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)

Three-dimensional tumor growth is dependent on the perpetual recruitment of host blood vessels to the tumor site. This recruitment process (mainly via angiogenesis) is thought to be triggered, at least in part, by the very same set of genetic alterations (activated oncogenes, inactivated/lost tumor suppressor genes) as those responsible for other aspects of malignant transformation (e.g., aberrant mitogenesis, resistance to apoptosis). Potent oncogenes are able to deregulate expression of both angiogenesis stimulators and inhibitors in cancer cells. For example, mutant ras expression is associated with increased production of vascular endothelial growth factor (VEGF) and downregulation of thrombospondin-1 (TSP-1). Upregulation of VEGF and angiogenesis can also be induced by constitutive activation of other oncogenic proteins (e.g., EGFR, Raf, MEK, PI3K) acting at various levels on the Ras signaling pathway. The mode and the magnitude of such proangiogenic influences can be significantly modified by cell type (fibroblastic or epithelial origin), epigenetic factors (hypoxia, changes in cell density), and/or presence of additional genetic lesions (e.g., preceding loss of p16 or p53 tumor suppressor genes). Activated oncogenes (e.g., ras, src, HER-2) induce co-expression of angiogenic properties concomitantly with several highly selectable traits (increased mitogenesis, resistance to apoptosis), a circumstance that may accelerate selection of the angiogenic phenotype at the cell population level. On the other hand oncogene-induced reduction in growth requirements may also endow tumor cells with a diminished (albeit not abrogated) dependence on (close) proximity to blood vessels, i.e., with reduced vascular dependence. Thus, oncogenes can impact several interconnected aspects of cellular growth, survival, and angiogenesis. Experimental evidence suggests that, in principle, many of these properties (including angiogenesis) can be simultaneously suppressed (and tumor stasis or regression induced) by effective use of the specific oncogene antagonists and signal transduction inhibitors.
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PMID:Oncogenes and angiogenesis: signaling three-dimensional tumor growth. 1114 71

The transforming growth factor-alpha/epidermal growth factor receptor (TGF-alpha-EGFR) autocrine pathway, which is involved in the development and the progression of human epithelial cancers, controls, in part, the production of angiogenic factors. These angiogenic factors, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), are secreted by cancer cells to stimulate normal endothelial cell growth through paracrine mechanisms. ZD1839 (Iressa) is a p.o.-active, selective EGFR-tyrosine kinase inhibitor (TKI) in clinical trials in cancer patients. In this study, we evaluated the antiangiogenic and antitumor activity of ZD1839 in human colon (GEO, SW480, and CaCo2), breast (ZR-75-1 and MCF-7 ADR), ovarian (OVCAR-3), and gastric (KATO III and N87) cancer cells that coexpress TGF-alpha and EGFR. ZD1839 treatment determined a dose- and time-dependent growth inhibition accompanied by the decrease of VEGF, bFGF and TGF-alpha production in vitro. Treatment of immunodeficient mice bearing well-established, palpable GEO xenografts with ZD1839 determined a cytostatic dose-dependent tumor growth inhibition. Immunohistochemical analysis of GEO tumor xenografts after ZD1839 treatment revealed a significant dose-dependent reduction of TGF-alpha, bFGF, and VEGF expression in cancer cells and of neoangiogenesis, as determined by microvessel count. Furthermore, the antitumor activity of ZD1839 was potentiated in combination with the cytotoxic drug paclitaxel in GEO tumor xenografts. Tumor regression was observed in all mice after treatment with ZD1839 plus paclitaxel, and it was accompanied by a significant potentiation in inhibition of TGF-alpha, VEGF, and bFGF expression with a few or no microvessels. Furthermore, 6 of 16 mice bearing well-established, palpable GEO xenografts had no histological evidence of GEO tumors at the end of treatment with ZD1839 plus paclitaxel. These results demonstrate that the antitumor effect of ZD1839 is accompanied by inhibition in the production of autocrine and paracrine growth factors that sustain autonomous local growth and facilitate angiogenesis, and that this effect can be potentiated by the combined treatment with certain cytotoxic drugs, such as paclitaxel.
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PMID:Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. 1135 Sep 18

