoxalase I overexpression was also found in invasive ovarian cancer and breast cancer.
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PMID:Protecting the genome: defence against nucleotide glycation and emerging role of glyoxalase I overexpression in multidrug resistance in cancer chemotherapy. 1464 Oct 66

Acyloxyalkyl ester prodrugs of histone deacetylase inhibitors, a family of anti-cancer agents, are metabolized intracellularly to acids and aldehyde(s). The purpose of this study was to assess the in vitro and in vivo anticancer activity, selectivity and oral bioavailability of these prodrugs. The prodrugs exhibited a hierarchal potency of AN-193 > or = AN-7 > AN-1 and AN-9 >> AN-10 against murine lung carcinoma (3LLD122) and human breast carcinoma (MCF-7) cell lines. AN-9, and to even greater extent AN-7, displayed preferential cytotoxicity against leukemic and glioblastoma cells compared to their normal cellular counterparts-normal mononuclear and astrocytes cells, respectively. In vivo, anti-metastatic activity was evaluated in a metastatic model of lung cancer in which Lewis lung carcinoma (3LLD122) cells are injected intravenously into C57/BL mice and produce lung nodules. The prodrugs administered orally demonstrated a significant inhibition of lung-lesion formation and their hierarchal potency concurred with that observed in vitro, with the exception of AN-193 that was the least active compound. Escalating doses of AN-7 (5-100 mg/kg), administered by oral or intraperitoneal routes and displayed equivalent anti-metastatic activities, confirmed the good oral bioavailability of AN-7. Consistent with these findings, a time course study of histone acetylation in subcutaneously implanted 3LL122 tumors showed 2-4 fold increases in histone acetylation within 0.5 h of intravenous, intraperitoneal, or oral administration of AN-7 (100 mg/kg). Relative contributions of the prodrug metabolites to the anti-neoplastic activity and the best candidate for clinical studies are discussed.
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PMID:The selectivty and anti-metastatic activity of oral bioavailable butyric acid prodrugs. 1650 48

Cyclophosphamide (CP), a widely used antineoplastic agent, is metabolized to species responsible for both the therapeutic and toxic effects of this drug. Acrolein is believed to be the primary toxic metabolite. This alpha,beta-unsaturated aldehyde reacts rapidly with glutathione (GSH) and can then be further metabolized to the mercapturic acid derivatives. The toxicities of the acrolein-glutathione adduct, 3-oxopropyl glutathione (oxoPrGSH) and the acrolein mercapturic acid derivatives S-3 oxopropyl N-acetylcysteine (oxoPrMCA) and S-3 hydroxypropyl N-acetylcysteine (hydroxyPrMCA) have not been fully tested. OxoPrMCA, hydroxyPrMCA and oxoPrGSH were synthesized. The toxicities of these compounds, along with those of CP and acrolein, were assessed by measuring their effects on the growth of human type II A549 lung carcinoma cells using the alamarBlue assay. Each compound was incubated with A549 cells under serum-free conditions for 2 hr, followed by 94 hr more growth in the presence of fresh medium with serum. A 50% reduction in cell growth 72 hr after treatment was achieved with 83 muM oxoPrMCA or 4 muM acrolein. No significant toxicity was seen with hydroxyPrMCA (10 mM) or oxoPrGSH (5 mm). CP (5 mM) also had no effect on the growth of A549 cells under these conditions. This latter finding is consistent with previous evidence that CP requires metabolic activation to exert its toxicity. When present during xenobiotic exposure, GSH (2 mm) almost completely protected against the growth inhibition caused by 1 mM oxoPrMCA or 10 mum acrolein. N-Acetylcysteine (1 mM) also prevented the toxicity caused by 1 mM oxoPrMCA and provided significant protection against the growth inhibition induced by 10 muM acrolein. These data support the concept that toxicity from oxoPrMCA may be due to the release of acrolein.
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PMID:Differential toxicities of cyclophosphamide and its glutathione metabolites to A549 cells. 2065 59

The cytotoxicity of 39 compounds, including eighteen flavonoids (flavanones, 1-10; flavones, 11-17; flavanol, 18), sixteen phenolic acid derivatives (aromatic acids, 19-24; aldehyde, 25; esters, 26-34) and five glycerides (35-39), isolated from Mexican propolis, were evaluated against a panel of six different cancer cell lines; murine colon 26-L5 carcinoma, murine B16-BL6 melanoma, murine Lewis lung carcinoma, human lung A549 adenocarcinoma, human cervix HeLa adenocarcinoma and human HT-1080 fibrosarcoma. A phenylpropanoid-substituted flavanol, (2R,3S)-8-[4-phenylprop-2-en-1-one]-4',7-dihydroxy-3',5-dimethoxyflavan-3-ol (18), showed the most potent cytotoxicity against A549 cells (IC50, 6.2 microM) and HT-1080 cells (IC50, 3.9 microM), stronger than those of the clinically used anticancer drug, 5-fluorouracil (IC50, 7.5 microM and 5.4 microM, respectively). Based on the observed results, the structure-activity relationships are discussed.
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PMID:Cytotoxicity of constituents from Mexican propolis against a panel of six different cancer cell lines. 2112 Dec 57


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