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Query: UNIPROT:P06889 (Mol)
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Studies have suggested that recombinant tumor necrosis factor-alpha (TNF-alpha) may potentiate the killing of murine tumor cells by drugs targeted at DNA topoisomerase II. We have examined the combined cytotoxic effects of the topoisomerase-targeted drug etoposide and TNF in small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) cell lines using clonogenic assays and a novel flow cytometry technique relying on differential uptake of fluorescein diacetate (FDA) and propidium iodide (PI) by viable and nonviable cells. Good correlation of IC50 determinations for etoposide were noted between clonogenic assays and the FDA/PI technique for both classic and variant SCLC cell lines. The effects of etoposide on the classic SCLC line H209 were potentiated by TNF with a decrease in the IC50 from 3.3 microM to 1.0 microM as determined by FDA/PI. Tumor necrosis factor alone had little effect on the growth or cloning efficiency of H209 cells. Tumor necrosis factor alone stimulated the growth and cloning of variant SCLC line N417, but the cytotoxicity of etoposide was not potentiated by TNF in N417 cells. Tumor necrosis factor alone inhibited the growth and cloning of the NSCLC line H125 but exerted a marked protective effect against higher concentrations of etoposide. It appears that the interaction of TNF with etoposide varies between cell lines and between subclasses of human lung cancer.
Mol Biother 1990 Sep
PMID:Interaction of recombinant human tumor necrosis factor and etoposide in human lung cancer cell lines. 217 61

Point mutations in genes can be etiologic of pulmonary diseases, as in the case of the inherited disorders alpha-1-antitrypsin deficiency and cystic fibrosis or in the context of dominant and recessive oncogenes in lung cancer. Various methodologies have been developed to screen for single-base mutations. These techniques include direct DNA sequencing, RNase protection, denaturing gradient gel electrophoresis, and chemical mismatch cleavage. The latter method offers the advantages of rapid and efficient analysis of genomic or cDNA and is thus ideally suited to screening applications. Furthermore, all possible single-base changes can theoretically be detected. In the present work, chemical mismatch cleavage was utilized to detect mutations in the p53 gene in small cell and non-small cell lung cancer. This technique was modified by using a two-step, hemi-nested PCR procedure for preparation of target genomic DNAs permitting an expanded target size for analysis. Evaluation by chemical mismatch cleavage of eight p53 cDNAs derived from lung tumors shown to have different mutations by DNA sequencing correctly detected the presence of a point mutation in all instances. Analysis of six additional tumor genomic DNAs with defined mutations in the corresponding p53 cDNAs accurately confirmed the mutation at the level of the genome. The technique also identified codon 72 and intron 6 polymorphisms. Using the intron 6 polymorphism, loss of heterozygosity at the p53 locus in tumor DNA was readily detected by chemical mismatch cleavage. Finally, utilizing this technique for scanning analysis of the p53 gene of uncharacterized lung tumor DNAs, additional mutations were identified in a prospective manner which were confirmed by sequence analysis.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1990 Nov
PMID:A chemical mismatch cleavage method useful for the detection of point mutations in the p53 gene in lung cancer. 222 98

Eighteen postoperative patients with non-small cell lung cancer were actively immunized with a vaccine that included autologous cryopreserved irradiated tumor cells admixed with bacillus Calmette-Guerin. Patients received three weekly intradermal immunizations beginning 1-3 months after surgery (15 patients) or after completion of postoperative radiotherapy (3 patients). There was marked heterogeneity in the relative proportion of tumor cells versus host infiltrating cells within individual vaccines (range of percent tumor cells 7-75%). Five patients exhibited positive delayed cutaneous skin test reactivity (DCR) to autologous irradiated tumor cells prior to immunization, whereas 8 of 13 converted from skin test negative to positive. There were no correlations between DCR reactivity and in vitro lymphoproliferative responses to autologous tumor cells or to clinical outcomes, i.e., freedom from relapse. Possible explanations for the heterogeneity of the lung cancer vaccine and approaches for improving its immunogenicity are discussed.
Mol Biother 1988
PMID:Active specific immunotherapy with an autologous tumor cell vaccine in patients with resected non-small cell lung cancer. 285 88

