Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The induction and augmentation of tumor non-specific immunity and of tumor-specific immunity by intrapleural, intraperitoneal and subcutaneous injection of interleukin-2 (IL-2) gene-modified Lewis lung carcinoma (LLC) cells (LLC-IL2) was tested in C57BL/6 mice. Intrapleural injection of LLC cells induced lung tumors with a malignant effusion, intraperitoneal injection induced peritoneal tumors with ascites and subcutaneous injection induced subcutaneous tumors. Intrapleural injection of irradiated LLC-IL2 cured pre-existing lung LLC tumors and extended the survival of the mice but did not affect survival of mice with pre-existing peritoneal tumors nor did it affect the growth of s.c. tumors. Intraperitoneal injection of irradiated LLC-IL2 cured pre-existing LLC peritoneal tumors and extended the survival of the mice but did not affect survival of mice bearing lung tumors nor did it affect the growth of s.c. tumors. Subcutaneous injection of irradiated LLC-IL2 did not affect the growth of preexisting s.c. tumors and also did not improve survival of mice bearing the lung or peritoneal tumors. Injection with irradiated LLC-IL2 by all routes, i.e., intrapleural, intraperitoneal and s.c., protected against subsequent re-challenge with LLC. Eight days after the initial immunization (early stage of immunization), non-adherent mononuclear cells in the peritoneal cavity of the mice treated with intraperitoneal injection of irradiated LLC-IL2 displayed enhanced cytotoxicity against LLC, B16-F10 and P815 cells, while the cytotoxic activity of spleen cells in the same mice did not change. The efficiency of induction of tumor-specific immunity was the strongest after intraperitoneal immunization and weakest after s.c. immunization. In vitro analysis using the spleen cells of mice immunized with irradiated LLC-IL2 suggested that CD8+ T cells play a key role in tumor-specific immunity.
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PMID:Genetic immunotherapy by intrapleural, intraperitoneal and subcutaneous injection of IL-2 gene-modified Lewis lung carcinoma cells. 939 64

The reductive conversion of ribonucleotides to deoxyribonucleotides by ribonucleotide reductase (RR) is a crucial and rate-controlling step in the pathway leading to the biosynthesis of DNA, since deoxyribonucleotides are present in extremely low levels in mammalian cells. Mammalian ribonucleotide reductase (RR) is composed of two dissimilar proteins, often referred to as R(1), which contains polythiols and R(2), which contains non-heme iron and a free tyrosyl radical. Both the R(1) and R(2) subunits contribute to the active site of the enzyme. Currently, there are two broad classes of RR inhibitors. The first class includes nucleoside analogs which bind to the R1 subunit of the enzyme, several of which are in development. Among those, Gemcitabine and MDL 101,731 have demonstrated impressive efficacy against various solid tumors. Gemcitabine has now been approved for the treatment of pancreatic cancer and non-small cell lung cancer. The most promising second class of inhibitors of RR includes HCTs [alpha--(N)-heterocyclic carboxaldehyde thiosemicarbazones, e.g., 3-AP and 3-AMP], which exert enzyme inhibitory effect through high affinity binding with non-heme iron. Based on the clinical success achieved by Gemcitabine, it seems reasonable that a strong inhibitor of RR, which is essential for cellular replication, would be a useful addition to the existing therapeutic agents against cancer. In this chapter, we wish to report several highly efficient syntheses for both 3-AP and 3-AMP based upon palladium mediated Stille/Suzuki/Heck coupling reactions. Based upon the in vivo efficacy profile observed with these two agents, 3-AP was chosen over 3-AMP as the candidate for further optimization with the intention to improve its biological and pharmaceutical properties. In this vein, we have completed the synthesis of two water soluble phosphate containing prodrugs and one disulfide-linked prodrug of 3-AP. As expected, bioconversion study using either alkaline phosphatase or glutathione showed that these prodrugs were indeed converted to the parent 3-AP. When evaluated against the murine M-109 lung carcinoma as well as the B16-F10 murine melanoma xenograft models, the newly prepared phosphate prodrugs displayed improved efficacy and safety profiles than that found with the parent. More significantly, the ortho-phosphate prodrug 21 demonstrated impressive antitumor effect using once-a-day dosing regimen. In summary, the results disclosed herein demonstrated that some of 3-AP prodrugs prepared indeed demonstrated improved pharmaceutical, biological and toxicity profiles over the parent 3-AP. Efforts directed towards further optimization of 3-AP prodrugs as novel anticancer agents is clearly warranted.
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PMID:Syntheses and antitumor activities of potent inhibitors of ribonucleotide reductase: 3-amino-4-methylpyridine-2-carboxaldehyde-thiosemicarba-zone (3-AMP), 3-amino-pyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) and its water-soluble prodrugs. 1117 70

