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 acridine derivative m-AMCA (methyl-N-[4-(9-acridinylamino)-2-methoxyphenyl]carbamate hydrochloride), a carbamate analogue of the topoisomerase II poison amsacrine, is distinguished by its high cytotoxicity against non-cycling tumour cells. We compared the response of cultured Lewis lung carcinoma cells to m-AMCA, amsacrine and the topoisomerase I poison camptothecin. The DNA polymerase inhibitor aphidicolin reversed the cytotoxicity of camptothecin fully, that of amsacrine partially, and that of m-AMCA minimally. The ability of m-AMCA to induce the enzyme poly(ADP-ribose)polymerase (PARP) was markedly lower than that of camptothecin or amsacrine. Cell cycle responses to m-AMCA and amsacrine were similar, with slowing of progress through S-phase and arrest in G2-phase. These cell cycle changes were also observed when plateau phase cultures were exposed to drug for 1 h, washed free of drug and cultured in fresh medium, with m-AMCA having a more pronounced effect than amsacrine and camptothecin having no effect. We also examined the role of p53 protein in the response using cultured human H460 cells. Both m-AMCA and amsacrine induced p53 protein expression in proliferating but not in non-proliferating H460 cells, and induced p21WAF1 regardless of proliferation status. Both induced G1-phase cell cycle arrest. It is suggested that two cytotoxicity mechanisms can be distinguished using these drugs. The first is specific for S-phase cells, is reversed by aphidicolin and induces PARP activity. The second is cell cycle non-specific, does not induce PARP and is unaffected by aphidicolin. Camptothecin activates only the first, m-AMCA primarily the second and amsacrine activates both.
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PMID:Cellular responses to methyl-N-[4-9-acridinylamino)-2-methoxyphenyl] carbamate hydrochloride, an analogue of amsacrine active against non-proliferating cells. 938 32

Cell cycle perturbations in three lung carcinoma cell lines (U-1285,U1906 and U-1810) with different intrinsic radiosensitivities (SF2 U-1285 = 0.25, SF2 U-1906 = 0.45, SF2 U-1810 = 0.88) were investigated following x-irradiation. Cell cycle flow calculations showed that the G1-->S-phase transit was accelerated in irradiated compared with untreated U-1285 cells, up to 24 hours postirradiation. In U-1810 cells and U-1906 cells the postirradiation G1-->S transit decreased compared with controls. All three cell lines showed no postirradiation induction of p53 and p21CIP1 proteins. Cyclin E was overexpressed and cyclin E-dependent kinase activity was substantially induced by irradiation in U-1285 cells compared with U-1906 and U1810 cells while p27KIP1 was detected at the highest intensity in U-1810 cells and lowest in U-1285 cells. We hypothesise that the accelerated postirradiation G1-->S transit in U-1285 cells is associated with induction of cyclin E-dependent kinase activity and may account for increased radiosensitivity in these cells.
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PMID:Characterisation of the G1/S cell cycle checkpoint defect in lung carcinoma cells with different intrinsic radiosensitivities. 941 76

Patients with non-small cell carcinoma of the lung (NSCLC) have a poor prognosis (64 and 41% survival rates in Stages I and II). It is currently not possible to predict which patients with Stage I or II NSCLC will survive the disease. Sixty-seven patients with NSCLC, including 49 patients with Stage I NSCLC and 18 with Stage II disease (11 with squamous cell carcinomas, 35 with adenocarcinomas, and 21 with large cell carcinomas) were treated with lobectomy and followed for a minimum of 5 years. The tumors were studied with DNA flow cytometry and quantitative immunocytochemical studies for proliferation cell nuclear antigen, p53 protein, and MIB-1. The data were analyzed with backpropagation neural networks, univariate analysis of variance, the Kaplan-Meier survival method, and Cox proportional hazards model. The dependent variables were "free of disease" and "recurrence or dead from disease." Twenty neural network models were trained, using all cases but one, after 1883 to 2000 training cycles. At 5 years, 30 patients were free of disease and 37 were dead or had recurrence. Proliferating cell nuclear antigen was the only statistically significant prognostic factor by univariate analysis of variance and Cox proportional hazards analysis. The S phase was statistically significant by univariate analysis of variance (P <.05). All of the 20 models classified the test cases correctly. Study with backpropagation neural networks using multiple prognostic features from patients with NSCLC suggests that this technology might be useful for prediction of survival. This preliminary study must be validated with data from a larger group of patients with NSCLC before its clinical adequacy is established.
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PMID:Neural networks as a prognostic tool for patients with non-small cell carcinoma of the lung. 943 67

