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)

Squalamine is a novel anti-angiogenic aminosterol that is postulated to inhibit neovascularization by selectively inhibiting the sodium-hydrogen antiporter exchanger. To determine how to most effectively use this agent in patients with cancer, we examined the antitumor effects of squalamine with or without cytotoxic agents in human lung cancer xenografts and correlated these observations with the degree of tumor neovascularization. No direct cytotoxic effects of squalamine against tumor cells were observed in vitro with or without cisplatin. Squalamine was effective in inhibiting the establishment of H460 human tumors in BALBc nude mice but was ineffective in inhibiting the growth of H460, CALU-6, or NL20T-A human tumor xenografts when administered i.p. to mice bearing established tumors. However, when combined with cisplatin or carboplatin, squalamine increased tumor growth delay by > or =1.5-fold in the three human lung carcinoma cell lines compared with cisplatin or carboplatin alone. No enhancement of antitumor activity was observed when squalamine was combined with paclitaxel, vinorelbine, gemcitabine, or docetaxel. Repeated cycles of squalamine plus cisplatin administration delayed H460 tumor growth >8.6-fold. Squalamine plus cisplatin reduced CD31 vessel formation by 25% compared with controls, squalamine alone, or cisplatin alone; however, no inhibition in CD31 vessel formation was observed when squalamine was combined with vinorelbine. These data demonstrate that the combination of squalamine and a platinum analog has significant preclinical antitumor activity against human lung cancer that is related to the anti-angiogenic effects of squalamine.
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PMID:Potentiation of platinum antitumor effects in human lung tumor xenografts by the angiogenesis inhibitor squalamine: effects on tumor neovascularization. 1063 72

The Wilms' tumor gene (WT1) encodes a transcriptional regulator involved in growth and differentiation of various tissue types. A continuous over-expression of WT1 was found in leukemic blasts, thus suggesting an oncogenic function. Solid cancer entities have also been described as expressing WT1. We systematically analyzed WT1 expression in small-cell and non-small-cell lung cancer, colon cancer and glioblastoma patients and in the respective tumor cell lines. Using reverse transcription/polymerase chain reaction, we found WT1 expression in glioblastoma (5 of 8), lung (5 of 11), and colon cancer (5 of 15) cell lines. While WT1 was expressed in only 1 of 12 lung cancer and 1 of 5 glioblastoma specimens, it was not detected in colon cancer or macroscopically tumor-free colon and lung tissue. In addition, HT29 colon cancer cells showed a loss of WT1 expression when grown to confluence or induced to differentiate by sodium butyrate. From this evidence, testing for WT1 expression is not clinically relevant for colon cancer, lung cancer, or glioblastoma patients. WT1 expression in cancer cell lines can probably be attributed to optimized in vitro growth conditions.
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PMID:Wilms' tumor gene (WT1) expression in lung cancer, colon cancer and glioblastoma cell lines compared to freshly isolated tumor specimens. 1078 96

Increased expression of cyclooxygenase-2 (COX-2) expression has been observed in several human tumor types and in selected animal and cell culture models of carcinogenesis, including lung cancer. Increased expression of COX-2 and production of prostaglandins appear to provide a survival advantage to transformed cells through the inhibition of apoptosis, increased attachment to extracellular matrix, increased invasiveness, and the stimulation of angiogenesis. In the present studies, we found that transforming growth factor beta1 (TGF-beta1) and epidermal growth factor (EGF) synergistically induced the expression of COX-2 and prostaglandin E2 (PGE2) production in mink lung epithelial (Mv1Lu) cells. EGF, but not PDGF or IGF-1, was able to inhibit TGF-beta1-induced apoptosis in Mv1Lu cells and this effect was blocked by NS-398, a selective inhibitor of COX-2 activity, suggesting a possible role for COX-2 in the anti-apoptotic effect of EGF receptor ligands. The combination of TGF-beta1 and EGF also significantly induced COX-2 expression in rat intestinal epithelial (RIE-1) cells and completely prevented sodium butyrate (NaBu)-induced apoptosis. The synergistic induction of COX-2 by TGF-beta1 and EGF was not observed in R1B-L17 cells, a line derived from Mv1Lu cells that lacks the TGF-beta type-I receptor. AG1478, a selective inhibitor of EGF receptor tyrosine kinase activity, completely suppressed the induction of COX-2 expression by either EGF or TGF-beta1+EGF. Also, PD98059, a specific inhibitor of MEK/ERK pathway, and SB203580, a specific inhibitor of p38 MAPK activity, significantly inhibited the induction of COX-2 in response to combined EGF and TGF-beta1. These results suggest an important collaborative interaction of TGF-beta1 and EGF signaling in the induction of COX-2 and prostaglandin production in Mv1Lu cells.
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PMID:Synergistic induction of cyclooxygenase-2 by transforming growth factor-beta1 and epidermal growth factor inhibits apoptosis in epithelial cells. 1093 98