Bioreductive antitumor quinones require reductive metabolism to produce their cytotoxic effects. A series of these compounds was screened for relative rates of reduction by the two-electron reductase, NAD(P)H:quinone oxidoreductase (DTD). The antitumor quinones streptonigrin (SN), 2,5-diaziridinyl-3-phenyl-1,4-benzoquinone (PDZQ), 2,5-diaziridinyl-3,6-dimethyl-1,4-benzoquinine (MeDZQ), and [3-hydroxymethyl-5-aziridinyl-1-methyl-2-(1H-indole-4,7-dione)-propen ol] (EO9) were all excellent substrates for recombinant rat and human DTD. All four compounds were reduced by DTD at least 100 times faster than the clinically important bioreductive alkylating agent, mitomycin C (MC). Reduction of the antitumor quinones was generally 4-5 times more efficient by rat DTD than by human DTD. The exception was EO9, which, surprisingly, was reduced 23 times faster by rat DTD than by human DTD. The rate of reduction of each individual quinone was similar under either aerobic or anaerobic conditions, suggesting that DTD may be an important activating enzyme in the hypoxic fraction of solid tumors. The cytotoxicity of MeDZQ and MC was examined in a panel of human breast and lung cancer cell lines. The data showed good correlations between DTD activity and toxicity for both MeDZQ (r = 0.57, p = 0.054) and MC (r = 0.69, p = 0.020), confirming biochemical data that both compounds are bioactivated by DTD. In addition, IC50 values were in general lower for MeDZQ than for MC in cell lines containing elevated DTD, a finding that was consistent with metabolic data that indicated that MeDZQ was a better substrate for DTD than MC. SR, defined as the ratio of the IC50 value for the H596 NSCLC cell line (undetectable DTD activity) to the IC50 value for the H460 NSCLC cell line (high DTD activity), were determined for all five antitumor quinones. SN was the most selective (SR = 86) followed by EO9 (SR = 62), MeDZQ (SR = 17), and MC (SR = 11). Surprisingly, PDZQ, an excellent substrate for DTD, was toxic to both cell lines (SR = 1.8). These data suggest that antitumor quionones that are substrates for DTD may be selectively toxic to tumors with high DTD activity and may be useful in the treatment of those tumors.
Mol Pharmacol 1995 Sep
PMID:Nicotinamide adenine dinucleotide (phosphate): quinone oxidoreductase (DT-diaphorase) as a target for bioreductive antitumor quinones: quinone cytotoxicity and selectivity in human lung and breast cancer cell lines. 756 31

Consistent loss of DNA sequences from several regions on the short arm of human chromosome 3 has suggested that multiple tumor suppressor genes reside on chromosome 3p in various types of cancer cells. We have focused our efforts on an analysis of chromosomal band 3p21.1 since aminoacylase-1 (ACY1), which is localized to this band, has been shown to have lower levels of expression in several small cell and non-small cell lung cancer cell lines. Starting with two cosmids within 3p21.1, D3S92 and D3S93, we have isolated two separate contigs of overlapping cosmids within 3p21.1, by screening a library of 5700 chromosome 3-specific cosmid clones. Detailed restriction maps for these two contigs show that they contain multiple clusters of rare cutting restriction endonuclease sites. One contig extends for 100 kb and encompassed both ACY1 and D3S92, and the other extends about 80 kb around the D3S93 locus. Many different restriction fragments derived from these two contigs were found to be evolutionarily conserved and hybridized to distinct message transcripts. These fragments were used to identify homologous cDNAs from an adenogastric cDNA library, and several of these cDNAs were partially sequenced. We have identified five new genes from these two contigs and there is evidence to suggest that several additional genes reside within these cosmid contigs. The genes identified from 3p21.1 were then hybridized to DNA, isolated from a series of lung cancer cell lines and matched normal and tumor DNA from lung cancer patients. No alterations were detected with any of these probes, both at the DNA or RNA levels. A similar analysis with DNA fragments derived from these two genomic regions also failed to detect any alterations.
Somat Cell Mol Genet 1994 Jul
PMID:Isolation of two contigs of overlapping cosmids derived from human chromosomal band 3p21.1 and identification of 5 new 3p21.1 genes. 797 2