To investigate whether p53 and proliferating cell nuclear antigen (PCNA) are maintained at relapse of non-small cell lung cancer (NSCLC), we examined tumor materials from nine patients with NSCLC who had undergone resection for primary cancer and also a second resection for its relapse to the lung. In each case, histological types of primary and relapsing tumor were identical (eight adenocarcinomas and one squamous cell carcinoma). Immunohistochemical staining analysis for p53 oncoprotein expression revealed that seven of the nine cases had identical p53 expression in primary and relapsing tumor (p53 positive in three cases and negative in four) and that in the remaining two cases, p53 positive conversion during relapse was found in one case and negative conversion in one. Immunostaining for PCNA expression revealed that PCNA expression was observed in five primary tumors, and at relapse these cases were also PCNA positive. Three of the remaining four cases showed PCNA positive conversion during relapse. This study of a small number of patients indicates that results of p53 and PCNA immunostaining of resected materials of NSCLC seem to be of little significance for predicting future relapse.
Lung Cancer 1997 Nov
PMID:Relationship of p53 oncoprotein and proliferating cell nuclear antigen expression between primary and relapsing non-small cell lung cancer. 944 50

The lactate dehydrogenase A (LDH-A) gene, whose product participates in normal anaerobic glycolysis and is frequently increased in human cancers, has been identified as a c-Myc-responsive gene. It was of interest, therefore, to compare the effect of glucose deprivation in c-Myc-transformed and nontransformed cells. We observed that glucose deprivation or treatment with the glucose antimetabolite 2-deoxyglucose caused nontransformed cells to arrest in the G0/G1 phase of the cell cycle. In contrast, c-Myc-transformed fibroblasts, lymphoblastoid, or lung carcinoma cells underwent extensive apoptosis. Ectopic expression of LDH-A alone in Rat1a fibroblasts was sufficient to induce apoptosis with glucose deprivation but not with serum withdrawal, suggesting that LDH-A mediates the unique apoptotic effect of c-Myc when glycolysis is blocked. The apoptosis caused by glucose deprivation was blocked by Bcl-2 expression but appeared to be independent of wild-type p53 activity. These studies provide insights on the coupling of glucose metabolism and the cell cycle in c-Myc-transformed cells and may in the future be exploited for cancer therapeutics.
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PMID:A unique glucose-dependent apoptotic pathway induced by c-Myc. 946 46

Histologic, immunohistochemical and ultrastructural features of a case of carcinosarcoma of the lung are described. The biphasic pattern of this neoplasm is characterized by the presence of a carcinomatous component that corresponds to an adenosquamous carcinoma, and a sarcomatous component with rhabdomyoblastic differentiation. Since the biphasic sarcomatoid carcinoma has an aggressive clinical behaviour, immunohistochemical expression of prognostic markers, such as Ki-67 and p53 is evaluated to individuate differences between the carcinomatous and the sarcomatous components of the tumor. The higher p53 expression and Ki-67 positivity in the former, suggests that the carcinomatous component probably represents the more aggressive portion of the tumor. Moreover, P53 expression is nuclear in both carcinomatous and sarcomatous areas, thus it is likely that the biphasic sarcomatoid carcinoma of the lung is monoclonal in origin.
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PMID:[Immunohistochemical and ultrastructural study of a case of carcinosarcoma (biphasic sarcomatoid carcinoma) of the lung with rhabdomyoblastic differentiation]. 947 10

The present study represents a continuation of previous works in which we observed that lung carcinomas co-expressing MDM2 protein and p53 mutants (mt p53) exhibited more aggressive behaviour. In the above studies, we suggested a 'gain of function' mechanism of mt p53 proteins based on the fact that the MDM2 gene possesses a p53-responsive element (MDM2-p53RE). In this study, to prove our hypothesis, we selected 12 cases from a series of 51 bronchogenic carcinomas. In these 12 cases, we examined the ability of the expressed mt p53 to bind the MDM2-p53RE and correlated the findings with MDM2 expression. Furthermore, we constructed four of these p53 mutants and studied their transactivation properties by co-transfecting them with a reporter plasmid carrying MDM2-p53RE in the p53 null non-small-cell lung carcinoma cell line (NSCLC) H1299. We observed mutant p53 protein DNA-binding activity, which depended on the nature and the position of the amino acid substitution. The fact that the cases with DNA-binding activity were accompanied with MDM2 protein isoforms' overexpression is indicative of a 'gain of function' phenotype. This hypothesis was enforced by the findings of the transfection experiments, which revealed that certain p53 mutants enhanced the expression of the luciferase reporter gene either directly or indirectly via a dominant positive effect on the wild-type p53. In conclusion, this work is one first attempt to examine if the deregulation of the p53/MDM2 autoregulatory feedback loop is due to novel properties of certain p53 mutants in the specific environment of a subset of bronchogenic carcinomas.
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PMID:Effects of p53 mutants derived from lung carcinomas on the p53-responsive element (p53RE) of the MDM2 gene. 947 31