A mutant epidermal growth factor receptor (variously called DeltaEGFR, de2-7 EGFR, or EGFRvIII) containing a deletion of 267 amino acids of the extracellular domain is frequently highly expressed in human malignant gliomas and has been reported for cancers of the lung, breast, and prostate. We tested the efficacy of a novel monoclonal anti-DeltaEGFR antibody, mAb 806, on the growth of intracranial xenografted gliomas in nude mice. Systemic treatment with mAb 806 significantly reduced the volume of tumors and increased the survival of mice bearing xenografts of U87 MG.DeltaEGFR, LN-Z308.DeltaEGFR, or A1207.DeltaEGFR gliomas, each of which expresses high levels of DeltaEGFR. In contrast, mAb 806 treatment was ineffective with mice bearing the parental U87 MG tumors, which expressed low levels of endogenous wild-type EGFR, or U87 MG.DK tumors, which expressed high levels of kinase-deficient DeltaEGFR. A slight increase of survival of mice xenografted with a wild-type EGFR-overexpressing U87 MG glioma (U87 MG.wtEGFR) was effected by mAb 806 concordant with its weak cross-reactivity with such cells. Treatment of U87 MG.DeltaEGFR tumors in mice with mAb 806 caused decreases in both tumor growth and angiogenesis, as well as increased apoptosis. Mechanistically, in vivo mAb 806 treatment resulted in reduced phosphorylation of the constitutively active DeltaEGFR and caused down-regulated expression of the apoptotic protector, Bcl-XL. These data provide preclinical evidence that mAb 806 treatment may be a useful biotherapeutic agent for those aggressive gliomas that express DeltaEGFR.
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PMID:Growth suppression of intracranial xenografted glioblastomas overexpressing mutant epidermal growth factor receptors by systemic administration of monoclonal antibody (mAb) 806, a novel monoclonal antibody directed to the receptor. 1145 73

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

The purpose of this study was to investigate the effects of a potent LHRH agonist, [D-Trp(6)]LHRH on the basal and EGF-induced cell proliferation and the metastasis-associated properties in A431 human epidermoid carcinoma. [D-Trp(6)]LHRH time-dependently inhibited the basal and EGF-stimulated growth of A431 cancer cells. It is assumed that phosphorylation/dephosphorylation of cellular proteins is highly related to cell growth. This study demonstrates that [D-Trp(6)]LHRH decreased the basal and EGF-induced total cellular kinase activity, particularly the tyrosine phosphorylation of several cellular proteins including the EGFR. In contrast, [D-Trp(6)]LHRH did not cause detectable changes in basal and EGF-stimulated serine/threonine phosphorylation of A431 cellular proteins. The inhibitory effect of [D-Trp(6)]LHRH on A431 cell proliferation was associated with apoptosis as evidenced by the cell morphology and DNA integrity (ladder pattern), the expression of interleukin 1beta-converting enzyme (ICE) and activation of caspase. Furthermore, EGF could rescue the remaining attached A431 cells following [D-Trp(6)]LHRH treatment for 48 hr, which suggests that limited exposure to [D-Trp(6)]LHRH did not channel all cells to irreversible apoptotic process. We also determined the effects of [D-Trp(6)]LHRH on metastasis-associated properties in A431 cells. [D-Trp(6)]LHRH reduced both basal and EGF-stimulated secretion of MMP-9 and MMP-2. In addition, [D-Trp(6)]LHRH suppressed the basal and EGF-induced invasive activity of A431 cells based on an in vitro invasion assay. In conclusion, this study indicates that [D-Trp(6)]LHRH may act partly through activating tyrosine phosphatase activity to inhibit cell proliferation and the metastasis-associated properties of A431 cancer cells. Our work suggests that [D-Trp(6)]LHRH may be therapeutically useful in limiting the tumor growth and metastasis of some neoplasms.
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PMID:Inhibitory effects of a luteinizing hormone-releasing hormone agonist on basal and epidermal growth factor-induced cell proliferation and metastasis-associated properties in human epidermoid carcinoma A431 cells. 1199 39

