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Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the growth of different cancer cell types, suggesting a broad role for their cyclooxygenase (COX) targets and eicosanoid products in tumor cell growth. Sulindac sulfide, a COX inhibitor, inhibited the growth of non-small-cell lung cancers (NSCLC) both in soft agar and as xenografts in nude mice. Importantly, the concentration of sulindac sulfide required to inhibit NSCLC cell growth greatly exceeded the concentration required to inhibit prostaglandin (PG) E(2) synthesis in NSCLC cells, suggesting that NSAID inhibition of cell growth is mediated by additional targets distinct from COX. Both sulindac sulfide and ciglitazone, a defined peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist, stimulated a promoter construct containing a PPAR response element linked to luciferase and potently inhibited NSCLC cell growth at similar concentrations, indicating a role for PPARgamma as a target of NSAID action in these cells. Overexpression of PPARgamma in NSCLC cells strongly inhibited the transformed growth properties of the cells, providing a molecular confirmation of the results obtained with the PPARgamma agonists. Increased expression of PPARgamma, as well as ciglitazone and sulindac sulfide induced expression of E-cadherin, which has been linked to increased differentiation of NSCLC. Despite the fact that SCLC cell lines expressed little or no cytosolic phospholipase A(2), COX-1, or COX-2, sulindac sulfide and PPARgamma agonists also inhibited the transformed growth of these lung cancer cells. We propose that PPARgamma serves as a target for NSAIDs that accounts for COX-independent inhibition of lung cancer cell growth.
Mol Pharmacol 2002 Nov
PMID:Peroxisome proliferator-activated receptor-gamma is a target of nonsteroidal anti-inflammatory drugs mediating cyclooxygenase-independent inhibition of lung cancer cell growth. 1239 Dec 85

The process of bronchial carcinogenesis is characterized by accumulated genetic abnormalities which ultimately lead to malignant transformation of bronchial epithelial cells, followed by invasion and metastasis. One of the most common and consistent of these genetic lesions is inactivation of the p53 tumor suppressor gene by mutation or deletion. The frequency of p53 alterations in lung cancer is highest in those subtypes of bronchial carcinomas that are most consistently associated with smoking, especially SCLC and squamous cell carcinomas. The frequency is lower in adenocarcinomas, in which the association with smoking, although present, is not as strong. The frequency of p53 abnormalities is higher in patients with greater cumulative tobacco exposure. Tobacco-specific carcinogens, in particular BPDE, cause a unique spectrum of p53 mutations, quite distinct from those found in cancers that are not associated with smoking. This characteristic genetic "signature" may persist even decades following smoking cessation. The prognostic significance of p53 mutations in lung cancer is not entirely clear despite the multitude of clinical studies that have been carried out. Nevertheless, the majority of clinical studies suggest that lung cancers with p53 alterations carry a worse prognosis. Furthermore, those tumors with mutant p53 may be relatively more resistant to chemotherapy and radiation. An understanding of the role of p53 in human lung cancer may lead to more rational targeted approaches for treating this disease. For example, the observation that the introduction of wild-type p53 into lung cancer cells with mutant or deleted p53 may reverse the malignant phenotype despite the presence of multiple other genetic abnormalities (14) suggests that replacement of this gene may be an effective clinical strategy. Preclinical and early clinical studies indicate that this is a promising approach, but clearly more effective means of gene delivery to the tumor cells are required (127-129), as discussed elsewhere in this volume.
Methods Mol Med 2003
PMID:Clinical implications of p53 mutations in lung cancer. 1240 35

In conclusion, we have identified several neuroendocrine markers of SCLC and it is likely that for a successful screening program a small panel would need to be employed. From our studies AVP, CCK-BR, and GRP would be the most appropriate of the classical markers, while certain transcription factors such as sNRSF will also prove useful. Although SCLC may not originate from neuroendocrine cells, these genes appear to be expressed early in disease. The application of neuroendocrine markers for screening clinical samples is discussed in detail in Chapter 20 of the companion to this volume: Detection of small cell lung cancer by RT-PCR for neuropeptides, neuropeptide receptors, or a splice variant of the neuron restrictive silencer factor, Coulson, J. M., et al.
Methods Mol Med 2003
PMID:Neuroendocrine phenotype of small cell lung cancer. 1241 86