104 surgery cases of non-small cell (NSLC) and small cell lung carcinoma (SLC) are studied. Oncoprotein bcl-2 is found in 49 out of 104 (47%) cases, more frequently in SLC (71%) than in NSLC (44%) and this correlated with carcinoma morphological malignancy. L-myc oncoprotein and EGFR were expressed practically in all cases, oncoprotein of the p53 mutated gene in 57% cases. The highest content of p53 was in SLC, large cell and poorly differentiated squamous cell carcinoma. Percentage of cells with mutated p53 statistically correlated with morphological malignancy of lung carcinoma. Oncoprotein of Rb gene was revealed in 51%, most frequently in squamous cell carcinoma (71%) and particularly in its well differentiated types. IGFII was found in 74% NSLC and in 100% SLC with cytoplasmic location in tumor cells; the level of expression was higher in SLC. IGFII 2 and 5 were more frequently observed in the foci of keratinization of squamous cell carcinoma. For the first time IGFP B3 was found not only in the cytoplasm but in the nuclei of tumor cells as well. There was a significant positive correlation between the content of IGFIBP3 in the nuclei of tumor cells and morphological malignancy (poor tumor cell differentiation, larger size and metastases). The mean number of proliferating Ki-67 positive cells was 24% but this figure was much higher (47%) in SLC. Squamous cell carcinoma is characterized by a more frequent and stronger expression of CD44 types 5 and 6 in the cytolemma and this may be considered as a marker of squamous cell differentiation of lung carcinoma.
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PMID:[Immunohistochemistry of biomolecular markers of lung cancer]. 948 14

In this study, we investigated the effect of the novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN/CD437) on the growth of human lung carcinoma cell lines. AHPN inhibits the proliferation of all cell lines tested, irrespective of the lung tumor type, in a concentration- and time-dependent manner. A dramatic reduction in cell number was observed in adenocarcinoma H460 cells, and was shown to be related to an induction of apoptosis. Bromodeoxyuridine (BrdU) incorporation and flow-cytometric analyses indicated that treatment of H460 cells with AHPN induces cell-cycle arrest at the G1 phase. We therefore investigated the effect of AHPN on several regulatory proteins of the G1 phase of the cell-cycle. The cell-cycle arrest induced by AHPN was accompanied by an inhibition of the hyperphosphorylation of the retinoblastoma (Rb) protein, an indication of G1 arrest. Furthermore, two cyclin-dependent kinases, cdk2 and cdk4, which are normally involved in the phosphorylation of Rb, were shown to have decreased activity. In some cell lines, the decrease in cdk activity may be partly related to an increase in p21(WAF1/Cip1) (p21), an inhibitor of cyclin-dependent kinases. No changes were observed in the cyclin-dependent kinase inhibitor p27(Kip1). The observed increase in p53 in response to AHPN could at least to some extent be responsible for the increased levels of p21. The increase in p53 expression was found to be regulated at a post-transcriptional level. Our results suggest that the growth inhibition of certain lung carcinoma cell lines by AHPN is at least partly related to an increase in p21. However, in other cell lines, different mechanisms appear to be involved. The specificity with which AHPN and other retinoids induce growth arrest and p21 expression indicates that the action of AHPN is not mediated by RAR or RXR receptors, but involves a novel signaling pathway.
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PMID:Inhibition of cell proliferation and induction of apoptosis by the retinoid AHPN in human lung carcinoma cells. 949 Jun 50

Adenovirus type 5 E4 open reading frame 4 (E4orf4) protein has been previously shown to counteract transactivation of the junB and c-fos genes by cyclic AMP plus E1A protein and to interact with protein phosphatase 2A (PP2A). Here, we show that the wild-type E4orf4 protein induces apoptosis in the E1A-expressing 293 cells, in NIH 3T3 cells transformed with v-Ras, and in the lung carcinoma cell line H1299. The induction of apoptosis is not accompanied by enhanced levels of p53 in 293 cells and occurs in the absence of p53 in H1299 cells, indicating involvement of a p53-independent pathway. A mutant E4orf4 protein that had lost the ability to induce apoptosis also lost its ability to bind PP2A. We suggest that E4orf4 antagonizes continuous signals to proliferate, like those given by E1A or v-Ras, and that the conflicting signals lead to the induction of cell death.
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PMID:Adenovirus type 5 E4 open reading frame 4 protein induces apoptosis in transformed cells. 952 19


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