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

We have examined regulation of the glutathione S-transferase pi gene by transient expression assay, and find that a fragment from 8 to 99 bp upstream of the cap site promotes transcription, but there is no evidence for any enhancer activity in a further 6 kb of flanking sequence. Analysis of this sequence by reference to a primate sequence database and Southern blotting revealed that as much as 5 kb of this flanking DNA were composed of repetitive insertion elements including an Alu and a LINE 1 repeat. The promoter fragment has been sequenced (Cowell et al (1988) Biochem. J. 255, 79-83) and contains a consensus AP1 binding site; in some cases, these have been associated with transcriptional induction by phorbol esters and ras oncogenes. We measured the steady state levels of glutathione S-transferase pi mRNA in human cell lines which were known to express ras oncogenes and compared them to human cell lines which have not been identified with ras activation. There was no correlation between expression of activated ras and expression of glutathione S-transferase pi mRNA. Treatment of HeLa cells, HepG2 cells and a small cell lung carcinoma line, GLC 8, with the phorbol ester 12-O-tetradecanoylphorbol 13-acetate failed to alter the steady state levels of endogenous glutathione S-transferase pi mRNA. The differences between these results and those of similar studies on rat glutathione S-transferase subunit 7, a structural orthologue of glutathione S-transferase pi, are discussed.
 ...
PMID:Control of expression of the human glutathione S-transferase pi gene differs from its rat orthologue. 278 23

A 6.4-fold cis-diamminedichloroplatinum(II) (CDDP) resistant human small cell lung carcinoma cell line (GLC4-CDDP) was developed to study acquired CDDP resistance in vitro. Compared to the sensitive cell line (GLC4), the GLC4-CDDP showed an increase in doubling time and a decrease in cloning efficiency, cellular size, double minutes per cell, cellular protein, and nuclear protein content. While a complete cross-resistance for tetraplatin and a partial cross-resistance for doxorubicin, melphalan, cadmium chloride, carboplatin, and cis-dichloro-trans-dihydroxo-cis-bis(isoprolylamine)platinum (IV) (resistance factor, respectively,4.0,5.8,2.1,1.5,2.9) was found, no cross-resistance for vincristine was found. In the GLC4-CDDP line in comparison to the GLC4 line, glutathione and total amount of sulfhydryl compounds was significantly increased, while glutathione S-transferase and glutathione reductase was the same. The platinum content in cells and nuclei was lower in the resistant line, but after correction for cellular protein or volume no difference was found. The amount of platinum bound to DNA was significantly lower in the GLC4-CDDP line. After a 1-h incubation with CDDP, the amount of Pt-GG adducts was the same and the amount of interstrand cross-links was reduced in the GLC4-CDDP line as compared to GLC4. In conclusion, in the GLC4-CDDP line the phenotype and genotype are changed and various mechanisms, such as decreased Pt-DNA binding, elevated glutathione, and reduced interstrand cross-links, play a role in the development of the CDDP resistance.
 ...
PMID:Characterization of a human small cell lung carcinoma cell line with acquired resistance to cis-diamminedichloroplatinum(II) in vitro. 284 61

Expression of glutathione S-transferase placental form (GST-pi) in human lung carcinoma tissue taken at autopsy or biopsy was investigated immunohistochemically. All of 34 cases of squamous cell carcinomas, including poorly, moderately and well-differentiated examples were shown to stain positively for GST-pi. Poorly differentiated adenocarcinomas were, however, negatively stained (0/5 cases), while moderately and well differentiated adenocarcinomas were found to stain with GST-pi at rates of 69% (9/13 cases) and 71% (5/7 cases), respectively. Six cases of small cell carcinomas examined were all negative. The results indicate that GST-pi may be a useful marker for non-small cell type lung cancer, especially squamous cell carcinoma which is in agreement with findings for rat lung neoplastic lesions reported previously.
 ...
PMID:Expression of the glutathione S-transferase placental form in human lung carcinomas. 284 80

Primary rat hepatocellular tumours, induced by a combination of diethylnitrosamine and 2-acetylaminofluorene, were examined for the presence of neuroendocrine peptides by immunocytochemical methods. Two-thirds of the tumours showed positive immunostaining for either neuron-specific enolase (NSE), protein S-100 or bombesin. NSE was commonly observed both in hepatocarcinomas and in neoplastic nodules, whereas protein S-100 was more frequently seen in carcinomas (49% positive) than in nodules (13% positive). Bombesin, previously shown to function as an autocrine growth factor in small-cell carcinoma of the lung, was present in neurosecretory granules in 13% of the nodules and 29% of the carcinomas. Normal, preneoplastic and peritumorous liver tissue, including the frequent atypical foci present in the latter two categories, was uniformly negative for all neuroendocrine markers. The foci, like the nodules and carcinomas, generally stained positively for the liver tumour marker glutathione S-transferase type P (GSTP). The results suggest that dysdifferentiation of altered hepatocytes in a neuroendocrine direction may be a common, late event in liver carcinogenesis which could possibly contribute to tumour formation, e.g. by establishing autocrine or paracrine circuits.
 ...
PMID:Neuroendocrine dysdifferentiation and bombesin production in carcinogen-induced hepatocellular rat tumours. 291 May 24

