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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cigarette smoke polyphenolic agents (catechol and hydroquinone) that generate oxidants have been shown to be tumor promoters. Furthermore, oxidants can influence protein kinase C (PKC)-mediated signal transduction. Since terpenoid tumor promoters, phorbol esters, increase invasion and metastasis by activating PKC, we have determined whether polyphenolic agents present in the cigarette smoke condensate (CSC) could also influence these events. Hydroquinone (50 microM), catechol (500 microM), or CSC (50 micrograms/ml) induced an initial cytosol-to-membrane translocation of PKC in LL/2 lung carcinoma cells, followed by a later down-regulation of the enzyme. LL/2 cells treated with these CSC-related agents for a limited time (45 min) and exhibiting high membrane-associated PKC activity, when injected into mice through the tail vein, produced an increase in metastatic nodules in the lungs after 20 days. However, cells treated with CSC-related agents for a prolonged period did not exhibit an increase in metastasis. Agents that decrease the rate of production of reactive oxygen species, such as catalase either alone or in combination with superoxide dismutase, and a cell-permeable iron-chelator, o-phenanthroline, inhibited CSC-mediated membrane association of PKC and metastasis. Prior treatment of CSC with tyrosinase to modify polyphenols resulted in a partial loss of CSC stimulation of metastasis. Furthermore, a cell-permeable Ca2+ chelator and diverse PKC inhibitors, such as calphostin C, hypericin, chelerythrine, and bisindolylmaleimide, inhibited CSC-enhanced metastasis. CSC increased in vitro tumor cell adhesion to endothelial monolayers and to reconstituted basement membrane (Matrigel) and also enhanced the invasion through Matrigel coated on the polycarbonate filters in Transwells. All these CSC effects were found to be temporary and were blocked by the above mentioned antioxidant systems and PKC inhibitors. Thus, these results suggest that the oxidants generated by autooxidation of polyphenolic agents present in tobacco smoke increase tumor cell invasion and metastasis, at least in part by activation of Ca2+/PKC signal transduction. Conceivably, cigarette smoke constituents not only promote tumorigenesis but also may increase the spread of cancer in the body.
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PMID:Tobacco smoke tumor promoters, catechol and hydroquinone, induce oxidative regulation of protein kinase C and influence invasion and metastasis of lung carcinoma cells. 799 11

Bronchoalveolar lavage (BAL) was performed in 48 subjects: 22 healthy controls, 13 patients with pulmonary sarcoidosis Stage I and 13 patients with lung cancer. All diagnoses were pathologically and clinically confirmed. Cytocentrifuge preparations were made, air-dried and stained for cytochemical examination of alveolar macrophages (AM) using indexing and scoring methods for the evaluation of esterase activity, intracellular amounts of glycogen, lipids and iron. Significant differences were found in the cytochemical examination of enzyme activity of AM and intracellular metabolic and ionic state, depending on pathological processes and smoking habits. There was a linear correlation between alpha naphthyl esterase activity and iron content in AM in patients with squamous cell lung carcinoma and in patients with pulmonary sarcoidosis, which makes it possible to assign individual patients to one of the groups. Cytochemical examination of BAL specimens might be of great significance for the prevention and early diagnosis of various malignant and non-malignant lung diseases.
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PMID:The importance of cytochemical analysis of alveolar macrophages in the evaluation of their biological properties. 877 8

Several studies were conducted in cities of Liaoning Province, one of the areas of China with heavy concentrations of industry, to investigate the effects of life-style factors and environmental pollutants on lung cancer causation. A case-control study involving 1249 lung cancer patients and 1345 population-based controls was conducted in 1985-1988 in Shenyang, the capital of Liaoning. Cigarette smoking was found to be the principal cause of lung cancer in this population, accounting for 55% of the disease in males and 37% in females. There was also a significant increase in lung cancer risk associated with an overall index of indoor air pollution due to coal-burning emission. The population attributable risk (PAR) for indoor air pollution was 13% for males and 17% for females. Risks were significantly increased for workers in the non-ferrous smelter (odds ratio (OR) = 2.6, 95% CI, 1.3-5.1), chemical and drug manufacturing (OR = 3.0, 95% CI, 1.0-8.0), and the glass and pottery industry (OR = 1.6, 95% CI, 1.0-2.5). Studies in the Anshan Iron-Steel Complex showed a significant excess of lung cancer for workers exposed to a variety of dusts. A standardized proportional mortality ratio (SPMR) study of 8887 deaths during 1980-1989 among male workers of the complex indicated a 37% excess risk of lung cancer compared to residents of the city. A nested case-control study was then conducted in that complex. A total of 610 cases of lung cancer diagnosed during 1987-1993 and 959 randomly selected controls from 196 993 active and retired employees of the complex were interviewed. Historical monitoring records for dust and benzo(a)pyrene (B(a)P) were collected from 1956-1992 to calculate cumulative exposure for each person. Results suggested that risks were increased for all occupations in which there was exposure to dusts, with the highest risks seen among coke oven workers (OR = 3.5, 95% CI, 2.0-6.4) and fire-resistant brick makers (OR = 2.9, 95% CI, 1.9-4.4). Significant dose-response patterns between cumulative total dust, cumulative total B(a)P and lung cancer risk were observed. The findings suggest that smoking and environmental pollution combine to account for elevated rates of lung cancer in cities of northeastern China.
Lung Cancer 1996 Mar
PMID:Lifestyle, environmental pollution and lung cancer in cities of Liaoning in northeastern China. 878 60