The amount of fluid covering the epithelium of the airways and alveolar space is modulated by active transport of Na+ from the lumen through the apical membrane Na+ permeant ion channels towards the interstitial space. We have measured the subunit expression of the amiloride-sensitive human Na+ channel (hENaC) by concomitant assessment of alpha-, beta-, and gamma-hENaC mRNA in the nasal, bronchial, and peripheral lung epithelia of adult patients undergoing lobectomy secondary to lung cancer. The study employed quantitative competitive reverse-transcriptase-polymerase chain reaction and qualitative in situ hybridization techniques. The hENaC mRNA content of each sample was normalized to the amount of epithelial cell-specific cytokeratin 18 (CK18) mRNA. Nasal epithelium contained significantly more (p < 0.05) alpha-hENaC mRNA (18 +/- 5 SD amol/fmol CK18), than bronchus (8 +/- 2 SD amol/fmol) and peripheral lung (9 +/- 2 SD amol/fmol). The ratio of gamma-hENaC/alpha-hENaC mRNA concentration was lowest in the nasal area, and it increased significantly towards the distal lung regions. The change in beta-hENaC mRNA was less profound. In situ hybridization studies of bronchial and peripheral lung sections selectively revealed expression of alpha-hENaC mRNA in superficial epithelium and submucosal glands of large airways, in bronchiolar epithelium, and in alveolar cells. We conclude that the relative expression of the hENaC subunit genes changes from the proximal to distal regions of the human respiratory tract.
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PMID:Expression of alpha-, beta-, and gamma-hENaC mRNA in the human nasal, bronchial, and distal lung epithelium. 1120 56

It has been reported that 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), have absorption characteristics of weakly basic drugs, suggesting that alkalization of the intestinal lumen might reduce reabsorption and its attendant side effects. Furthermore, stasis of stools containing these compounds is thought to induce damage to the intestinal mucosa. The prevention of CPT-11-induced side effects by oral alkalization (OA) combined with control of defecation (CD) was estimated in a case-control study of lung cancer patients. Coinciding with day 1 of CPT-11 infusion and for 4 days thereafter, OA and CD were practiced utilizing orally administered sodium bicarbonate, magnesium oxide, basic water and ursodeoxycholic acid. OA involved the daily use of all four therapeutics, and CD required doses of up to 4.0 g/day of magnesium oxide and 2 L/day of excess basic water. From three ongoing prospective phase I/II studies, we selected 37 consecutive patients who were treated with CPT-11 in combination with cisplatin in the presence of OA and CD (group B). Thirty-two control subjects who were matched to the background characteristics of the case patients were treated with the same regimen in the absence of OA and CD (group A). Toxicities induced by the CPT-11/cisplatin combination were evaluated and analyzed in group A and group B in a case-control format. The use of OA and CD resulted in significantly higher stool pH (p < 0.0001), while reducing the incidence of delayed diarrhea (> or = grade 2: group A 32.3% versus group B 9.4%; p = 0.005), nausea (p = 0.0001), vomiting (p = 0.001) and myelotoxicity, especially granulocytopenia (p = 0.03) and lymphocytopenia (p = 0.034). In addition, dose intensification was well tolerated in patients receiving OA and CD, allowing dose escalation from 35.6 +/- 6.0 to 39.9 +/- 5.6 mg/m(2)/week (p < 0.001). Tumor response rates for non-small cell lung cancer were 59.3% (16/27 patients) in group B compared with 38.5% (10/26 patients) in group A. Multivariate analysis revealed that the risk of CPT-11-induced delayed diarrhea greater than grade 2 was associated with OA and CD (odds ratio for delayed diarrhea, 0.14 with use of OA and CD; 95% confidence interval, 0.05 to 0.4; p = 0.0002) and age (odds ratio, 1.08 per increase in age; 95% confidence interval, 1.02 to 1.15; p = 0.009). OA and CD appear to be useful in preventing the dose-limiting side effects of CPT-11 noted in clinical practice, mainly nausea, vomiting, granulocytopenia and especially delayed diarrhea. Risk factors statistically associated with delayed diarrhea include advanced age and the use of CPT-11 without OA and CD.
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PMID:Prevention of irinotecan (CPT-11)-induced diarrhea by oral alkalization combined with control of defecation in cancer patients. 1129 Oct 56