ZD6474 [N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine]is a potent, p.o. active, low molecular weight inhibitor of kinase insert domain-containing receptor [KDR/vascular endothelial growth factor receptor (VEGFR) 2] tyrosine kinase activity (IC(50) = 40 nM). This compound has some additional activity versus the tyrosine kinase activity of fms-like tyrosine kinase 4 (VEGFR3;IC(50) = 110 nM) and epidermal growth factor receptor (EGFR/HER1; IC(50) = 500 nM) and yet demonstrates selectivity against a range of other tyrosine and serine-threonine kinases. The activity of ZD6474 versus KDR tyrosine kinase translates into potent inhibition of vascular endothelial growth factor-A (VEGF)-stimulated endothelial cell (human umbilical vein endothelial cell) proliferation in vitro (IC(50) = 60 nM). Selective inhibition of VEGF signaling has been demonstrated in vivo in a growth factor-induced hypotension model in anesthetized rat: administration of ZD6474 (2.5 mg/kg, i.v.) reversed a hypotensive change induced by VEGF (by 63%) but did not significantly affect that induced by basic fibroblast growth factor. Once-daily oral administration of ZD6474 to growing rats for 14 days produced a dose-dependent increase in the femoro-tibial epiphyseal growth plate zone of hypertrophy, which is consistent with inhibition of VEGF signaling and angiogenesis in vivo. Administration of 50 mg/kg/day ZD6474 (once-daily, p.o.) to athymic mice with intradermally implanted A549 tumor cells also inhibited tumor-induced neovascularization significantly (63% inhibition after 5 days; P < 0.001). Oral administration of ZD6474 to athymic mice bearing established (0.15-0.47 cm(3)), histologically distinct (lung, prostate, breast, ovarian, colon, or vulval) human tumor xenografts or after implantation of aggressive syngeneic rodent tumors (lung, melanoma) in immunocompetent mice, produced a dose-dependent inhibition of tumor growth in all cases. Statistically significant antitumor activity was evident in each model with at least 25 mg/kg ZD6474 once daily (P < 0.05, one-tailed t test). Histological analysis of Calu-6 tumors treated with 50 mg/kg/day ZD6474 for 24 days showed a significant reduction (>70%) in CD31 (endothelial cell) staining in nonnecrotic regions. ZD6474 also restrained growth of much larger (0.9 cm(3) volume) Calu-6 lung tumor xenografts and induced profound regression in established PC-3 prostate tumors of 1.4 cm(3) volume. ZD6474 is currently in Phase I clinical development as a once-daily oral therapy in patients with advanced cancer.
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PMID:ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. 1218 21

To explore the hypothesis that aging not only increases breast cancer incidence but also alters breast cancer biology, we correlated patient age and diagnosis with tumor histology, stage and biomarkers independently determined from two different tumor archives: an American collection of approximately 800 paraffin-embedded and immunohistochemically analyzed primary breast cancers, and an European collection of approximately 3000 cryobanked primary breast cancers analyzed by ligand-binding and enzyme immunoassay (EIA). The prognostic biomarkers chosen for comparison represented surrogate measures of tumor: (i). proliferation, growth and genetic instability (mitotic and apoptotic indices, Ki-67/MIB-1-positivity, nuclear grade, p53-positivity), (ii). endocrine-dependence (estrogen receptor (ER), progesterone receptors (PR), pS2, Bcl2), (iii). growth factor receptor-dependence (ErbB2, EGFR/ErbB1), and (iv). angiogenic, invasive and proteolytic potential (uPA, PAI-1, Cathepsin D, VEGF). No biomarker reflecting tumor angiogenic, invasive or proteolytic potential showed a significant correlation with patient age at diagnosis. In contrast, significant inverse correlations (|r|>0.1; P< or =0.05) were observed for all measures of tumor growth and genetic instability as well as growth factor receptor overexpression (ErbB2 or EGFR positivity). Only one marker of endocrine-dependence, ER expression, showed a significant positive correlation with patient age at diagnosis. In summary, these findings support the hypothesis that breast cancer biology is significantly affected by patient age. In particular, breast tumors arising in older patients have slower growth rates, are more likely to be ER-positive, and are less likely to be p53-positive, EGFR-positive or ErbB2-positive.
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PMID:Age-associated biomarker profiles of human breast cancer. 1220 28

A mutated form of the EGF receptor (EGFRvIII), resulting from deletion of exons 2-7, is an oncogenic protein that is expressed in multiple human tumors. This mutation induces ligand-independent activation of the EGFR tyrosine kinase and thereby can initiate unregulated cell growth and tumorigenesis. Thus, inhibition of the kinase activity of EGFRvIII is a potential means of suppressing its oncogenic properties. Certain tyrosine kinase inhibitors (tyrphostins) specifically inhibit the wild-type EGFR and thereby inhibit tumor growth both in vitro and in vivo. We demonstrate that the quinazoline tyrphostins AG 1478 and AG 1517 can suppress morphologic transformation of cell lines by EGFRvIII. Quinazolines were found to inhibit receptor autophosphorylation and signaling through MAP kinase, but had minimal effects on association of EGFRvIII with Grb2/SOS. Low concentrations of quinazoline also increased receptor dimerization and phosphotyrosine content. This was associated with increases in colony formation in soft agar and increased invasion through matrigel for AG 1478. Thus, both AG 1478 and AG 1517 can inhibit multiple EGFRvIII signaling pathways, but at low concentrations AG 1478 can enhance colony formation, presumably related to augmented homodimerization of the receptor and activation of downstream signaling.
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PMID:Antagonistic and agonistic effects of quinazoline tyrosine kinase inhibitors on mutant EGF receptor function. 1220 87

