Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Direct in vivo gene delivery is a prerequisite for many gene therapy strategies; however, efficacy has been limited by a lack of therapeutic gene transfer. In studying intrapleural malignancy as a model for the gene therapy of non-small cell lung cancer, we previously identified soluble chondroitin sulfate-proteoglycans/glycosaminoglycans (CS-PG/GAGs) in malignant pleural effusions (MPE) as factors that inhibit retroviral vector (RV) transduction. Similarly, we have observed inhibition to gene transfer in the fluid component of MPE using adenoviral (Ad) vectors. Analyses indicate that the factors responsible for the block are filterable, soluble, titrable, and heat stable (56 degrees C). Passage through microporous membranes fractionates the inhibitory factors into large (> 100 kD) components of the effusions. In contrast to RV transduction, hyaluronic acid or CS-PG/GAGs are not the inhibitors because the block is not reversed by pretreatment of the effusions with mammalian hyaluronidase, and exogenous addition of GAGs into the transduction media does not diminish Ad transduction. In considering the mechanism of action of the inhibitory factors, we observe that Ad entry, and specifically the binding of radiolabeled Ad to its target cell, is inhibited in the presence of MPE. Ad internalization may also be impaired; however, these studies exclude soluble fibronectin in MPE as a competitive inhibitor of Ad transduction. Lastly, sepharose A- mediated immunoglobulin depletion of MPE only partially reverses the block, and significant inhibition to Ad gene transfer persists at lower adenovirus:target cell ratios. Identifying the structural and functional basis for inhibition to Ad gene transfer may yield specific strategies to enable better in vivo translation of gene therapy approaches.
Am J Respir Cell Mol Biol 2000 May
PMID:Adenoviral gene transfer is inhibited by soluble factors in malignant pleural effusions. 1078 34

Although MDM2, p21/WAF1, and p53 are considered as regulating each other based on in vitro studies, the relation in human lung cancer is not fully understood. The expressions of these proteins were examined immunohistochemically in 112 resected non-small cell lung cancer specimens and the correlation between them were analyzed. MDM2 was expressed in 45% of all lung cancers. In advanced stage, MDM2-positive cases were observed more frequently than in early stage, showing significant difference. No significant difference was observed in the prognosis of the patients regardless of the expression of any protein. Although no correlation was observed between MDM2 expression and p53 expression, or between p21/WAF1 expression and p53 expression, MDM2 expression was strongly related with p21/WAF1 expression. Therefore, MDM2 expression may relate to the progress of the stage of lung cancer, and MDM2 expression and p21/WAF1 expression may be associated not through the p53-related pathway.
Int J Mol Med 2000 Jun
PMID:MDM2 expression is associated with progress of disease and WAF1 expression in resected lung cancer. 1081 14

ras mutations represent one of the most common oncogenetic lesions in human non-small cell lung cancer (NSCLC) and adversely affect the survival of patients afflicted with this disease. ras-directed gene therapy in the past employed primarily antisense oligonucleotides (AS-ODN) or expression vectors (such as a viral vector construct) that deliver the antisense sequence to inactivate the mutant oncogene message. These approaches produced minimal toxicity, and yet were limited in efficacy. Ribozymes present a viable alternative in antisense therapy by virtue of their renewable catalytic capability for site-specific RNA cleavage. We recently produced an adenoviral vector with a hammerhead ribozyme transgene (KRbz) that is specific for the K-ras codon 12 mutant sequence GUU, given the considerations that (a) in the United States, approx 30% of human NSCLCs express K-ras oncogene mutations, nearly all of which reside in codon 12; (b) anti-K-ras, anti-H, as well as anti-N-ras hammerhead ribozymes are potent growth inhibitors in various human cancers tested; and (c) in vitro and animal model studies suggest that ribozymes directed at oncogene (K- and H-ras C-fos, BCR-ABL) or human immunodeficiency viral gene messages are more effective than their antisense counterpart. This article describes the techniques involved in the production of the KRbz-adenoviral vector that is specific for the K-ras mutation GTT, and summarizes its in vivo antitumor effect against NSCLC xenografts expressing the relevant K-ras mutation in athymic mice.
Mol Biotechnol 2000 May
PMID:Generation of a ribozyme-adenoviral vector against K-ras mutant human lung cancer cells. 1091 21