PGP 9.5 is a neurospecific peptide that functions to remove ubiquitin from ubiquitinated cellular proteins, thereby preventing them from targeted degradation by the proteasome-dependent pathway or regulating their localization, activity or structure. Using the serial analysis of gene expression method (SAGE), we initially found that the PGP9.5 transcript and protein was highly expressed in more than 50% of primary lung cancers and nearly all lung cancer cell lines but was not detectable in the normal lung. This increased expression could be the result of transcriptional regulation accompanied by methylation changes at the CpG island of the promoter region. We studied the methylation status of the cytosines at the promoter region of human PGP9.5 using sodium bisulfite genomic sequencing in normal and neoplastic cells. Although no methylation of PGP9.5 promoter was observed in the normal lung, normal cervical tissue, and lung cancer cell lines, this region was densely methylated in the HeLa cell line. Exposure to HeLa cells to the demethylating agent, 5-aza-2'-deoxycytidine, led to re-expression of PGP9.5. This data suggested that while other mechanisms may be involved in the frequent overexpression of PGP9.5 gene in lung tumors and lung cancer cell lines, promoter methylation may play a role in the transcriptional suppression of PGP9.5 gene expression in the cervical tissue-derived HeLa cell line.
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PMID:Methylation status in the promoter region of the human PGP9.5 gene in cancer and normal tissues. 1144 37

Photodynamic therapy (PDT) is a cancer treatment modality that is based on the administration of a photosensitiser, which is retained in tumour tissues more than in normal tissues, followed by illumination of the tumour with visible light in a wavelength range matching the absorption spectrum of the photosensitiser. The photosensitiser absorbs light energy and induces the production of reactive oxygen species in the tumour environment, generating a cascade of events that kills the tumour cells. The first generation photosensitiser, Photofrin (porfirmer sodium), has been approved for oesophageal and lung cancer in the US and has been under investigation for other malignant and non-malignant diseases. Sub-optimal light penetration at the treatment absorption peak of Photofrin and prolonged skin photosensitivity in patients are limiting factors for this preparation. Several new photosensitisers have improved properties, especially absorption of longer wavelength light which penetrates deeper into tissue and faster clearance from normal tissue. This paper reviews the current use of first- and second-generation photosensitisers in oncology. The use of PDT in oncology has been restricted to certain cancer indications and has not yet become an integral part of cancer treatment in general. The main advantage of PDT is that the treatment can be repeated multiple times safely, without producing immunosuppressive and myelosuppressive effects and can be administered even after surgery, chemotherapy or radiotherapy. The current work on new photosensitisers and light delivery equipment will address some of the present shortcomings of PDT. Much has been learned in recent years about the mechanisms of cellular and tissue responses to PDT and protocols designed to capitalise on this knowledge showed lead to additional improvements.
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PMID:Photodynamic therapy in oncology. 1158 8

Semaphorins SEMA3B and its homologue SEMA3F are 3p21.3 candidate tumor suppressor genes (TSGs), the expression of which is frequently lost in lung cancers. To test the TSG candidacy of SEMA3B and SEMA3F, we transfected them into lung cancer NCI-H1299 cells, which do not express either gene. Colony formation of H1299 cells was reduced 90% after transfection with wild-type SEMA3B compared with the control vector. By contrast, only 30-40% reduction in colony formation was seen after the transfection of SEMA3F or SEMA3B variants carrying lung cancer-associated single amino acid missense mutations. H1299 cells transfected with wild-type but not mutant SEMA3B underwent apoptosis. We found that lung cancers (n = 34) always express the neuropilin-1 receptor for secreted semaphorins, whereas 82% expressed the neuropilin-2 receptor. Because SEMA3B and SEMA3F are secreted proteins, we tested conditioned medium from COS-7 cells transfected with SEMA3B and SEMA3F and found that medium from wild-type SEMA3B transfectants reduced the growth of several lung cancer lines 30-90%, whereas SEMA3B mutants or SEMA3F had little effect in the same assay. Sequencing of sodium bisulfite-treated DNA showed dense methylation of CpG sites in the SEMA3B 5' region of lung cancers not expressing SEMA3B but no methylation in SEMA3B-expressing tumors. These results are consistent with SEMA3B functioning as a TSG, the expression of which is inactivated frequently in lung cancers by allele loss and promoter region methylation.
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PMID:Inhibition of lung cancer cell growth and induction of apoptosis after reexpression of 3p21.3 candidate tumor suppressor gene SEMA3B. 1171 52