Aberrant methylation of CpG islands in promoter regions of tumor cells is one of the major mechanisms for silencing of tumor suppressor genes. We determined the frequency of aberrant promoter methylation of the p16, adenomatous polyposis coli (APC), H-cadherin (CDH13), glutathione S-transferase P1 (GSTP1), O6-methylguanine-DNA-methyltransferase (MGMT), retinoic acid receptor beta-2 (RAR beta), E-cadherin (CDH1), and RAS association domain family 1A (RASSF1A) genes in 198 tumors consisting of small cell lung cancers [SCLCs (n = 43)], non-small cell lung cancers [NSCLCs (n = 115)], and bronchial carcinoids (n = 40). The profile of methylated genes in the two neuroendocrine tumors (SCLC and carcinoids) were very different from that of NSCLC. However, whereas the overall pattern of aberrant methylation of carcinoids was similar to that of SCLC, carcinoids had lower frequencies of methylation for some of the genes tested. There were also significant differences in the methylation profiles between the two major types of NSCLC, adenocarcinoma and squamous cell carcinoma. We performed cluster analysis and found that SCLCs clustered with other SCLCs and carcinoids but not with NSCLCs, whereas the NSCLCs tended to cluster together. Within NSCLCs, adenocarcinomas and squamous cell carcinomas clustered with their respective histological types. Finally, we compared the methylation profiles of SCLC and NSCLC tumors and their respective cell lines (n = 44). In general, methylation frequencies were higher in tumor cell lines, but these differences were seldom significant. Thus, tumor cell lines appear to be suitable models to study aberrant DNA methylation. We conclude that SCLC, carcinoids, squamous cell carcinomas, and adenocarcinomas of the lung have unique profiles of aberrant methylation. Our findings should help us understand differences in the pathogenetic mechanisms of lung cancers.
Mol Cancer Ther 2001 Nov
PMID:DNA methylation profiles of lung tumors. 2207 5

The vasopressin (VP) gene is largely expressed in hypothalamic neurons, where the resultant pro-VP protein is enzymatically cleaved into its peptide hormone components, which include the neuropeptide VP, VP-associated neurophysin, and VP-associated glycopeptide (VAG). Small cell lung cancer (SCLC) tumors also express the VP gene, but the tumor pro-VP protein can remain intact and localize to the cell surface membrane. Previous studies have shown that polyclonal antibodies directed against different regions of the pro-VP protein bind specifically to the surface of cultured SCLC cells and recognize proteins of approximately 20 and approximately 40 kDa in cultured SCLC whole-cell lysate. Thus, these proteins have been designated neurophysin-related cell surface antigen (NRSA). A monoclonal antibody (mAb) designated MAG-1 was raised in this laboratory using a synthetic peptide representing the COOH-terminal sequence of VAG. The MAG-1 mAb recognizes NRSA in SCLC cell and tissue lysates by Western analysis, whereas immunofluorescent cytometric and microscopic analyses indicate that MAG-1 reacts specifically with NRSA on the surface of viable SCLC cells of both the classical and the variant subtype. Immunohistochemical analysis demonstrates that MAG-1 reacts with human SCLC tumor, but not with normal pulmonary epithelial cells in lung tissue. Additionally, a MAG-1 Fab fragment was generated that was also able to recognize NRSA. This is the first study to demonstrate that a mAb directed to the VAG region of the pro-VP protein has the potential for development into an in vivo diagnostic and therapeutic tool that targets plasma membrane-incorporated NRSA.
Mol Cancer Ther 2002 Nov
PMID:Targeting the neurophysin-related cell surface antigen on small cell lung cancer cells using a monoclonal antibody against the glycopeptide region (MAG-1) of provasopressin. 1247 96