Previous studies have shown that the expression of the cell-cell adhesion molecule (C-CAM1), located at chromosome 19, is down-regulated in several types of human cancers, including prostate and breast cancers. Two major isoforms of C-CAM1, the long or L-form C-CAM1 and the short or S-form C-CAM1, are derived from the C-CAM1 gene through alternative splicing. Tumor cells transfected with L-form C-CAM1, which contains a cytoplasmic domain, display significantly lower growth rates and less tumorigenicity in both in vitro and in vivo models compared with untransfected tumor cells, suggesting that L-form C-CAM1 may be a tumor suppressor. The transfection of the cytoplasmic domain of L-form C-CAM1 could also cause suppression of tumor growth, further supporting the role of L-form C-CAM1 in tumorigenesis. In contrast to reports of most of the tumor types tested, Ohwada et al. (Am. J. Respir. Cell Mol. Biol., 11: 214-220, 1994) reported that C-CAM1 was not down-regulated or even up-regulated in lung cancer. Because the cytoplasmic domain of L-form C-CAM1 is critical for the tumor suppressor function of C-CAM1, we hypothesized that switching of the isoform rather than down- regulation of C-CAM1 gene expression occurs during lung tumorigenesis. To test this hypothesis, we analyzed pairs of tumor tissue and corresponding normal-appearing lung tissue from 51 patients with non-small cell lung cancer (NSCLC) and 43 cell lines to determine expression profiles of L-form C-CAM1 and S-form C-CAM1 using reverse transcription-PCR. We found that L-form C-CAM1 was the predominant form (75%; 38 of 51) in normal-appearing lung tissue, whereas most (84%; 43 of 51) of the primary NSCLC tissue samples expressed predominantly S-form C-CAM1 (P < 0.0001). Similarly, 19 (79%) of the 24 NSCLC cell lines and 17 (85%) of the 20 small cell lung cancer cell lines expressed predominantly S-form C-CAM1. The frequent alteration of the C-CAM1 expression pattern suggests that C-CAM1 has an important role in lung tumorigenesis.
 ...
PMID:C-CAM1, a candidate tumor suppressor gene, is abnormally expressed in primary lung cancers. 1095 75

Increased expression of cyclooxygenase-2 (COX-2) causes enhanced production of prostaglandins, which are emerging as important mediators of growth stimulation of cancer cells. Overexpression of COX-2 has been found in human non-small cell lung cancer tissues and cell lines. In vitro and in vivo studies showed that nonselective cyclooxygenase inhibitors (like aspirin and indomethacin) may suppress growth of lung cancer cells and may prevent lung tumorigenesis induced by the tobacco-specific carcinogens. However, the molecular mechanisms that mediated the anticancer action of these inhibitors are not well defined. In this study, we examined the effect of a specific COX-2 inhibitor, N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide (NS398), on high COX-2-expressing A549 lung cancer cells. Our results indicated that NS398 inhibited prostaglandin E(2) synthesis and induced G(1) growth arrest in these cells. NS398 specifically up-regulated cyclin-dependent kinase inhibitor p27(KIP1), whereas the expressions of G(1)-acting cyclins and cyclin-dependent kinases were not changed. Additionally, NS398 effectively suppressed cyclin E-associated kinase activity in A549 cells. The molecular mechanism responsible for the induction of p27(KIP1) by NS398 was characterized. We found that NS398 did not induce p27(KIP1) through transcriptional activation because this drug could not stimulate the p27(KIP1) promoter. Metabolic labeling experiments showed that the synthesis rate of p27(KIP1) protein was not altered by NS398. Conversely, pulse-chase assays demonstrated that degradation of p27(KIP1) protein was obviously reduced in NS398-treated cells. We conclude that NS398 enhances p27(KIP1) expression via post-translational regulation, and our results provide a new mechanism by which specific COX-2 inhibitors suppress proliferation of cancer cells.
Mol Pharmacol 2000 Dec
PMID:Induction of p27(KIP1) as a mechanism underlying NS398-induced growth inhibition in human lung cancer cells. 1109 79

Biomira is developing the MUC-1 peptide-based vaccine BLP-25 for the potential treatment of cancer. It is in phase II trials for non-small cell lung cancer (NSCLC) [335997], [353448], [384703]. The MUC-1 mucin secreted by cancer cells has been shown to decrease the activity of certain immune response cells, including killer T-cells, and can inhibit the immune T-cell response by > 70%. BLP-25 is designed to target an immune response to the MUC-1 mucin that is shown by > 90% of common solid tumors. The introduction of IL-2 reverses the T-cell suppression caused by MUC-1 mucin, and enhances the cellular immune response > 100-fold. Biomira has been incorporating IL-2 into a liposomal delivery system for BLP-25 [274576]. In late 1998, Biomira entered into a research collaboration with Axis Genetics. The collaboration will assess the further potential of therapeutic cancer vaccines against MUC-1. Each company has developed a vaccine targeting the MUC-1 peptide and Biomira will be evaluating Axis's vaccine in preclinical trials [313395]. In December 1996, Biomira signed a licensing agreement whereby it was granted the rights to use Dana-Farber Cancer Institute's two US patents relating to MUC-1 (based on pioneering work at the Institute on the identification of cell-surface molecules that are characteristic of cancer cells) for peptide-based cancer vaccines [228101].
Curr Opin Mol Ther 2001 Feb
PMID:Technology evaluation: BLP-25, Biomira Inc. 1124 25

