Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patterns of drug sensitivities in relation to topoisomerase II gene expression and activity were studied in eight human lung cancer cell lines not selected in vitro for drug resistance. The cytotoxicities of doxorubicin, etoposide, teniposide, cisplatin, camptothecin, and 5-fluorouracil were measured and, remarkably, these unselected cell lines were shown to have a common pattern of multidrug sensitivity, i.e., a multidrug sensitivity phenotype. In fact, drug sensitivities were significantly correlated with each other in the studied cell lines, the correlation being best for the topoisomerase II-targeted agents and cisplatin, less strong with camptothecin, and weak with 5-fluorouracil. Almost 1-log range difference of topoisomerase II gene expression was found in these cell lines, and this was not explained by the cell-doubling time or cell cycle distribution. The level of topoisomerase II gene expression was positively and highly correlated with the cell sensitivity to epipodophyllotoxins, doxorubicin, and cisplatin in seven cell lines. Although weaker, an association was also observed between topoisomerase II gene expression and camptothecin cytotoxicity, while no association was observed with 5-fluorouracil. However, a non-small cell lung cancer cell line with neuroendocrine properties had very low levels of expression of the topoisomerase II gene, despite being highly sensitive to all drugs tested. The levels of topoisomerase I gene expression were not found to be correlated with the cytotoxicity of any drug tested. A specific enzymatic activity assay and a teniposide-stimulated DNA cleavage assay showed that the extent of active topoisomerase II present in nuclear extracts paralleled the level of topoisomerase II gene expression. Furthermore, in addition to the normal transcript, an abnormally sized topoisomerase II message and a rearrangement of the topoisomerase II gene were detected in a poorly sensitive small cell lung cancer cell line. Therefore, low levels of topoisomerase II gene expression, and possibly mutations, may predict a reduced sensitivity of unselected human lung cancer cell lines to several drugs, including agents with a cellular target other than topoisomerase II. It is hypothesized that topoisomerase II might be involved in a common pathway of cell death induced by drugs in tumor cell lines which present a multidrug sensitivity phenotype.
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PMID:Multidrug sensitivity phenotype of human lung cancer cells associated with topoisomerase II expression. 131 95

Poly(ADP-ribose) polymerase has been generally assumed to be involved in DNA repair. The level of the enzyme in various lung cancer cell lines was examined to determine if it is involved in drug resistance. Among nine cell lines of lung cancer tested, small-cell lung cancer lines, which showed higher sensitivity to cisplatin and etoposide, were unexpectedly found to contain significantly higher poly(ADP-ribose) polymerase activity than five non-small-cell lung cancer cell lines. This activity inversely correlated with IC50 values of lung cancer cell lines to etoposide, an inhibitor of topoisomerase II. The polymerase activity was also examined in several cisplatin-resistant variants of the cell lines. However, no difference was observed between parental and cisplatin-resistant cells. There was no significant relation between poly(ADP-ribose) polymerase activity and IC50 values for cisplatin and carboplatin. Although this enzyme was considered to play some role in the resistance to specific drugs, it might not be a critical factor in cisplatin-induced cytotoxicity.
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PMID:Participation of poly(ADP-ribose) polymerase in the drug sensitivity in human lung cancer cell lines. 131 78

We investigated the interaction between human lung cancer cells, laminin, and several differentiating agents. When grown on laminin coated substrate eight out of 11 small cell lung cancer (SCLC) cell lines exhibited attachment to laminin and three had extensive outgrowth of long neurite-like processes. Of seven non-small cell lung cancer cell lines, selected for their in vitro anchorage-independent growth, attachment was observed in only three cell lines, and process formation was far less extensive than in SCLC cell lines. Among several differentiating agents, only dcAMP, which alone induced attachment and some process formation, increased laminin-mediated attachment and process formation of two SCLC cell lines, NCI-N417 a variant cell line, and NCI-H345, a classic cell line. The expression of several neuroendocrine and neuronal markers was investigated in these two SCLC cell lines. The expression of the light subunit of neurofilaments increased in NCI-N417 within 3 to 4 days of seeding, while NCI-H345 exhibited approximately 5 fold increase in expression of the GRP gene and a 3 fold increase expression of the beta-actin gene. The expression of a number of other neuroendocrine and neuronal markers did not change following growth on laminin. The doubling times remained unchanged independent of the presence of and attachment to laminin while topoisomerase II gene expression levels in NCI-N417 cells decreased approximately 5 fold when cells were growing on laminin.
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PMID:Increased expression of differentiation markers can accompany laminin-induced attachment of small cell lung cancer cells. 132 26