Transforming growth factor (TGF)-beta strongly inhibits epithelial cell proliferation. Alterations of TGF-beta signaling are thought to play a role in tumorigenesis. We show in the present study that most lung cancer cell lines have lost the growth-inhibitory response to TGF-beta signal, and that those with TGF-beta unresponsiveness can be divided into two major groups, TGF-beta type II receptor (TGFbetaRII)(+)/Smad7(+) and TGFbetaRII(-)/Smad7(-), suggesting the heterogeneous mechanisms underlying the TGF-beta responsiveness. The mechanism of the loss of TGFbetaRII expression of the latter group was further studied, identifying aberrant DNA methylation of the promoter region in a limited fraction of cell lines. Interestingly, we found that the alteration of chromatin structure because of histone deacetylation may also be involved, showing a good correlation with loss of TGFbetaRII expression. This notion was supported by the findings of a restriction enzyme accessibility assay, of a chromatin immunoprecipitation assay with anti-acetyl histone antibodies, and of an in vivo induction of TGFbetaRII expression by histone deacetylase inhibitors including trichostatin A (TSA) and sodium butyrate. In vitro induction of TGFbetaRII promoter reporter activity by TSA was also detected and found to require the CCAAT box within the -127/-75 region. A positive regulatory mechanism for TGFbetaRII expression in a TGF-beta-expressing cell line was also investigated, and a TPA-responsive element (TRE)-like motif, TRE2, was detected in addition to the previously reported TRE-like motif Y element in the positive regulatory region. Alterations in two discrete proteins interacting with these two TRE-like motifs were also suspected of being involved in the loss of TGFbetaRII expression. This is the first study to demonstrate that, in addition to the TSA-responsive region and TRE2 motif in the TGFbetaRII promoter, the alteration of histone deacetylation may be involved in the loss of TGFbetaRII expression in lung cancer cell lines.
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PMID:Heterogeneous transforming growth factor (TGF)-beta unresponsiveness and loss of TGF-beta receptor type II expression caused by histone deacetylation in lung cancer cell lines. 1171 67

A novel secondary sponge metabolite, peloruside A (peloruside), isolated from the marine sponge Mycale sp. (New Zealand), was tested for its cytotoxic effects on mammalian cells in culture. The macrolide structure of peloruside is similar to that of the protein kinase C (PKC) activator, bryostatin-1 (bryostatin), both containing a pyranose ring adjacent to a gemdimethyl moiety. Peloruside is a potent inhibitor of cell proliferation. Treatment of different mammalian cell lines with peloruside for 48-96 h gave IC50 values ranging from 4 to 15 nM, using the colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium (MTT) cell proliferation assay. Peloruside was shown to be both cytostatic and cytotoxic by trypan blue dye exclusion tests. Peloruside induced apoptosis in a dose-dependent manner in murine (32D) and human (HL-60) myeloid cell lines, revealed by DNA laddering in agarose gels and flow cytometric analysis of annexin-V- and propidium iodide-stained cells. Treatment of HL-60 cells caused vacuolisation, partial substrate adherence, and the appearance of multi-lobed nuclei, suggesting the induction of a differentiation pathway. Vacuolisation was also observed in a human lung cancer cell line (H441). Opening of the pyranose ring of peloruside by sodium borohydride reduction increased the 48 h IC50 value by 26-fold in 32D cells, suggesting a similar active site to that proposed for bryostatin. However, unlike bryostatin, peloruside failed to bind to PKC in HL-60 cells and was unable to synergize with the calcium ionophore, ionomycin, or with interleukin-2, to activate T-lymphocytes in culture. In summary, although structurally similar to bryostatin, peloruside is a potent inhibitor of cell proliferation, has apoptosis-inducing properties and has a unique mode of action independent of PKC.
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PMID:The novel cytotoxic sponge metabolite peloruside A, structurally similar to bryostatin-1, has unique bioactivity independent of protein kinase C. 1196 13


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