Cytochemical examination of alveolar macrophages (AM) obtained by bronchoalveolar lavage (BAL) was performed in healthy volunteers (11 non-smokers and 11 smokers) and in 9 patients with squamous lung carcinoma (all of them smokers or ex-smokers) in order to analyze its peculiarities related to the smoking habit and to lung malignancy. Assessment of non-specific esterases: alpha-naphthyl acetate esterase (ANAE) and butyrate esterase (BUT), chloroacetate esterase (CHL), acid phosphatase (AcP), intracellular glycogen (PAS reaction), lipids (Sudan black B reaction-SBB) and iron (Perl's reaction) was performed by a semiquantitative cytochemical method (1). A significant correlation was obtained between BUT and stage of squamous lung carcinoma (varying between I and IV) (r = 0.52, p < 0.05). There was a correlation between BUT and Perl's in healthy controls (r = 0.76, p < 0.05). The same type of correlation was observed in control smokers (r = 0.64, p < 0.05), in addition to a correlation between CHL and AcP (r = 0.69, p < 0.05). There was no significant BUT/Perl's correlation in patients with squamous cell lung carcinoma (r = 0.23, p > 0.05), but significant AcP/CHL correlation as was observed in control smokers (r = 0.73, p < 0.05), and a "new" type of correlation was shown to exist between ANAE and SBB (r = 0.77, p < 0.05). In spite of the unresolved nature of lung cancer, correlation analysis of cytochemical parameters in AM might have an important part in the analysis of their relative contribution to the development of smoking-related disorders and lung malignancies.
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PMID:Correlation analysis of alveolar macrophage cytochemical parameters in smoking and pulmonary oncology. 934 37

The purpose of this study was to determine the safety, efficacy and impact on quality of life of recombinant human erythropoietin (r-HuEPO) for cancer patients undergoing radiotherapy (RT). An open-labelled randomized design was used, with patients randomized to either treatment or control arms. Patients in the treatment arm received r-HuEPO given by subcutaneous injection at a dose of 200 units kg(-1) day(-1) plus oral iron supplements (ferrous sulphate 325 mg p.o. t.i.d.). Entry was restricted to patients with carcinoma of the lung, uterine cervix, prostate or breast who presented for RT with anaemia parameters reflective of 'the anaemia of chronic disease'. Radiotherapy policies (portals, doses, fraction size, etc.) were determined by the site and stage of disease. Complete blood counts (CBCs) were obtained weekly. The target level of haemoglobin was 15 g dl(-1) for men and 14 g dl(-1) for women. Quality of life (QOL) was assessed weekly by using an analogue scale to judge energy, activities of daily living and overall quality of life. Forty-eight patients were entered in the study, 24 in the treatment arm and 24 in the control arm. The prerandomization demographic characteristics and mean laboratory values were comparable in both arms. The mean haemoglobin at completion was 13.6 g dl(-1) for r-HuEPO-treated patients compared with 11.0 g dl(-1) for control subjects (P = 0.0012). Patients who received r-HuEPO demonstrated a mean weekly haemoglobin increase of 0.41 g dl(-1) compared with a decrease in mean haemoglobin level in controls for 6 of the 7 weeks of the study (mean weekly decrease of 0.073 g dl(-1)). Target levels of haemoglobin were achieved by 41.6% of r-HuEPO-treated patients compared with none of the control subjects. The mean platelet count declined in both arms of the study with RT but the decline from pretreatment was less rapid in r-HuEPO-treated patients (11.2% decrease) compared with controls (26.3% decrease) and was statistically significant during weeks 4-6. Toxicity was minor with only mild irritation at the injection site. Mean quality of life end points were superior in the treatment arm but not statistically significant. r-HuEPO had a beneficial effect on weekly haemoglobin levels in patients undergoing RT with response rates similar to other studies. There was also a less rapid decline in weekly platelet counts in r-HuEPO-treated patients compared with control subjects. Further studies are needed to address the optimum dose and scheduling as well as the impact of r-HuEPO on clinical outcomes.
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PMID:Effect of subcutaneous recombinant human erythropoietin in cancer patients receiving radiotherapy: final report of a randomized, open-labelled, phase II trial. 966 81