CPT-11, a recently developed topoisomerase I (Topo I) inhibitor, attracts the attention not only of basic researchers but also of clinicians because of its high antitumor activity. The CPT-11 resistant human lung cancer cell line, PC-7/CPT, showed 10-fold resistance compared to parental cell line, PC-7. The total activity of Topo I in the resistant cell line was one fourth that of the parental sensitive cell line. The Topo I from the resistant cells was also 5-fold more resistant to the inhibitory effect of CPT-11 than that of the parental cells. We speculated that the alteration of the Topo I gene may be responsible for the change in topoisomerase activity of the CPT-11 resistant cell line. Therefore, we analyzed the mutation of Topo I gene using the method of single strand conformation polymorphism of polymerase chain reaction and the reverse transcriptase. We divided Topo I cDNA into ten fragments which overlapped each other and covered whole coding sequences of the Topo I cDNA. We observed mobility shift of two fragments in the PC-7/CPT, suggesting the presence of some mutations in these fragments. We performed the direct-sequencing of these portions by the dideoxy chain termination method and observed an altered sequence having a G to A base change in PC-7/CPT. This base substitution results in replacement of the conserved threonine at 729 position with alanine. These results suggest that the point mutation of Topo I gene is related to the decreases of Topo I activity and the sensitivity to Topo I inhibitor in PC-7/CPT cells.
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PMID:Detection of topoisomerase I gene point mutation in CPT-11 resistant lung cancer cell line. 133 3

DNA was prepared from normal tissue and 19 lung cancer cell lines. Using probes which detect restriction fragment length polymorphisms at both the topoisomerase II alpha and beta loci, heterozygosity was detected at a frequency of 0.17 and 0.37 for the alpha and beta loci, respectively. Southern blot analysis of DNA extracted from lung cancer cell lines detected amplification of both the topoisomerase II alpha and ERBB2 genes in the adenocarcinoma line Calu3. These results indicate that topoisomerase II alpha and ERBB2 may be closely linked on chromosome 17 and coamplified during adenocarcinoma progression. Since topoisomerase II is a target for several anticancer drugs, it will be of interest to study alterations to topoisomerase II genes during tumour development, as these may in part determine the response of the tumour to chemotherapy.
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PMID:Amplification of the topoisomerase II alpha gene in a non-small cell lung cancer cell line and characterisation of polymorphisms at the human topoisomerase II alpha and beta loci in normal tissue. 137 18

Etoposide, a podophyllotoxin derivative, has demonstrated antitumor efficacy in a number of human malignancies, including lymphomas, germinal tumors, and lung cancer (especially small cell). Etoposide's antineoplastic activity is achieved through DNA strand breakage, which likely results from the formation of a complex involving drug, DNA, and the DNA unwinding enzyme, topoisomerase II. The drug's steady state volume of distribution ranges from 5 to 17 L/m2, and it is highly bound to plasma protein with an average free plasma fraction of 6%. A number of etoposide metabolites have been confirmed or postulated. Several cell lines have been shown to acquire resistance to etoposide through membrane transport changes. Considerable intrapatient variability exists in pharmacokinetic parameters following intravenous (IV) and oral dosing. Approximately 30% to 40% of unchanged IV drug is excreted in the urine, whereas biliary excretion appears a minor route of drug elimination. The bioavailability of oral etoposide averages 50%, although wide variability exists both among and within different patients. Bioavailability decreases as the dose of oral etoposide is increased. Several recent studies have attempted to correlate etoposide plasma concentrations with toxicity (primarily myelosuppression) in hopes of using this information to optimize drug dosing.
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PMID:Etoposide pharmacology. 149 25

In an attempt to understand the underlying cellular/biochemical factors of sensitivity/resistance in human small-cell lung cancer (SCLC), 2 SCLC tumor lines were compared with respect to tumor responsiveness to drug treatment, cell sensitivity, cellular doxorubicin accumulation, and DNA topoisomerase-II-mediated DNA cleavage. The tumor lines growing in nude mice with similar growth characteristics (doubling time around 10 days) were selected since one (POCI tumor) was found to be hypersensitive and the other (POSG tumor) resistant to doxorubicin treatment. The pattern of anti-tumor drug response of the doxorubicin-resistant tumor was atypical (i.e., non-adherent to the well-characterized multi-drug-resistant phenotype), since it responded to vincristine. The markedly different in vivo tumor response reflected the intrinsic cellular sensitivity to doxorubicin. No correlation was found between cellular drug accumulation and doxorubicin sensitivity following in vitro exposure to the drug. In agreement with this observation, the expression of mdr-I gene was undetectable in these tumors. Thus, in the POSG tumor, resistance to doxorubicin occurred without expression of the P-glycoprotein and reduction of cellular drug accumulation. In contrast, the extent of DNA cleavage produced by doxorubicin was markedly higher in the doxorubicin-hypersensitive than in the doxorubicin-resistant tumor. These results, taken together with previous observations in SCLC cell lines, support the important role of DNA topoisomerase-mediated effects in the sensitivity of SCLC to doxorubicin.
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PMID:Relationships among tumor responsiveness, cell sensitivity, doxorubicin cellular pharmacokinetics and drug-induced DNA alterations in two human small-cell lung cancer xenografts. 197