A promising therapeutic alternative to inhibition of growth factor receptors is the inhibition of downstream signal transduction pathways. Such an approach may be especially important in tumors that can use signals from multiple growth factor receptors for growth and survival. Both stem cell factor (SCF) and insulin-like growth factor (IGF)-I, components of prominent small cell lung cancer (SCLC) autocrine loops, as well as FCS, can potently activate phosphatidylinositol 3-kinase (PI3K)-Akt signaling, albeit with different kinetics. SCF-induced PI3K-Akt activation occurs rapidly but fades within 60 min; IGF-I and FCS-induced activation persists for at least 6 h. SCF and IGF-I-mediated growth was potently inhibited by LY294002 in proportion to its ability to inhibit phosphatidylinositol 3-kinase (PI3K)-Akt signaling. A panel of six SCLC cell lines grown in 10% FCS was also very sensitive to LY294002, with average IC50 and LD50 of 5 and 25 microM, respectively. These drug concentrations suppressed the growth of the MRC-5 pulmonary fibroblast cell line and primary bronchial epithelial cells but did not induce significant cell death. Because LY294002 can also inhibit PI3K-related enzymes, we confirmed the role of the PI3K-Akt pathway in SCLC using doxycycline-regulated expression of a dominant-negative (kinase dead) and a constitutively active (CA; myristolated) Akt allele. Expression of dominant-negative Akt, which could only be achieved at relatively low levels, completely inhibited growth in the absence of exogenous growth factors and inhibited SCF-mediated growth but had no effect on IGF-I-mediated growth at the expression levels attained. Expression of CA Akt markedly augmented growth in the absence of exogenous growth factors but had minimal effect on growth in the presence of saturating concentrations SCF or IGF-I. Because PI3K-Akt signaling is known to promote survival under apoptotic stresses, we determined the effect of this pathway on SCLC sensitivity to etoposide. LY294002 potentiated the effect of low concentrations of etoposide in inhibiting growth and inducing apoptosis. The effect of low concentrations of LY294002 could largely be reversed by expression of CA Akt, suggesting that it was mediated by inhibition of Akt signaling. Expression of CA Akt by itself also induced resistance to etoposide-mediated apoptosis. Taken together, these data demonstrate that PI3K-Akt signaling promotes SCLC growth, survival, and chemotherapy resistance. Therefore, selective inhibitors of PI3K or Akt could potentially be useful as novel therapeutic agents in the treatment of SCLC.
Mol Cancer Ther 2002 Sep
PMID:Inhibition of phosphatidylinositol 3-kinase-Akt signaling blocks growth, promotes apoptosis, and enhances sensitivity of small cell lung cancer cells to chemotherapy. 1248 12

Positron emission tomography (PET) utilizing fluorine-18 fluorodeoxyglucose (FDG) has been used in the evaluation of non-small cell lung cancer (NSCLC). Recently its use in the staging of small cell lung cancer (SCLC) has been reported. However, the prognostic value of FDG-PET imaging in SCLC has not been studied. We performed a retrospective analysis to assess this, with the following hypotheses: (1) PET-positive patients would have a less favorable prognosis than PET-negative patients and (2) a high standardized uptake value (SUV) would be associated with a poor prognosis. Retrospective review of a mixed population of treated and untreated patients imaged between 1995 and 2000 was performed. Results of 62 scans in 46 patients were analyzed. There were 8 untreated and 38 treated patients. Findings were correlated with pathology, computed tomography/magnetic resonance imaging and clinical data. The sensitivity of PET scanning was 100% with pathological correlation. The prognostic value of a positive PET study was determined. Overall survival in PET-positive cases was significantly worse than that in PET-negative cases ( P=0.0108). Correlation of SUV(max) with survival showed a significant negative correlation ( P=0.0021). In the eight untreated patients, scans were strongly positive and in all cases the scan results concurred with the final clinical stage assigned on the basis of conventional methods. We conclude that FDG-PET imaging provides prognostic information in treated patients. A positive study and a high SUV(max) are significantly associated with poor survival. Additionally, FDG-PET may be helpful in staging and follow-up.
Eur J Nucl Med Mol Imaging 2003 Jan
PMID:Prognostic value of [18F]FDG-PET imaging in small cell lung cancer. 1248 13

