Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0598934 (tumor growth)
58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several epithelial tumors display epidermal growth factor receptor (EGFR) overexpression (with or without EGFR gene amplification) that is often associated with increased production of EGFR ligands. This permits the activation of endogenous tumor EGFR via autocrine mechanisms, resulting in cellular proliferation and tumor growth. Interruption of receptor signaling with bivalent EGFR antibodies or with small molecule inhibitors of the EGFR tyrosine kinase results in inhibition of tumor cell proliferation or viability in vitro and in vivo. One small molecule currently undergoing preclinical and clinical investigation is ZD1839 (Iressa), a synthetic anilinoquinazoline capable of inhibiting EGFR tyrosine kinase in vitro. The early results of clinical trials indicate this drug possesses antitumor activity in certain malignancies of the upper aerodigestive tract.
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PMID:Tyrosine kinase inhibitors-ZD1839 (Iressa). 1167 90

Overexpression of the erbB family of receptor tyrosine kinases has been implicated in a variety of tumors including breast, lung, prostate, and brain. Most solid tumors express one or more of these receptors, which can often be related to tumor aggressiveness and poor patient prognosis. CI-1033, a pan-erbB tyrosine kinase inhibitor, is a clinically promising agent that is active against all four members of the erbB receptor tyrosine kinase family. In vitro studies of human cancer cell lines indicate that CI-1033 results in prompt, potent, and sustained inhibition of tyrosine kinase activity. This inhibition is highly selective for erbB1 (epidermal growth factor receptor), erbB2, erbB3, and erbB4 without inhibiting tyrosine kinase activity of receptors such as platelet-derived growth factor receptor, fibroblast growth factor receptor, and insulin receptor, even at high concentrations. Treatment of athymic nude mice bearing xenografts of human A431 epidermoid carcinoma, H125 non-small cell lung carcinoma, and SF-767 glioblastoma results in highly significant suppression of tumor growth. The major toxicity in animals is diarrhea, which is more severe at higher doses. In animal models, all side effects are reversible on cessation of treatment. Thus, CI-1033, which is currently undergoing phase I clinical trials, holds significant potential for use in a broad range of solid tumors.
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PMID:CI-1033, a pan-erbB tyrosine kinase inhibitor. 1170 99

Exponential tumor growth is angiogenesis-dependent. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are potent angiogenic inducers that act synergistically in vivo and in vitro. We assessed the effect of specific inhibitors of VEGF receptor (VEGFR)-2 tyrosine kinase activity in in vivo and in vitro models of VEGF- and bFGF-induced angiogenesis. In an implant mouse model of angiogenesis, VEGFR-2 inhibitors completely blocked angiogenesis induced by VEGF, and, surprisingly, also inhibited the effect of bFGF to various extents. In vitro, VEGF- and bFGF-induced bovine microvascular and aortic endothelial (BME and BAE) cell collagen gel invasion could be blocked by the VEGFR-2 inhibitors by 100 and approximately 90%, respectively. Similar results were obtained with VEGFR-1-IgG and VEGFR-3-IgG fusion proteins and with VEGFR-2 blocking antibodies. Both BME and BAE cells produce VEGF and VEGF-C, which is not modulated by bFGF. Thus, the unexpected inhibition of bFGF-induced angiogenesis by VEGFR-2 antagonists reveals a requirement for endogenous VEGF and VEGF-C in this process. These findings broaden the spectrum of mediators of angiogenesis that can be inhibited by VEGFR-2 antagonists and highlight the importance of these compounds as agents for inhibiting tumor growth sustained by both VEGF and bFGF.
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PMID:Vascular endothelial growth factor (VEGF) receptor-2 antagonists inhibit VEGF- and basic fibroblast growth factor-induced angiogenesis in vivo and in vitro. 1171 97

