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)

Chemically stabilized hammerhead ribozymes are nuclease-resistant, RNA-based oligonucleotides that selectively bind and cleave specific target RNAs. Due to their potential for specifically inhibiting gene expression, ribozymes are being investigated for therapeutic applications as well as for the elucidation of gene function. In particular, we have investigated ribozymes that target the mRNA of the vascular endothelial growth factor (VEGF) receptors because VEGF signaling is an important mediator of tumor angiogenesis and metastasis. Here we report pharmacodynamic studies testing anti-Flt-1 (VEGFR-1) and anti-KDR (VEGFR-2) ribozymes in animal models of solid tumor growth and metastasis. Ribozymes targeting either Flt-1 or KDR significantly inhibited primary tumor growth in a highly metastatic variant of Lewis lung carcinoma. However, only treatment with the anti-Flt-1 ribozyme resulted in a statistically significant and dose-dependent inhibition of lung metastasis in this model. The anti-Flt-1 ribozyme was then tested in a xenograft model of human metastatic colorectal cancer in which significant inhibition of liver metastasis was observed. Taken together, these data represent the first demonstration that synthetic ribozymes targeting VEGF receptor mRNA reduced the growth and metastasis of solid tumors in vivo.
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PMID:Antitumor and antimetastatic activity of ribozymes targeting the messenger RNA of vascular endothelial growth factor receptors. 1081 37

Vascular endothelial growth factor (VEGF) and its two receptors, Fms-like tyrosine kinase 1 (Flt-1) (VEGFR-1) and KDR/Flk-1 (VEGFR-2), have been demonstrated to be an essential regulatory system for blood vessel formation in mammals. KDR is a major positive signal transducer for angiogenesis through its strong tyrosine kinase activity. Flt-1 has a unique biochemical activity, 10-fold higher affinity to VEGF, whereas much weaker tyrosine kinase activity compared with KDR. Recently, we and others have shown that Flt-1 has a negative regulatory function for physiological angiogenesis in the embryo, possibly with its strong VEGF-trapping activity. However, it is still open to question whether the tyrosine kinase of Flt-1 has any positive role in angiogenesis at adult stages. In this study, we examined whether Flt-1+ could be a positive signal transducer under certain pathological conditions, such as angiogenesis with tumors overexpressing a Flt-1-specific, VEGF-related ligand. Our results show clearly that murine Lewis lung carcinoma cells overexpressing placenta growth factor-2, an Flt-1-specific ligand, grew in wild-type mice much faster than in Flt-1 tyrosine kinase domain-deficient mice. Blood vessel formation in tumor tissue was higher in wild-type mice than in Flt-1 tyrosine kinase-deficient mice. On the other hand, the same carcinoma cells overexpressing VEGF showed no clear difference in the tumor growth rate between these two genotypes of mice. These results indicate that Flt-1 is a positive regulator using its tyrosine kinase under pathological conditions when the Flt-1-specific ligand is abnormally highly expressed. Thus, Flt-1 has a dual function in angiogenesis, acting in a positive or negative manner in different biological conditions.
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PMID:Involvement of Flt-1 tyrosine kinase (vascular endothelial growth factor receptor-1) in pathological angiogenesis. 1122 52

Tumour angiogenesis is the result of the imbalance between a large number of mediators with angiogenic and antiangiogenic activity. It may be a very early process in vivo and it may follow different pathways in different organs. Moreover, different roles of angiogenic molecules have been observed in normal and neoplastic lung and striking differences between non-small cell lung carcinomas (NSCLC) and SCLC have been observed. Contradictory results are reported in the literature on the association of angiogenesis with poor prognosis in NSCLC. Among the currently available antiangiogenic therapies, the inhibitors of vascular endothelial growth factor (VEGF), and their receptor (VEGFR) and matrix metallo-proteinase (MMP), some antivascular agents and the antiangiogenic scheduling of chemotherapy are beginning to show clinical efficacy. The best use of the antiangiogenic therapies will probably be in presence of low tumour burdens and in association with chemotherapy. However, new surrogate markers of tumour response have to be defined.
Lung Cancer 2001 Dec
PMID:Angiogenesis and antiangiogenic agents in non-small cell lung cancer. 1174 95