Allelic losses at 1p32-pter have been reported as frequent events in human non-small cell lung cancer (NSCLC). To further characterize the region of deletions, we studied loss of heterozygosity on a panel of 102 microdissected NSCLC samples with 20 polymorphic markers spanning 1p32-pter. Two shortest regions of the overlap of the deletions (SROs) were found: SRO 2a (D1S417--D1S57) and SRO 2b (D1S450--D1S243). Allelic losses at either region correlated independently with advanced stage of disease and with postoperative metastasis and relapse (P < 0.05), suggesting that crucial genes in these regions are involved in NSCLC progression. Mol. Carcinog. 30:151--158, 2001.
Mol Carcinog 2001 Mar
PMID:Two consistently deleted regions within chromosome 1p32-pter in human non-small cell lung cancer. 1130 75

C242-DM1 is a tumor-activated immunotoxin under development by GlaxoSmithKline plc (formerly SmithKline Beecham plc), under licence from ImmunoGen Inc, as a potential treatment for colon tumor. It consists of a colon cancer-specific humanized antibody, C242, conjugated to the maytansine derivative DM1. In preclinical studies, C242-DM1 caused complete tumor regression in animal models of both human pancreatic and non-small cell lung cancer (NSCLC) at non-toxic doses. C242-DM1 has also been evaluated in an immunoconjugate combination with J-591 (Cornell University). The J591-DM1 immunoconjugate demonstrated effective, antigen-specific delivery of a highly cytotoxic drug to PSMA-positive Pca cells in vitro and in vivo with low systemic toxicity. Results from studies in monkeys showed that C242-DM1 had no significant toxicity or side effects, when administered at doses higher than those that were previously shown to completely eradicate human colon tumors in mice [271420]. ImmunoGen acquired the right to evaluate, and an option to license, technology related to maytansines from Takeda. In February 1999, ImmunoGen and SmithKline Beecham signed a US $45 million development and commercialization agreement for C242-DM1 [313493]. In August 1997, Immunogen received an SBIR grant to advance development of huC242-DM1 [258356]. EP-00425235, held by ImmunoGen, covers conjugated forms of ansamitocin (maytansine) derivatives. Takeda holds several patents for the production of ansamitocin and its analogs, the first one being JP-53124692.
Curr Opin Mol Ther 2001 Apr
PMID:Technology evaluation: C242-DM1, ImmunoGen Inc. 1133 34

Significant progress has been made toward identifying growth factors that display autocrine or paracrine effects on the growth of lung cancer cells. Determining the in vivo relevance of specific growth factors on lung tumor formation, however, has not often been demonstrated in laboratory models. Although hepatocyte growth factor (HGF) has been shown to have mitogenic and motogenic effects on human lung cancer cells in vitro, and to have prognostic importance in patients with lung cancer, the effects of HGF on tumor behavior in vivo remain unknown. We therefore developed an airway tumor xenograft model that allowed us to test the hypothesis that HGF promotes human non-small cell lung cancer (NSCLC) growth in vivo. Human airway tumor xenografts were created in Severe Combined Immunodeficient mice by injecting human lung adenocarcinoma cells into human bronchial segments. After determining the optimal times for tumor-cell injection and the time course of tumor growth, we evaluated the effects of HGF on tumor growth by injecting recombinant HGF, or saline as a control, into the lumen of tumor xenografts for 10 consecutive days. Histologic evaluation 2 to 3 wk later revealed that the HGF-injected xenografts had a significantly greater tumor volume and more tumor cells were located in the submucosal space than were found in the saline-injected xenografts. These data demonstrate the usefulness of this novel in vivo model to study NSCLC, and show that HGF promotes both the growth and invasion of human lung cancer in vivo.
Am J Respir Cell Mol Biol 2001 May
PMID:Hepatocyte growth factor promotes tumor growth in a novel in vivo model of human lung cancer. 1135 Aug 24

Nitric oxide synthase expression has been documented in lung tumors, but a potential role for nitric oxide (NO) in induction of capillary formation remains to be elucidated. The purpose of this report was to characterize the direct effects of NO at the level of the tumor-endothelium interface with respect to angiogenesis. A Transwell two-compartment culture system, human endothelial cells (EC), and two human non-small cell lung cancer (CA) lines that constitutively produce NO were used to simulate the EC-tumor cell interface. Both histological types of lung CA, squamous and adenocarcinoma, induced baseline capillary formation by EC within 3 days. This process was inhibited by NO in the microenvironment because decreasing NO production with 100 microM aminoguanidine (AG) significantly increased capillary formation, whereas coincubation with 100 microM AG plus 400 microM L-arginine returned angiogenesis to baseline values. We demonstrate further that NO may exert its inhibitory effects by influencing matrix metalloproteinase expression/activity and tyrosine phosphorylation of proteins in the sprouting tips of nascent capillaries.
Am J Physiol Lung Cell Mol Physiol 2001 Jul
PMID:Nitric oxide modulates capillary formation at the endothelial cell-tumor cell interface. 1140 71


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>