Angiogenesis is critical for tumor development, growth and metastasis. The vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) and their tyrosine kinase receptors are major regulators of angiogenesis. Radiation induces the production of VEGF, FGF and PDGF in many tumor cells. We hypothesized that inhibition of the function of these growth factors could inhibit tumor angiogenesis and thereby enhance the efficacy of radiation therapy. To test this hypothesis, we used the small molecule inhibitors SU5416 (an inhibitor for Vegf receptor) and SU6668 (an inhibitor for Vegf, Fgf and Pdgf receptors) alone and in combination with fractionated irradiation to treat C3H mice bearing SCC VII carcinomas. The SCC VII tumors express Vegf, Fgf2 (also known as bFGF), Pdgf and their associated receptors. Animals were given either SU5416 or SU6668 daily before or after irradiation (2 Gy per fraction per day for 5 days). The results from these experiments demonstrate that administration of either SU5416 or SU6668 without radiation delayed tumor growth. Administration of SU5416 at a dose of 25 mg/kg per day (the maximum tolerated effective dose) inhibited tumor growth by 17.9% on day 7 (P < 0.05 compared to untreated control mice) and produced an average tumor growth delay time of 0.5-2.0 days. When combined with fractionated irradiation, administration of SU5416 increased the inhibition of tumor growth to 50-53% on day 7 and the tumor growth delay time to 5.7-6.5 days (P < 0.001 compared with SU5416 alone; P < or = 0.05 compared with radiation alone). SU6668 alone inhibited tumor growth in a dose-dependent manner. Administration of SU6668 at a dose of 75 mg/kg per day (a suboptimal dose) inhibited tumor growth by 36% on day 7 and produced an average tumor growth delay time of 3.3 +/- 1.4 days. The combination of SU6668 with fractionated radiation increased inhibition of tumor growth to 66-70% and the tumor growth delay time from 3.3 days to 11.9 days (P < or = 0.001 compared with either radiation alone or SU6668 alone). Administration of these agents before or after irradiation produced similar results (P = 0.40 for SU5416; P = 0.98 for SU6668). SU5416 or SU6668 alone or in combination with radiation was very well tolerated with little or no toxicity. These results suggest that inhibition of Vegf, Fgf and Pdgf receptor function by SU5416 and SU6668 can enhance the efficacy of irradiation. The targeting of multiple tyrosine kinase receptors by SU6668 is more effective than inhibition of the Vegf receptor alone by SU5416 for the enhancement of tumor cell killing by fractionated irradiation.
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PMID:The antiangiogenic agents SU5416 and SU6668 increase the antitumor effects of fractionated irradiation. 1175 41

Compelling evidence suggests that vascular endothelial growth factor (VEGF) and its receptors play an important role in angiogenesis associated with tumor growth and metastasis. VEGF exerts its biologic activities through 2 transmembrane tyrosine kinase receptors: the fms-like tyrosine kinase receptor (Flt-1, or VEGFR1) and kinase insert domain-containing receptor (KDR or VEGFR2). We have previously produced a panel of antibodies directed against KDR from mice immunized with the recombinant form receptor. These antibodies efficiently neutralized VEGF-induced KDR activation and mitogenesis of human umbilical vascular endothelial cells (HUVEC). Murine antibodies, however, may not be suitable candidates for human therapy because of their propensity to elicit human anti-mouse antibody response. Here we isolated several high-affinity human Fab antibody fragments directed against KDR from an antibody phage display library constructed from the pooled B lymphocytes of nonimmunized healthy human donors. These human Fab fragments bind specifically to KDR with nanomolar affinity and block KDR/VEGF interaction with IC(50) of approximately 2-20 nM. Further, they effectively inhibit VEGF-stimulated mitogenesis of HUVEC and migration of human leukemia cells. Epitope mapping studies demonstrated that all neutralizing human antibodies bound the epitope(s) located within the first 3 N-terminal immunoglobulin-like domains of KDR, the same region that encompasses the binding site of VEGF. Our results suggest that these human anti-KDR antibodies may have potential application in the treatment of cancer and other diseases in which pathologic angiogenesis occurs.
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PMID:Selection of high affinity human neutralizing antibodies to VEGFR2 from a large antibody phage display library for antiangiogenesis therapy. 1177 95

The simultaneous presence of the EGFR and its ligand TGF-alpha in human tumor tissues suggests that autocrine TGF-alpha stimulation drives tumor growth. Here we show that autocrine TGF-alpha stimulation does cause increased tumor growth in vivo, an effect that was proven to be mediated via EGFR activation, and that this TGF-alpha/EGFR autocrine loop was accessible to an EGFR specific tyrosine kinase inhibitor. Clones of the EGFR expressing glioma cell line U-1242 MG were transfected with TGF-alpha cDNA using a tetracycline-inhibitory system for gene expression. TGF-alpha expression was inhibited by the presence of tetracycline, and subcutaneous tumors forming from cell lines injected into nude mice could be inhibited by feeding mice tetracycline. We confirmed that TGF-alpha mRNA and protein were present in these tumors and that, subsequently, the endogenous EGFR was activated. Tumor growth could be inhibited by an EGFR specific tyrosine kinase inhibitor of the type 4-(3-chloroanilino)-6,7-dimethoxy-quinazoline, administered daily by intraperitoneal injection, thereby interrupting the autocrine loop.
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PMID:TGF-alpha-driven tumor growth is inhibited by an EGF receptor tyrosine kinase inhibitor. 1177 76

Until a primary tumor can successfully produce clinically relevant metastases, the seed cells have to go through a series of stepwise changes (mutations) which have to overcome a sizeable cascade of obstacles. Some of the experimentally proven and clinically suspected changes involve cell surface adhesion, general and local growth factor responsiveness, protease and glycosidase production, motility and deformability. In addition to this tumor cell centered view, one begins to broaden the vision to include changes in the interactions between the tumor cell and its immediate environment. In this context it turns out that the tumor cell seems to learn how to entice neighboring cells and tissues to support its progress with several different responses: extracellular matrix degrading enzymes, growth factors in the target organ, angiogenesis etc. The multitude of phenotype variants is due to genome instability, which is higher in metastatic cells than in primary tumor cells. Recently, it could be shown that even chemotherapy drug resistance is increased in the metastatic organ surrounding (lung) compared to non-metastatic organ targets. The role of the immune system for organ specific metastasis is--if anything--less clear than earlier assumed. Important for the surgeon is the fact that his efforts with the primary tumor could become yet even more successful if the dormant or micrometastases could be abolished. New therapeutic approaches include specific inhibitors of angiogenesis receptors (tyrosine kinase inhibitors). Recently, it was found that continuous low dose chemotherapy together with antiinflammatory agents which block endothelial cell migration and growth prevent not only tumor growth, but abolish micrometastases efficiently in animals. Clinical phase II studies are underway. This, as so many other promising starts in cancer therapy, needs, however, solid confirmation on a very expanded scale before any hopes can be raised.
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PMID:[Mechanisms of metastasis]. 1179 30