The anti-invasive and anti-metastatic effects with new retinoid 4-acetamidophenyl retinoate (4-APR) were studied using in vitro and in vivo experiments. 4-APR, at the dose of 43.3 mg.kg-1.day-1 p.o., was shown to reduce the spontaneous lung metastatic foci of Lewis lung carcinoma. 4-APR was also found to inhibit the artificial lung metastasis of B16-F10 cells by 67.9% and 36.6% and suppress the reconstituted basement membrane invasion of B16-F10 cells by 54.2% and 41.9% at the concentrations of 10(-5) mol.L-1 and 10(-6) mol.L-1, respectively.
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PMID:[Inhibition of tumor invasion and metastasis by retinoid 4-APR]. 1124 15

Treatment of advanced, poorly immunogenic tumors in animal models, considered the closest simulation available thus far for conditions observed in cancer patients, remains a major challenge for cancer immunotherapy. We reported previously that established tumors in mice receiving an agonistic mAb to the T cell costimulatory molecule 4-1BB (CD137) regress due to enhanced tumor antigen-specific cytotoxic T lymphocyte responses. In this study, we demonstrate that several poorly immunogenic tumors, including C3 tumor, TC-1 lung carcinoma, and B16-F10 melanoma, once established as solid tumors or metastases, are refractory to treatment by anti-4-1BB mAb. We provide evidence that immunological ignorance, rather than anergy or deletion, of tumor antigen--specific CTLs during the progressive growth of tumors prevents costimulation by anti-4-1BB mAb. Breaking CTL ignorance by immunization with a tumor antigen-derived peptide, although insufficient to stimulate a curative CTL response, is necessary for anti--4-1BB mAb to induce a CTL response leading to the regression of established tumors. Our results suggest a new approach for immunotherapy of human cancers.
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PMID:Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors. 1187 73

We have recently reported that evodiamine can suppress in vitro invasion and lung metastasis by colon 26-L5 carcinoma cells. To extend our study, we examine here the anti-invasive and metastatic effects of evodiamine on Lewis lung carcinoma (LLC) and B16-F10 melanoma in addition to colon 26-L5 carcinoma. Critical structures of evodiamine for the activities were also evaluated by comparison with compounds possessing structures similar to that of evodiamine. Evodiamine concentration-dependently inhibited the invasion of B16-F10, LLC and colon 26-L5 cells with IC(50) values of 2.4 micro M, 4.8 micro M and 3.7 micro M, respectively. Pre-treatment of colon 26-L5 cells with evodiamine before inoculation into mice caused significant suppression of the liver metastasis as well as the lung metastasis. Lung metastasis by LLC is also inhibited significantly by pre-exposure to evodiamine. When the anti-migratory activity of evodiamine was compared with that of evodiamine-like compounds, rutaecarpine lacking a methyl group at N-14 and a hydrogen at C-13 b exhibited much less effect than evodiamine. In addition, reserpine, having beta-configurated hydrogen at C-13 b, inhibited tumor cell migration more potently than yohimbine, having alpha-configurated hydrogen at the same position. These results suggest that evodiamine may be useful as a leading compound for agents in tumor metastasis therapy. Also, the presence of a methyl group at N-14 and the configuration of hydrogen at C-13 b may be responsible for the inhibitory activities of evodiamine.
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PMID:Anti-invasive and metastatic activities of evodiamine. 1241 68

A series of analogues of NAMI-A, a reference compound active on solid tumor metastases, were synthesized (NAMI-A type complexes). They share the same chemical structure of NAMI-A, and differ from it in the nature of the coordinated nitrogen ligand, such as pyrazole, thiazole and pyrazine, which are less basic than imidazole. This modification confers to the new NAMI-A type complexes a better stability in aqueous solution compared to the parent compound, a very important characteristic for a class of compounds that, with NAMI-A, is currently completing a phase I clinical trial at the Netherlands Cancer Institute of Amsterdam. Cytotoxicity and the effects on cell cycle and invasion were investigated on TS/A, B16-F10 and MCF-7 tumor cell lines, while the inhibition of lung metastases was determined on the mouse experimental tumors Lewis lung carcinoma and MCa mammary carcinoma. The new complexes show a pharmacological activity very similar to that of the parental compound NAMI-A: in vitro they are devoid of meaningful cytotoxicity against tumor cells, and in vivo they inhibit metastasis formation and growth approximately to the same extent as NAMI-A. Thus the new NAMI-A type complexes retain the same potent characteristic of NAMI-A to selectively interact with solid tumor metastases. However, compared to NAMI-A they do not stop cell cycle progression at G2-M level and are more active in preventing the spontaneous invasion of Matrigel by tumor cells exposed for 1 h to 10(-4) M concentration. Globally, these complexes take advantage of the knowledge on NAMI-A and appear particularly interesting for future clinical handling and applications.
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PMID:Ruthenium-based NAMI-A type complexes with in vivo selective metastasis reduction and in vitro invasion inhibition unrelated to cell cytotoxicity. 1242 85