Transferrin is a serum glycoprotein involved in iron transport. Transferrin acts also in cell growth regulation through membrane receptors. The number of transferrin receptors is increased in tumor and other rapidly dividing cells. This renders transferrin suitable for use in cytotoxic drugs targetting tumor cells. Paclitaxel was derivatized on 2' carbon and coupled with trasferrin using glutaraldehyde. The cytotoxicity of the conjugate was evaluated on small cell carcinoma of the lung cell line (H69). As compared to paclitaxel, the conjugate exhibited a slight decrease in cytotoxicity.
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PMID:In vitro cytotoxicity of paclitaxel-transferrin conjugate on H69 cells. 976 72

The reductive conversion of ribonucleotides to deoxyribonucleotides by ribonucleotide reductase (RR) is a crucial and rate-controlling step in the pathway leading to the biosynthesis of DNA, since deoxyribonucleotides are present in extremely low levels in mammalian cells. Mammalian ribonucleotide reductase (RR) is composed of two dissimilar proteins, often referred to as R(1), which contains polythiols and R(2), which contains non-heme iron and a free tyrosyl radical. Both the R(1) and R(2) subunits contribute to the active site of the enzyme. Currently, there are two broad classes of RR inhibitors. The first class includes nucleoside analogs which bind to the R1 subunit of the enzyme, several of which are in development. Among those, Gemcitabine and MDL 101,731 have demonstrated impressive efficacy against various solid tumors. Gemcitabine has now been approved for the treatment of pancreatic cancer and non-small cell lung cancer. The most promising second class of inhibitors of RR includes HCTs [alpha--(N)-heterocyclic carboxaldehyde thiosemicarbazones, e.g., 3-AP and 3-AMP], which exert enzyme inhibitory effect through high affinity binding with non-heme iron. Based on the clinical success achieved by Gemcitabine, it seems reasonable that a strong inhibitor of RR, which is essential for cellular replication, would be a useful addition to the existing therapeutic agents against cancer. In this chapter, we wish to report several highly efficient syntheses for both 3-AP and 3-AMP based upon palladium mediated Stille/Suzuki/Heck coupling reactions. Based upon the in vivo efficacy profile observed with these two agents, 3-AP was chosen over 3-AMP as the candidate for further optimization with the intention to improve its biological and pharmaceutical properties. In this vein, we have completed the synthesis of two water soluble phosphate containing prodrugs and one disulfide-linked prodrug of 3-AP. As expected, bioconversion study using either alkaline phosphatase or glutathione showed that these prodrugs were indeed converted to the parent 3-AP. When evaluated against the murine M-109 lung carcinoma as well as the B16-F10 murine melanoma xenograft models, the newly prepared phosphate prodrugs displayed improved efficacy and safety profiles than that found with the parent. More significantly, the ortho-phosphate prodrug 21 demonstrated impressive antitumor effect using once-a-day dosing regimen. In summary, the results disclosed herein demonstrated that some of 3-AP prodrugs prepared indeed demonstrated improved pharmaceutical, biological and toxicity profiles over the parent 3-AP. Efforts directed towards further optimization of 3-AP prodrugs as novel anticancer agents is clearly warranted.
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PMID:Syntheses and antitumor activities of potent inhibitors of ribonucleotide reductase: 3-amino-4-methylpyridine-2-carboxaldehyde-thiosemicarba-zone (3-AMP), 3-amino-pyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) and its water-soluble prodrugs. 1117 70