Receptor tyrosine kinases (RTKs) are a diverse group of transmembrane proteins involved in signal transduction. Their function in many cell types is to drive a wide variety of cellular functions, including growth, differentiation and angiogenesis, by transducing growth factor signals from the external milieu to intracellular processes. In malignancies, these pathways are often exploited by tumor cells to optimize tumor growth and metastasis. Indeed, alterations in RTK pathways have been implicated in oncogenic activation, tumor angiogenesis and mitogenic stimulation. Thus, RTKs are logical targets for novel anticancer agent development. There are currently a large number of small-molecule RTK antagonists in phase I to III clinical development. These agents inhibit the intracellular tyrosine kinase activity of receptors for epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF). The biology and results of clinical trials with these agents will be discussed.
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PMID:Receptor tyrosine kinase inhibitors. 1181 45

We used the hypomorphic Egfr(wa2) allele to genetically examine the impact of impaired epidermal growth factor receptor (Egfr) signaling on the Apc(Min) mouse model of familial adenomatous polyposis. Transfer of the Apc(Min) allele onto a homozygous Egfr(wa2) background results in a 90% reduction in intestinal polyp number relative to Apc(Min) mice carrying a wild-type Egfr allele. This Egfr effect is potentially synergistic with the actions of the modifier-of-min (Mom1) locus. Surprisingly, the size, expansion, and pathological progression of the polyps appear Egfr-independent. Histological examination of the ilea of younger animals revealed no differences in the number of microadenomas, the presumptive precursor lesions to gross intestinal polyps. Pharmacological inhibition with EKI-785, an Egfr tyrosine kinase inhibitor, produced similar results in the Apc(Min) model. These data suggest that normal Egfr activity is required for establishment of intestinal tumors in the Apc(Min) model between initiation and subsequent expansion of initiated tumors. The role of Egfr signaling during later stages of tumorigenesis was examined by using nude mice xenografts of two human colorectal cancer cell lines. Treatment with EKI-785 produced a dose-dependent reduction in tumor growth, suggesting that Egfr inhibitors may be useful for advanced colorectal cancer treatment.
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PMID:Importance of epidermal growth factor receptor signaling in establishment of adenomas and maintenance of carcinomas during intestinal tumorigenesis. 1181 67

Altered expression of alphav integrins plays a critical role in tumor growth, invasion, and metastasis. In this study, we show that normal human epithelial ovarian cell line, HOSE, and ovarian cancer cell lines, OVCA 429, OVCA 433, and OVHS-1, expressed alphav integrin and associated beta1, beta3, and beta5 subunits, but only ovarian cancer cell lines OVCA 429 and OVCA 433 expressed alphavbeta6 integrin. The expression of alphavbeta6 in OVCA 429 and OVCA 433 was far higher than alphavbeta3 and alphavbeta5 integrin and correlated with high p42/p44 mitogen activated protein kinase (MAPK) activity and high secretion of high molecular weight urokinase plasminogen activator (HMW-uPA), pro-metalloproteinase 2 and 9 (pro-MMP-9 and pro-MMP-2). In contrast to HOSE and OVHS 1, OVCA 433 and OVCA 429 exhibited approximately 2-fold more plasminogen-dependent [3H]-collagen type IV degradation. Plasminogen-dependent [3H]-collagen IV degradation was inhibited by inhibitor of uPA (amiloride) and MMP (phenanthroline) and by antibodies against uPA or MMP-9 or alphavbeta6 integrin, indicating the involvement of alphavbeta6 integrin, uPA and MMP-9 in the process. The alphavbeta6 correlated increase in HMW-uPA and pro-MMP secretion could be inhibited by tyrosine kinase inhibitor genistein or the MEK 1 inhibitor U0126, consistent with a role of active p42/44 MAPK in the elevation of uPA, MMP-9, and MMP-2 secretion. Under similar conditions, genistein and U0126 inhibited plasminogen-dependent [3H]-collagen type IV degradation. These data suggest that sustained elevation of p42/44 MAPK activity may be required for the co-expression of alphavbeta6 integrin, which in turn may regulate the malignant potential of ovarian cancer cells via proteolytic mechanisms.
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PMID:Association between alphavbeta6 integrin expression, elevated p42/44 kDa MAPK, and plasminogen-dependent matrix degradation in ovarian cancer. 1183 93


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