In two Adriamycin (Adr) resistant sublines (GLC4-Adr1 and GLC4-Adr2) of a human small cell lung carcinoma cell line, GLC4, cross-resistance for radiation was found. GLC4-Adr1 has an acquired Adr resistance factor of 44 after culturing without Adr for 20 days and GLC4-Adr2, the same subline cultured without Adr for 3 months, has a decreased but stable resistance factor of 8. One of the assumed mechanisms of Adr is that the effect is mediated through the formation of free radicals. Therefore free radical scavenging might play a role in these Adr resistant cell lines. Adr, H2O2, and X-ray induced cytotoxicity were evaluated. Glutathione (GSH) levels and activities of associated enzymes were determined as well as Adr, H2O2, and X-ray induced DNA breaks and repair. GSH level was decreased in GLC4-Adr1, but restored to the normal level in GLC4-Adr2. Superoxide dismutase, catalase, glutathione-peroxidase, and glutathione S-transferase were not elevated in the resistant sublines. Adr induced a decreased amount of DNA breaks in GLC4-Adr1 compared to GLC4. For X-ray and H2O2 a comparable amount of DNA damage was found. GLC4-Adr1 was able to repair DNA breaks induced by Adr, X-ray, and H2O2 better than GLC4. In conclusion, no increased enzyme capacity for detoxification of free radicals could be detected in the cytosol of the resistant cells. The resistance against free radicals in the GLC4-Adr1 line may at least in part be a result of increased DNA repair.
 ...
PMID:Role of free radicals in an adriamycin-resistant human small cell lung cancer cell line. 304 Feb 27

Epoxide hydratase activity with benzo[a]pyrene 4,5-oxide and glutathione S-transferase activity with 2,4-dinitrochlorobenzene as substrates were determined in cultured fibroblasts from skin biopsies of different donors and from several biopsies of the same donor. Variation of the results from experiment to experiment was reduced by the use of a reference cell strain and expression of the results as activities relative to those of the reference cells. Epoxide hydratase activity varied 2.3-fold in 39 cultures from the same subject (the variation coefficients were 0.22 and 0.15, respectively). The results indicate that, at least in skin fibroblasts, genetically caused interindividual differences in epoxide hydratase activities do not exist or are negligibly small or very rare. Glutathione S-transferase activity varied more in cultures from different donors (variation coefficient = 0.22) than in different cultures from the same donor (variation coefficient = 0.08), but the highest and the lowest activities only differed by a factor of 2.3. No significant differences in either enzyme activity were observed between males, females, subjects without tumours, lung carcinoma bearers and melanoma patients.
 ...
PMID:Interindividual comparison of epoxide hydratase and glutathione S-transferase activities in cultured human fibroblasts. 727 71

The expression of intrinsic resistance to cisplatin in two lung cancer cell lines, one derived from a small cell carcinoma (SW1271) and the other from an adenocarcinoma (A549), relative to a drug-sensitive small cell line SW900, was characterized by: (i) expression of cross-resistance to mitomycin C and cadmium chloride, but increased sensitivity to adriamycin and etoposide; (ii) significantly decreased cisplatin uptake; (iii) elevated levels of glutathione which could be reduced by buthionine L-sulfoximine resulting in significant sensitization of the cells to cisplatin; (iv) a lack of consistent modification of metallothionein content and expression of levels of glutathione S-transferase, glutathione reductase and glutathione peroxidase or of activities of DT-diaphorase or catalase; (v) significantly reduced total DNA-platination levels immediately following a 1 h cisplatin treatment with 10 micrograms/ml (33.3 microM); (vi) increased removal of Pt-GG and Pt-AG adducts by the A549 cells, consistent with increased repair capacity, but a lack of removal of these major adducts by the SW1271 cells indicative of tolerance of this drug-induced DNA damage. These data therefore provide evidence of differential formation, repair and tolerance of DNA damage following exposure of three human lung carcinoma cell lines to cisplatin.
 ...
PMID:Evidence of differential cisplatin-DNA adduct formation, removal and tolerance of DNA damage in three human lung carcinoma cell lines. 840 Mar 52