Cancer-related causes of anaemia include anaemia of chronic disorders, infections, autoimmune haemolysis associated with malignant conditions, bone marrow invasion by the tumour or clonogenic marrow dysfunction, iron, folate, or vitamin B 12 deficiency and bleeding from tumour erosion. Treatment-related anaemia results from chemotherapy, radiotherapy and bone marrow fibrosis. Severe anaemia increases the burden of treatment, contributes to fatigue, reduces the quality of life and may also delay or limit further treatment. Blood transfusion is currently the most common form of treatment and patients rarely require transfusion unless the haemoglobin is less than 8 g/l. It is often difficult to predict which patients will develop anaemia and require treatment, but the proportion of patients receiving transfusions increases markedly if the pre-treatment haemoglobin concentration is below 10 g/dl. Four studies have systematically evaluated the effects of erythropoietin on anaemia in lung cancer patients and each of these trials is likely to contribute information concerning the clinical benefit of erythropoietin in treating or preventing treatment-related or disease-related anaemia. Most of the improvements in quality of life observed with erythropoietin administration occurred with haemoglobin levels between 10 and 12 g/dl, and not with levels between 7 and 10 g/dl, with a plateau effect above 12 g/dl. Consequently, a 'functional' level of haemoglobin that appears to be more important is 12 g/dl, because it may be favourably associated with a significant improvement in fatigue compared with lower haemoglobin levels. This 'functional' level would be in keeping with the body's physiological erythropoietin response.
Lung Cancer 2001 Dec
PMID:Role of erythropoietin in the treatment of lung cancer associated anaemia. 1174 10

Anthracyclines are included in clinical treatments against various malignancies, but severe cardiotoxic side-effects and the development of resistance mechanisms limit their usefulness. Many aspects of the cellular response to anthracyclines remain debated. The status of the main regulator of iron homeostasis, namely the RNA-binding activity of iron regulatory proteins (IRPs), has been assessed herein for two types of human tumor cells and their derived doxorubicin-resistant sublines. IRPs were always fully activated in the latter, whereas only partial activation occurred in the former. Doxorubicin exposure reversibly inactivated IRP1 in small cell lung carcinoma (GLC(4)) and myelogenous leukemia (K562) cell lines, but was without effect in their derived doxorubicin-resistant sublines. In contrast, adding doxorubicin to cytosolic fractions of untreated cells or to purified IRPs led to the irreversible alteration of the RNA-binding activity of IRP1. In these different conditions, interaction between doxorubicin and the iron regulatory system disturbs iron metabolism, and cells having developed a resistance mechanism are tuned to maximize the iron supply. The results reported herein may lead the path toward a better therapeutic management of cancer patients receiving doxorubicin by discriminating between the antiproliferative and cardiotoxic properties of this anthracycline.
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PMID:Interactions between doxorubicin and the human iron regulatory system. 1258 65

Both NADH dehydrogenase (complex I) and aconitase are inactivated partially in vitro by superoxide (O2-.) and other oxidants that cause loss of iron from enzyme cubane (4Fe-4S) centers. We tested whether hypoxia-reoxygenation (H-R) by itself would decrease lung epithelial cell NADH dehydrogenase, aconitase, and succinate dehydrogenase (SDH) activities and whether transfection with adenoviral vectors expressing MnSOD (Ad.MnSOD) would inhibit oxidative enzyme inactivation and thus confirm a mechanism involving O2-. Human lung carcinoma cells with alveolar epithelial cell characteristics (A549 cells) were exposed to <1% O2-5% CO2 (hypoxia) for 24 h followed by air-5% CO2 for 24 h (reoxygenation). NADH dehydrogenase activity was assayed in submitochondrial particles; aconitase and SDH activities were measured in cell lysates. H-R significantly decreased NADH dehydrogenase, aconitase, and SDH activities. Ad.MnSOD increased mitochondrial MnSOD substantially and prevented the inhibitory effects of H-R on enzyme activities. Addition of alpha-ketoglutarate plus aspartate, but not succinate, to medium prevented cytotoxicity due to 2,3-dimethoxy-1,4-naphthoquinone. After hypoxia, cells displayed significantly increased dihydrorhodamine fluorescence, indicating increased mitochondrial oxidant production. Inhibition of NADH dehydrogenase, aconitase, and SDH activities during reoxygenation are due to excess O2-. produced in mitochondria, because enzyme inactivation can be prevented by overexpression of MnSOD.
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PMID:Mitochondrial complex I, aconitase, and succinate dehydrogenase during hypoxia-reoxygenation: modulation of enzyme activities by MnSOD. 1266 64


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