The main function of K vitamins is to act as co-factors for gamma-glutamyl carboxylase. However, they have also recently been shown to inhibit cell growth. We have chemically synthesized a series of K vitamin analogs with various side chains at the 2 or 3 position of the core naphthoquinone structure. The analogs with short thio-ethanol side chains are found to be more potent growth inhibitors in vitro of various tumor cell lines. Cpd 5 or [2-(2-mercaptoethanol)-3-methyl-1,4-naphthoquinone] is one of the most potent. The anti-proliferation activity of these compounds is antagonized by exogenous thiols but not by non-thiol antioxidants. This suggests that the growth inhibition is mediated by sulfhydryl arylation of cellular glutathione and cysteine-containing proteins and not by oxidative stress. The protein tyrosine phosphatases (PTP) are an important group of proteins that contain cysteine at their catalytic site. PTPs regulate mitogenic signal transduction and cell cycle progression. PTP inhibition by Cpd 5 results in prolonged tyrosine phosphorylation and activation of several kinases and transcription factors including EGFR, ERK1/2, and Elk1. Cpd 5 could activate ERK1/2 either by signaling from an activated EGFR, which is upstream in the signaling cascade, or by direct inhibition of ERK1/2 phosphatase(s). Prolonged ERK1/2 phosphorylation strongly correlates with Cpd 5-mediated growth inhibition. Cpd 5 can also bind to and inhibit the Cdc25 family of dual specific phosphatases. As a result, several Cdc25 substrates (Cdk1, Cdk2, Cdk4) involved in cell cycle progression are tyrosine phosphorylated and thereby inhibited by its action. Cpd 5 could also inhibit both normal liver regeneration and hepatoma growth in vivo. DNA synthesis during rat liver regeneration following partial hepatectomy, transplantable rat hepatoma cell growth, and glutathione-S-transferase-pi expressing hepatocytes after administration of the chemical carcinogen diethylnitrosamine, are all inhibited by Cpd 5 administration. The growth inhibitory effect during liver regeneration and transplantable tumor growth is also correlated with ERK1/2 phosphorylation induced by Cpd 5. Thus, Cpd 5-mediated inhibition of PTPs, such as Cdc25 leads to cell growth arrest due to altered activity of key cellular kinases involved in signal transduction and cell cycle progression. This prototype K vitamin analog represents a novel class of growth inhibitor based upon its action as a selective PTP antagonist. It is clearly associated with prolonged ERK1/2 phosphorylation, which is in contrast with the transient ERK1/2 phosphorylation induced by growth stimulatory mitogens.
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PMID:K vitamins, PTP antagonism, and cell growth arrest. 1238 79

The receptors for luteinizing hormone-releasing hormone (LHRH) are found in 80% of human ovarian carcinomas. These receptors can be used for targeted chemotherapy with cytotoxic analogs of LHRH, such as AN-207, consisting of 2-pyrrolinodoxorubicin (AN-201) linked to [D-Lys ]LHRH. We investigated the effects of AN-207 and AN-201 on the growth of LHRH receptor-positive ES-2 human ovarian cancers. The effects of the treatment on mRNA and protein levels of human epidermal growth factor (EGF) receptors (EGFR and HER-2) in ovarian tumors were determined by RT-PCR and immunoblotting. In Experiment 1, nude mice bearing ES-2 ovarian tumors were injected i.v. with 250 nmol/kg doses of AN-207, AN-201, the carrier [D-Lys ]LHRH, an unconjugated mixture of AN-201 and [D-Lys ]LHRH or vehicle. AN-207 caused a significant ( <0.01) 59.5% inhibition in tumor growth while its components were ineffective. In Experiment 2, mice with large ES-2 tumors were treated with AN-207 or AN-201 at 250 nmol/kg. Again, AN-207, but not AN-201, inhibited tumor growth. In Experiment 3, the site of action of AN-207 was investigated. The blockade of LHRH receptors with Cetrorelix partially suppressed the antitumor effect of AN-207. Treatment with AN-207 significantly ( <0.01) decreased the expression of mRNA for EGFR, and HER-2 by 27 and 34%, respectively, as compared to controls and reduced the receptor protein levels of EGFR and HER-2 by 35 and 36%, respectively ( <0.05). The results indicate that cytotoxic LHRH analog AN-207 could be considered for chemotherapy of ovarian cancers expressing LHRH receptors.
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PMID:Effective treatment of experimental ES-2 human ovarian cancers with a cytotoxic analog of luteinizing hormone-releasing hormone AN-207. 1239 58


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