Cross-resistance presents an obstacle in cancer chemotherapy. Cadmium is a potential carcinogen whose exposure has been shown in epidemiological and laboratory experiments to cause lung cancer. Cadmium also induces various forms of resistance in human lung carcinoma cells. This resistance may be shared by antineoplastic agents, which should be a concern for chemotherapy of cadmium-induced lung cancer. In the present study, two subpopulations of human lung carcinoma A549 cells with a different magnitude of resistance to cadmium toxicity were shown to have a parallel resistance to the cytotoxic action of Adriamycin (ADR), an important anticancer drug. Several factors were examined to investigate the mechanism(s) for the cross-resistance, including cellular metallothionein and glutathione (GSH) concentrations, glutathione S-transferase activity, mdr1 expression, and antioxidant enzyme activities including superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. Only cellular GSH content was elevated consistently in the cadmium/ADR-resistant cells relative to the cadmium/ADR-sensitive cells. Treatment with buthionine sulfoximine, a specific inhibitor of GSH synthesis sensitized both cell lines to ADR only when the cellular GSH levels were depleted to about 5% of control. This BSO treatment, however, did not affect cell viability. Further study revealed that the cadmium/ADR-resistant cells have a greater capacity in recovery of cellular GSH content following BSO treatment. The results demonstrate that cross-resistance to ADR exists in cadmium-resistant human lung carcinoma A549 cells, and enhanced GSH synthesis capacity, rather than elevated levels of cellular GSH, may be related to this resistance.
 ...
PMID:Decreased sensitivity to adriamycin in cadmium-resistant human lung carcinoma A549 cells. 911 95

The newly identified p53 homolog p73 mimics the transcriptional function of p53. We have investigated the regulation of p73's transcriptional activity by p300/CREB binding protein (CBP). p73-p300 complexes were identified in HeLa cell extracts by cofractionation and coimmunoprecipitation assays. The p73-p300 interaction was confirmed in vitro by glutathione S-transferase-protein association assays and in vivo by coimmunoprecipitating the overexpressed p300 and p73 in human p53-free small-cell lung carcinoma H1299 or osteosarcoma Saos-2 cells. The N terminus but not the N-terminal truncation of p73 bound to the CH1 domain (amino acids [aa] 350 to 450) of p300/CBP. Accordingly, this p73 N-terminal deletion was unable to activate transcription or to induce apoptosis. Overexpression of either p300 or CBP stimulated transcription mediated by p73 but not its N-terminally deleted mutant in vivo. The N-terminal fragment from aa 19 to 597, but not the truncated fragment from aa 242 to 1700 of p300, reduced p73-mediated transcription markedly. p73-dependent transcription or apoptosis was partially impaired in either p300- or CBP-deficient human breast carcinoma MCF-7 or H1299 cells, suggesting that both coactivators mediate transcription by p73 in cells. These results demonstrate that the N terminus of p73 directly interacts with the N-terminal CH1 domain of p300/CBP to activate transcription.
 ...
PMID:The N-terminal domain of p73 interacts with the CH1 domain of p300/CREB binding protein and mediates transcriptional activation and apoptosis. 1064 16

Combined modalities are currently used for cancer therapy, although their mechanisms of activity remain incompletely deciphered. The design of new drug combinations suffers from our inability to anticipate accurately their efficacy or toxicity. They can be evaluated in vivo, using human tumors grafted into immunodeficient mice, as we did here with combined protocols used in the clinical setting. Xenografts of small cell lung carcinoma (SCLC) from eight patients were used to test the tumor sensitivity to etoposide (VP16; 12-16 mg/kg/days, days 1, 2, and 3), cisplatin (CDDP; 6-9 mg/kg/day, day 1) and ifosfamide (IFO; 90-210 mg/kg/day, days 1, 2, and 3) as single agents and to evaluate the efficacy of the two-drug or three-drug combinations. Five xenografts came from untreated patients (SCLC-61, SCLC-6, SCLC-10, SCLC-41, and SCLC-96) and three after treatment (SCLC-74, SCLC-101, and SCLC-108). p53 was inactivated in all of them. Tumor growth inhibition, growth delay, and the survival rate of tumor-bearing mice reflected individual SCLC chemosensitivity. As single agents, IFO inhibited tumor growth in a dose-dependent manner, whereas CDDP and VP16 had little or no effect. Both CDDP and IFO potentiated VP16, inducing complete regressions in the most sensitive SCLCs; VP16-IFO was more effective than VP16-CDDP, with complete regressions in six versus three of the eight tumors tested, respectively. CDDP-IFO was less effective than VP16-IFO, with three of eight SCLCs giving complete regressions. The three-drug combination led to modest improvement over the best two-drug combination but only for sensitive SCLCs. Because drug-responses distinguished two classes of SCLCs, as sensitive or refractory, MDR1, glutathione S-transferase pi, lung-related multidrug resistance protein, multidrug resistance protein, and topoisomerase IIalpha mRNA expression was studied by semiquantitative reverse transcription. There was no correlation with SCLC sensitivity; topoisomerase IIalpha and multidrug resistance protein was expressed in all cases, lung-related multidrug resistance protein and glutathione S-transferase pie in seven of eight, and MDR1 gene in four of eight. In conclusion, these SCLC xenografts displayed a pattern of chemotherapy response close to that observed in patients. This model confirmed that in two-drug combinations, each component potentiated the effects of the other, with VP16-IFO tending to be the best two-drug combination, both of which were more effective than VP16-CDDP and better tolerated than CDDP-IFO. The addition of a third agent gave a modest, if any, therapeutic benefit in the responders but none in refractory SCLCs. There was no correlation between the extent of response and resistance markers.
 ...
PMID:Distinctive potentiating effects of cisplatin and/or ifosfamide combined with etoposide in human small cell lung carcinoma xenografts. 1081 35


1 2 Next >>