Small cell lung cancer (SCLC) is an aggressive illness with early metastases. There are several receptor tyrosine kinases (RTKs) overexpressed in SCLC, including c-Met. c-Met contains an external semaphorin-like domain, a cytoplasmic juxtamembrane domain, tyrosine kinase domain and multiple tyrosines that bind to adapter molecules. We have previously reported that c-Met is abundantly expressed in the NCI-H69 SCLC cell line and now have determined the downstream effects of stimulating c-Met via its ligand hepatocyte growth factor (HGF). Utilizing unique phospho-specific antibodies generated against various tyrosines of c-Met, we show that Y1003 (binding site for c-Cbl and a negative regulatory site), Y1313 (binding site for PI3K), Y1230/Y1234/Y1235 (autophosphorylation site), Y1349 (binding site for Grb2), Y1365 (important in cell morphogenesis) are phosphorylated in response to HGF (40 ng/ml, 7.5 min) in H69 cells. Since multiple biological and biochemical effects are transduced through the PI3K pathway, we determine the role of PI3K in the c-Met/HGF stimulation pathway. We initially determined that by inhibiting PI3K with LY294002 (50 microM over 72 hours), there was at least a 55% decrease in viability of H69 cells. Since H69 SCLC cells form clusters in cell culture, we determined the effects of HGF and LY294002 on cell motility of the clusters by time-lapse video microscopy. In response to HGF, SCLC moved much faster and formed more clusters, and this was inhibited by LY294002. Finally, we determined the downstream signal transduction of HGF stimulation of c-Met with and without inhibition of c-Met (with geldanamycin, an anisamycin antibiotic that inhibits c-Met in SCLC) or PI3K (with LY294002). We show that association of c-Met with PI3K and GAB2 is diminished by inhibiting c-Met. In summary, activation of the c-Met pathway targets the PI3K pathway in SCLC and this may be an important therapeutic target.
J Cell Mol Med
PMID:Activated c-Met signals through PI3K with dramatic effects on cytoskeletal functions in small cell lung cancer. 1261 39

Amplification of oncogenes is an important mechanism that can cause gene overexpression and contributes to tumor development. The identification of amplified regions might have both prognostic and therapeutic significance. We used primary lung carcinomas and lung cancer cell lines for restriction landmark genomic scanning (RLGS) to identify novel amplified sequences. Enhanced RLGS fragments that indicate gene amplification were observed in primary tumors and lung cancer cell lines of both non-small cell lung cancer and small cell lung cancer. We identified one novel amplicon on chromosome 11q22, in addition to previously reported amplicons that include oncogenes MYCC, MYCL1 and previously identified amplification of chromosomal regions 6q21 and 3q26-27. Amplification of 11q22 has been reported in other types of cancer and was refined to an approximately 1.19 Mbp region for which the complete sequence is available. Based on a patient sample with a small region of low-level amplification we were able to further narrow this region to 0.92 Mbp. Genes localized in this region include two inhibitors of apoptosis (cIAP1 and cIAP2). Immunohistochemistry and western blot analysis identified cIAP1 and cIAP2 as potential oncogenes in this region as both are overexpressed in multiple lung cancers with or without higher copy numbers.
Hum Mol Genet 2003 Apr 01
PMID:A comprehensive search for DNA amplification in lung cancer identifies inhibitors of apoptosis cIAP1 and cIAP2 as candidate oncogenes. 1265 74

The purpose of this study was to evaluate the activity of the indolinone kinase inhibitor SU11248 against the receptor tyrosine kinase KIT in vitro and in vivo, examine the role of KIT in small cell lung cancer (SCLC), and anticipate clinical utility of SU11248 in SCLC. SU11248 is an oral, multitargeted tyrosine kinase inhibitor with direct antitumor and antiangiogenic activity through targeting platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor, KIT, and FLT3 receptors. Treatment of the KIT-expressing SCLC-derived NCI-H526 cell line in vitro with SU11248 resulted in dose-dependent inhibition of stem cell factor-stimulated KIT phosphotyrosine levels and proliferation. The biological significance of KIT inhibition was evaluated in vivo by treating mice bearing s.c. NCI-H526 tumors with SU11248 or another structurally unrelated KIT inhibitor, STI571 (Gleevec), which is also known to inhibit Bcr-Abl and PDGFRbeta. SU11248 treatment resulted in significant tumor growth inhibition, whereas inhibition from STI571 treatment was less dramatic. Both compounds reduced phospho-KIT levels in NCI-H526 tumors, with a greater reduction by SU11248, correlating with efficacy. Likewise, phospho-PDGFRbeta levels contributed by tumor stroma and with known involvement in angiogenesis were strongly inhibited by SU11248 and less so by STI571. Because platinum-based chemotherapy is part of the standard of care for SCLC, SU11248 was combined with cisplatin, and significant tumor growth delay was measured compared with either agent alone. These results expand the profile of SU11248 as a KIT signaling inhibitor and suggest that SU11248 may have clinical potential in the treatment of SCLC via direct antitumor activity mediated via KIT as well as tumor angiogenesis via vascular endothelial growth factor receptor FLK1/KDR and PDGFRbeta.
Mol Cancer Ther 2003 May
PMID:SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. 1274 9


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