The vascular endothelial growth factor (VEGF) receptor fetal liver kinase 1 (flk1; VEGFR-2, KDR) is an endothelial cell-specific receptor tyrosine kinase that mediates physiological and pathological angiogenesis. We hypothesized that an active immunotherapy approach targeting flk1 may inhibit tumor angiogenesis and metastasis. To test this hypothesis, we first evaluated whether immune responses to flk1 could be elicited in mice by immunization with dendritic cells pulsed with a soluble flk1 protein (DC-flk1). This immunization generated flk1-specific neutralizing antibody and CD8+ cytotoxic T cell responses, breaking tolerance to self-flk1 antigen. Tumor-induced angiogenesis was suppressed in immunized mice as measured in an alginate bead assay. Development of pulmonary metastases was strongly inhibited in DC-flk1-immunized mice challenged with B16 melanoma or Lewis lung carcinoma cells. DC-flk1 immunization also significantly prolonged the survival of mice challenged with Lewis lung tumors. Thus, an active immunization strategy that targets an angiogenesis-related antigen on endothelium can inhibit angiogenesis and may be a useful approach for treating angiogenesis-related diseases.
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PMID:Active immunization against the vascular endothelial growth factor receptor flk1 inhibits tumor angiogenesis and metastasis. 1207 Feb 85

Several classes of agents now exist that target the different steps involved in angiogenesis. These include drugs inhibiting matrix breakdown, the matrix metalloproteinase inhibitors (MMPIs), such as marimastat, prinomastat, BMS275291, BAY12-9566, and neovastat. Trials of this class of agents have all been negative to date. Drugs that block endothelial cell signaling via vascular endothelial growth factor (VEGF) and its receptor (VEGFR) including rhuMAb VEGF, SU5416, SU6668, ZD6474, CP-547,632 and ZD4190 are all in earlier stages of clinical trial. Drugs that are similar to endogenous inhibitors of angiogenesis including interferons have also been evaluated without success. Endostatin has been shown to have an acceptable toxicity profile, but clinical evidence of activity has not yet been demonstrated. There has also been renewed interest in thalidomide. Drugs such as squalamine, celecoxib, ZD6126, TNP-470 and those targeting the integrins are also being evaluated in lung cancer. Despite early enthusiasm for many of these agents, Phase III trials have not yet demonstrated significant increases in overall survival and toxicity remains an issue. It is hoped that as our understanding of the complex process of angiogenesis increases, so will our ability to design more effective targeted therapies.
Lung Cancer 2003 Aug
PMID:Angiogenesis inhibitors under study for the treatment of lung cancer. 1286 64

It has now been almost 30 years since Dr J. Folkman first proposed that inhibition of angiogenesis could play a key role in treating cancer; however, it is only recently that anti-angiogenesis agents have entered the clinical setting. The search for novel therapies is particularly important in lung cancer, where the majority of patients succumb to their disease despite aggressive treatments. Several classes of agents now exist that target the different steps involved in angiogenesis. These include drugs inhibiting matrix breakdown, the matrix metalloproteinase inhibitors (MMPIs), such as marimastat, prinomastat, BMS275291, BAY12-9566, and neovastat drugs that block endothelial cell signaling via vascular endothelial growth factor (VEGF) and its receptor (VEGFR) including rhuMAb VEGF, SU5416, SU6668, ZD6474, CP-547,632 and ZD4190. Drugs that are similar to endogenous inhibitors of angiogenesis including endostatin, angiostatin and interferons. There has also been renewed interest in thalidomide. Drugs such as squalamine, celecoxib, ZD6126, TNP-470 and those targeting the integrins are also being evaluated in lung cancer. Despite early enthusiasm for many of these agents, Phase III trials have not yet demonstrated significant increases in overall survival and toxicity remains an issue. It is hoped that as our understanding of the complex process of angiogenesis increases, so will our ability to design more effective targeted therapies.
Lung Cancer 2003 Dec
PMID:Targeting angiogenesis: a review of angiogenesis inhibitors in the treatment of lung cancer. 1461 19