p185HER2, the product of the c-erbB-2 or HER2 gene, is a membrane-bound tyrosine kinase that has structural similarity to the epidermal growth factor receptor. Functionally, interaction of HER2 with its ligand or p185HER2 antibodies affects the growth and differentiation of HER2-expressing breast cancer cell lines. As p185HER2 is also expressed in human lung cancers and human lung cancer cell lines, we hypothesized that these cell lines would also respond to p185HER2 antibodies. To test this hypothesis, we cultured human non-small cell lung cancer cell lines in the presence of a p185HER2 monoclonal antibody called 4D5. 4D5 inhibited the growth of p185HER2-expressing cell lines in a dose-dependent fashion. In addition, BEAS.2B, a p185HER2-nonexpressing bronchial epithelial cell line, was transfected with the HER2 cDNA, resulting in high-level p185HER2 expression, and growth of BEAS.HER2 was now inhibited by 4D5 exposure. Mechanistically, 4D5 appeared to have a weak agonist effect on the tyrosine kinase function of p185HER2, as exposure of p185HER2-expressing cell lines to 4D5 resulted in increased p185HER2 phosphorylation. Furthermore, inhibition of tyrosine kinase function with Genistein reversed the 4D5-induced growth inhibition. Therefore, 4D5 can regulate the growth of p185HER2-expressing lung cancer cell lines through agonist effects on p185HER2.
Am J Respir Cell Mol Biol 1993 Oct
PMID:Inhibition of human lung cancer cell line growth by an anti-p185HER2 antibody. 810 37

Abundant evidence suggests that growth factors are important mediators of non-small cell lung cancer (NSCLC) growth. Although multiple growth factors have been found to be produced by NSCLC tissues, little is known about possible differences in growth factor expression between malignant and adjacent normal lung tissues. Variation in growth factor expression between normal and malignant lung tissues could be potentially useful diagnostically and therapeutically. In studies reported here, the expression of the angiogenic growth factor pleiotrophin (PTN) and homolog midkine (MK) was assessed in resected normal and malignant lung tissues. Primers specific for the two growth factors were used to amplify reverse transcriptase-produced DNA copies of RNA transcripts harvested from the tissues. This analysis revealed that all normal lung tissues examined (n = 17) expressed PTN but only two expressed MK. Conversely, all of the resected lung cancers (n = 20) expressed MK but only one expressed PTN. These results demonstrated a striking reciprocal expression pattern of MK and PTN in normal versus malignant lung tissue.
Am J Respir Cell Mol Biol 1993 Nov
PMID:Reciprocal expression of pleiotrophin and midkine in normal versus malignant lung tissues. 821 86