The lamins, an intranuclear class of intermediate filament proteins, are major structural proteins of the nuclear envelope. In the present study, the three abundant mammalian lamins (lamins A, B, and C) were observed to be present in roughly equivalent amounts in the Calu-1, Calu-3, H157, and SK-MES-1 non-small cell lung cancer lines. In the small cell lung cancer lines OH-1, OH-3, NCI-H82, NCI-H209, and NCI-H249, levels of lamin B were similar to those observed in the non-small cell lines, but the levels of lamins A and C were diminished by greater than or equal to 80%. The relationship between lung cancer phenotype and lamin expression was explored further in the NCI-H249 small cell line. Introduction of the v-rasH oncogene into this line gives rise to a cell line (NCI-H249rasH) with many features of large cell carcinoma of the lung (Falco, J. P., Baylin, S. B., Lupu, R., et al. J. Clin. Invest., 85: 1740-1745, 1990). Concomitant with the v-rasH-induced change in phenotype, a greater than 10-fold increase in the amounts of lamins A and C was observed. Levels of the cytoplasmic intermediate filament protein vimentin also increased. In contrast, levels of a variety of nonlamin nuclear polypeptides including topoisomerase I, topoisomerase II, poly(ADP-ribose) polymerase, and the nucleolar protein B23/nucleophosmin did not change. Comparison of polyadenylated RNA from NCI-H249 and NCI-H249rasH cells on Northern blots revealed similar levels of the mRNA for lamin B but higher levels of the mRNAs for lamins A and C in the v-rasH-expressing cell line. These observations provide evidence for differences in nuclear envelope structure in histologically different neoplastic cells derived from the same epithelial cell system and suggest that differences in lamina structure result from phenotype-specific differences in lamin gene expression.
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PMID:Differential expression of nuclear envelope lamins A and C in human lung cancer cell lines. 198 76

In an attempt to clarify the role of drug-induced protein-associated DNA breaks (i.e., DNA topoisomerase II-mediated DNA cleavage) in the cytotoxic activity of doxorubicin and etoposide, their cellular effects were compared in 2 human small-cell lung cancer (SCLC) lines, characterized by differential sensitivity to DNA topoisomerase II inhibitors. These drugs were selected for comparative studies since they are among the most effective agents in the treatment of SCLC. H146 and N592 cell lines were obtained from pleural effusion and bone-marrow aspirate of pretreated patients, respectively. Both cell lines grew as floating aggregates with similar doubling times (30 and 33 hr for N592 and H146 cells, respectively). Although, immediately after 1 hr exposure to equitoxic drug levels, the extent of DNA cleavage produced by doxorubicin was markedly lower than that produced by etoposide, DNA lesions produced by doxorubicin persisted and even increased following drug removal. In contrast, an almost complete disappearance of etoposide-induced DNA breaks was noted 1 hr after drug removal. Resealing of strand breaks was faster in N592 than in H146 cells. These findings suggest that reversal of these lesions plays a major role in cell survival rather than the occurrence of DNA breaks immediately following drug exposure. This observation is consistent with the view that inhibition of DNA re-ligation rather than stimulation of DNA cleavage is the critical step for drug action. The different response of these cell lines to cytotoxic action of the topoisomerase inhibitors is associated with a differential drug effect on DNA integrity (detected as DNA double-strand breaks and DNA-protein cross-links). However DNA lesions were comparable when cells were exposed to equitoxic drug levels. The observation that etoposide-induced DNA breaks were similar in isolated nuclei from both cell lines suggests that drug-target interaction is modulated in a different manner in the intact cell. As indicated by doxorubicin uptake and retention, cellular drug pharmacokinetics do not account for the different drug response of the studied SCLC lines, presumably, reflecting a different extent of DNA break formation and/or a different cytotoxic consequence of DNA damage.
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PMID:Comparison of DNA cleavage induced by etoposide and doxorubicin in two human small-cell lung cancer lines with different sensitivities to topoisomerase II inhibitors. 215 11

Tumor necrosis factor alpha (TNF) exhibits cytotoxic activity on some solid tumors and has been reported to be synergistic with topoisomerase-II-targeted antineoplastic agents. A wide range of TNF concentrations (from 10 to 10,000 U/ml) was tested in 9 human lung cancer cell lines (5 small-cell and 4 non-small-cell carcinomas) using a semi-automated MTT assay. TNF was not cytotoxic in 8 cell lines, while an adenocarcinoma cell line was marginally sensitive to the cytokine. Using 125I-TNF we were able to show the presence of specific binding sites for TNF in 4/9 human lung cancer cell lines. Scatchard analysis of the marginally sensitive cell line showed high-affinity, saturable binding. With 5 cell lines we also tested whether TNF affected the cytotoxicity of doxorubicin and etoposide, 2 topoisomerase II-targeted drugs which are widely used in the therapy of lung cancer. No significant increase in cytotoxicity was seen when TNF was added to the 2 anti-neoplastic agents. In contrast to certain other human and mouse lines, human lung cancer cell lines appear to be resistant to TNF, despite the presence of the receptor in some of them; moreover, no synergistic effect of TNF and 2 topoisomerase-II-targeted drugs was evident in these human cell lines.
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PMID:Effects of tumor necrosis factor, alone or in combination with topoisomerase-II-targeted drugs, on human lung cancer cell lines. 216 14


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