Despite advances in the management of solid tumours, the development of metastases continues to be the most significant problem and cause of death for cancer patients. To define genetic determinants of pulmonary metastases, we have applied oligonucleotide microarrays to established murine models of highly metastatic D122 Lewis lung carcinoma and B16-F10.9 melanoma cell lines. These models are characterised by primary subcutaneous growth in C57BL/6J mice, a period of minimal residual disease and spontaneous pulmonary metastases. Microarray analysis defined seven genes, namely - arginase, brain natriuretic peptide (BNP), interleukin-1 alpha (IL-1 alpha), plasminogen activator inhibitor-2 (PAI-2), surfactant protein C (SP-C), uteroglobin (UG) and wnt-1-induced secreted protein-1 (WISP-1), which were consistently elevated in pulmonary metastases compared to the primary tumour of both D122 and B16-F10.9 models. Previous studies demonstrated that two of these seven genes, IL-1 alpha and PAI-2, are involved in the metastatic process. The results obtained by the microarrays were confirmed by real-time quantitative PCR, for three chosen genes - PAI-2, WISP-1 and UG. Our approach aimed to identify genes essential for the metastatic process in general and for pulmonary metastases specifically. Further research should address the precise role of these genes in the metastasising process to the lungs and test if they could be used as targets for future therapies.
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PMID:Overexpression of a set of genes, including WISP-1, common to pulmonary metastases of both mouse D122 Lewis lung carcinoma and B16-F10.9 melanoma cell lines. 1286 23

Tumor cell motility plays a crucial role in the establishment of tumor metastasis and is affected by a variety of host-derived factors during the event. Hepatocyte growth factor (HGF) is one of these factors and stimulates tumor cell migration remarkably. We previously reported that evodiamine has a marked inhibitory activity on tumor cell invasion and migration in vitro. In this study, the effects of evodiamine on HGF-induced invasion and migration of tumor cell lines, colon 26-L5 carcinoma, B16-F10 melanoma and Lewis lung carcinoma (LLC) were examined. HGF promoted invasive activity of tumor cell lines with maximal induction of 1.8 times at 30 ng/ml for colon 26-L5 and LLC cells, and 2.0 times at 10 ng/ml for B16-F10 cells. Evodiamine inhibited the HGF-stimulated tumor cell invasion and migration in a concentration-dependent manner, and achieved complete suppression at 30 microM in all of the cell lines tested. When tumor cells were seeded on fibronectin-coated plates with evodiamine, their spreading on the plate was obviously inhibited, while their adhesiveness to fibronectin was unaffected. Evodiamine showed a marginal effect on tumor cell growth in a 24-h incubation, although it exhibited a marked inhibition in an over 48-h incubation. These results suggest that evodiamine suppressed HGF-stimulated invasion and migration of tumor cells partly through inhibition of cell spreading.
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PMID:Inhibition by evodiamine of hepatocyte growth factor-induced invasion and migration of tumor cells. 1505 71

In this review we focus on a promising novel histone deacetylase (HDAC) inhibitor (HA-But) obtained by the esterification of butyric acid (BA), the smallest HDAC inhibitor, with hyaluronic acid (HA), the main constituent of the extracellular matrix which selectively recognizes a transmembrane receptor (CD44) overexpressed in most primary cancers and associated with tumor progression. In vitro, HA-But has proved to be 10-fold more effective than BA in inhibiting the proliferation of a panel of human cancer cell lines, representative of the most common human cancers, and, similar to BA, to regulate the expression of some cell cycle-related proteins, to induce growth arrest in the G1/G0 phase of the cell cycle and to increase histone acetylation. In vivo, HA-But treatment has demonstrated a marked potency in inhibiting primary tumor growth and lung metastases formation from murine Lewis lung carcinoma (LL3) as well as liver metastases formation from intrasplenic implantation of LL3 or B16-F10 murine melanoma cells. In particular, the effect of s.c. and i.p. treatment with HA-But on liver metastases resulted, respectively, in 87 and 100% metastases-free animals, and in a significant prolongation of the survival time compared to the control groups. The results suggest that the presence of the HA backbone does not interfere with the biological activity of butyric residues and that HA-But could represent a promising cell-targetable antineoplastic agent for the treatment of primary and metastatic tumors.
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PMID:Hyaluronic acid butyric esters in cancer therapy. 1574 73

Melanoma B16-F10 cells and Lewis lung carcinoma LL/2 cells were engineered with a bacterial gene -- chloramphenicol acetyl transferase (CAT) -- by establishing stable transductants. Expression of CAT in both cell types did not alter the ability of these cells to grow into tumors when injected subcutaneously into mice. In addition, the measurement of CAT levels in the lung using a simple ELISA assay revealed a close correlation with direct counting of metastatic nodules. Thus, the CAT-expressing cells will likely have wide ranging applications to quantify tumor metastasis especially in situations where visual counting is difficult. The availability of genetically labeled mouse B16-F10 melanoma and Lewis lung carcinoma cell lines will facilitate future studies of the mechanism and progression of cancer and the discovery of new therapies.
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PMID:Genetically engineered mouse melanoma and mouse Lewis lung carcinoma models. 1580 14


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