Angiogenesis is a precondition to invasion and metastasis for all solid tumors. Vascular endothelial growth factor (VEGF) and its family of receptors (VEGFR) play a critical role in cancer progression by promoting new blood vessel formation. Overexpression of VEGF and VEGFR has been correlated with poor prognosis in a variety of malignancies. In this era of targeted therapies for cancer, inhibiting angiogenesis through antiangiogenic and/or vascular targeting agents seems logical. Disturbing the angiogenesis process is an alternative or complementary strategy to inhibition of growth factor signaling. Blocking angiogenesis may enhance conventional anticancer treatments such as radiation therapy in situations where tumors are unresponsive to current antigrowth factor efforts. Compounds currently under investigation in cancer therapy include anti-VEGF/VEGFR antibodies, small molecule VEGFR tyrosine kinase inhibitors, antisense suppression of VEGF, immunotherapy, viral-directed targeting of VEGFR signaling, ribozymes, and various toxin conjugates. Preclinical investigations are exploring the benefits of combining angiogenic inhibitors with radiation. This article will provide an overview of these preclinical studies and the rationale for this therapeutic strategy in the treatment of non-small-cell lung cancer.
Clin Lung Cancer 2004 Jul
PMID:Angiogenesis inhibitors: a rational strategy for radiosensitization in the treatment of non-small-cell lung cancer? 1531 Apr 17

Studies have suggested that the vascular endothelial growth factors (VEGFs)/VEGF receptors (VEGF-Rs) system plays an important role in tumour growth and metastasis. We conducted the present study to clarify whether small cell lung cancer (SCLC) cells express functional VEGF-Rs and VEGFs, and their biological significance in the SCLC progression. We examined expression of VEGF and VEGF-C, and their receptors, VEGFR-2 and VEGFR-3, in five SCLC cell lines, NCI-H82, H209, H510, H526 and H660, by Western blotting. We evaluated whether hypoxic conditions up-regulate these protein expressions. We also examined whether VEGF addition and VEGF-D addition cause phosphorylation of the mitogen-activated protein kinase (MAPK) as well as VEGFR-2 and VEGFR-3. Further, we investigated whether VEGF addition and VEGF-D addition induced the proliferation and migration of the SCLC cells. VEGF, VEGF-C, VEGFR-2 and VEGFR-3 were detectable by Western blotting in all five SCLC cell lines,. The VEGF-Rs and VEGFs expression levels were increased by an incubation under hypoxic conditions in NCI-H82. VEGF addition and VEGF-D addition caused phosphorylation of MAPK as well as the VEGF-Rs themselves, and induced proliferation and migration of the SCLC cells. These results suggested potential of VEGF signal-pathway inhibitors as anti-cancer agents in SCLC treatment disturbing growth and migration of the cancer cells.
Lung Cancer 2004 Oct
PMID:Human small cell lung cancer cells express functional VEGF receptors, VEGFR-2 and VEGFR-3. 1536 28

Molecular targeting is a promising option to increase the radiation response of tumours and to decrease normal tissue reactions, i.e. to achieve therapeutic gain. Molecular targeting substances in themselves are not curative while radiation is a highly efficient cytotoxic agent, with local recurrences often occurring from only few surviving clonogenic cells. High-dose radiotherapy therefore offers optimal conditions to evaluate the potential of specific biology-driven drugs for oncology. This review summarises the current status of preclinical and clinical research on combined radiation with examples of molecular targeting substances relevant for the treatment of NSCLC (EGFR, COX-2, VEGFR, KGF, TGF-beta, BBI).
Lung Cancer 2004 Aug
PMID:Molecular targeting in radiotherapy of lung cancer. 1555 99

A series of substituted 4-(2,4-difluoro-5-(methoxycarbamoyl)phenylamino)pyrrolo[2,1-f][1,2,4]triazines was identified as potent and selective inhibitors of the tyrosine kinase activity of the growth factor receptors VEGFR-2 (Flk-1, KDR) and FGFR-1. The enzyme kinetics associated with the VEGFR-2 inhibition of compound 50 (K(i) = 52 +/- 3 nM) confirmed that the pyrrolo[2,1-f][1,2,4]triazine analogues are competitive with ATP. Several analogues demonstrated low-nanomolar inhibition of VEGF- and FGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation. Replacement of the C6-ester substituent of the pyrrolo[2,1-f][1,2,4]triazine core with heterocyclic bioisosteres, such as substituted 1,3,5-oxadiazoles, afforded compounds with excellent oral bioavailability in mice (i.e., 50 F(po) = 79%). Significant antitumor efficacy was observed with compounds 44, 49, and 50 against established L2987 human lung carcinoma xenografts implanted in athymic mice. A full account of the synthesis, structure-activity relationships, pharmacology, and pharmacokinetic properties of analogues within the series is presented.
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PMID:Design, synthesis, and evaluation of orally active 4-(2,4-difluoro-5-(methoxycarbamoyl)phenylamino)pyrrolo[2,1-f][1,2,4]triazines as dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 inhibitors. 1594 73


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