Cyclin and cyclin-dependent kinase (CDK) complexes play important roles in modulating the cell cycle. The CDK inhibitors (CDKIs) inhibit the kinase activities of these complexes and block the cell cycle. The p16/multiple tumor suppressor (MTS) 1/inhibitor of CDK4 (INK4) a/CDKN2 gene, a CDKI, is frequently deleted in a variety of human cancers. Recently another CDKI gene, p15/MTS2/INK4b, was cloned and localized to within 20 kb of the p16 gene. Moreover, a third CDKI gene, named p18/INK4c and having a high degree of protein homology to p16, has now been cloned. To elucidate the importance of these CDKI genes in non-small cell lung cancers (NSCLCs), we examined DNAs from 34 NSCLC samples for alterations in these genes by Southern blot and polymerase chain reaction (PCR)-single-strand conformational polymorphism (SSCP) analyses. Matched control normal tissues from the same individuals were also examined. Homozygous deletions of the p15 gene were found in three cases. Furthermore, comparative PCR analysis confirmed these deletions and suggested that one additional case had an abnormality of the p15 gene. Neither rearrangements nor deletions of the p18 gene were detected. By PCR-SSCP and direct sequencing of the aberrantly migrating bands, we detected only polymorphic nucleotide substitutions in both the p15 and p18 genes. In summary, the frequency of deletions of the p15 gene was 12% (four of 34 cases), and no point mutations in the p15 gene were detected in the NSCLCs. For the p18 gene, no abnormalities were detected. A previous analysis of these NSCLC samples for p16 gene alterations revealed that the three cases with homozygous deletions of the p15 gene also have homozygous deletions of the p16 gene.
Mol Carcinog 1995 Dec
PMID:Molecular analysis of a family of cyclin-dependent kinase inhibitor genes (p15/MTS2/INK4b and p18/INK4c) in non-small cell lung cancers. 851 15

Vasoactive intestinal peptide (VIP) is a neuropeptide of multiple functions affecting development and aging. In cancer, for example, VIP was found to function as an autocrine growth factor in nonsmall cell lung cancer (NSCLC) promotion. Furthermore, a VIP hybrid antagonist (neurotensin(6-11)-VIP(7-28)) was found to inhibit NSCLC growth. In the present study, the expression of VIP mRNA was studied using human lung cancer cells. RNA prepared from 19 cell lines was fractionated by 1% agarose gel electrophoresis followed by blotting onto nitrocellulose membranes and hybridization to a VIP-specific RNA probe. VIP mRNA was detected in about 50% of the cell lines tested with a greater abundance in NSCLC. Cultures of the NSCLC NCI-H727 cell line were treated with forskolin, an activator of cyclic AMP (cAMP), and separately with the tumor promoter phorbol 12-myristate 13-acetate (PMA). Northern blot hybridization analysis showed an increase in VIP mRNA levels after 4 h treatment with 50 microM forskolin. Incubation with PMA also showed a significant increase in the levels of VIP transcripts. Cultures were then incubated with PMA in the presence of actinomycin D, a transcription blocker. Results indicated that PMA treatment may induce both VIP mRNA synthesis as well as VIP mRNA stabilization, and suggested a 4-5 h half-life for the VIP mRNA in the absence of PMA. Thus, lung cancer tumor proliferation may be regulated, in part, at the level of VIP gene expression.
J Mol Neurosci 1996
PMID:Regulation of VIP gene expression in general. Human lung cancer cells in particular. 887 94

Cytokeratins form part of the cytoskeleton of both normal and malignant epithelium. A novel tumor marker measuring cytokeratin 19 (CK-19) fragment has been introduced and proven to be suitable for monitoring therapy and following cases of non-small cell lung cancer, squamous cell lung cancer in particular. However, whether the serum level of CK-19 fragment reflects the number of proliferating tumor mass remains unknown. We studied the CK-19 fragment produced by two human squamous cell lung cancer cell lines. In Western blotting analysis, culture supernatants of both cell lines displayed bands of 37 and 40 kDa, which represented the CK-19 fragment and the intact CK-19, respectively. Gel filtration demonstrated that a part of soluble CK-19 was released as a large complex form in culture supernatants. The level of CK-19 fragment in culture supernatants increased during the exponential growth phase. CK-19 level decreased by an addition of a cytotoxic agent to non-significant level though the transient release of CK-19 fragment occurred during the first 2 days. After all, soluble CK-19 fragments were detected in culture supernatants of human lung cancer cell lines and its level reflected proliferating cancer cells though it was not determined whether CK-19 fragments were released directly from live cells.
Am J Respir Cell Mol Biol 1997 May
PMID:Production of cytokeratin 19 fragment by human squamous lung cancer cell lines. 916 Aug 42


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