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)

Epidemiological and preclinical studies demonstrate that consumption of diets high in omega-3 fatty acids (n-3 PUFAs) reduce the risk of colon cancer. Docosahexaenoic acid (DHA), a long chain polyunsaturated fatty acid (PUFAs) is a major constituent of nutrients rich in n-3 PUFAs. There are studies to indicate that colon tumor inhibition by n-3 PUFA-rich diets is, in part, mediated through modulation of signaling pathways that alter gene expression which are involved in colon tumor growth. In the present study using CaCo-2 colon cancer cell lines we examined the effects of DHA on the genetic precursors of human colon cancer at the transcription level using DNA oligonucleotide arrays. Our results indicated that DHA inhibits the growth of CaCo-2 cells and induces apoptosis. For gene expression analysis using DNA microarrays, total RNA extracted from DHA treated CaCo-2 cells was converted to cDNA, labeled with Cy5-dCTP (DHA-treated) and Cy3-dCTP (untreated cells) and used as probes for hybridization in human chip spotted with 3,800 oligonucleotides consisting of 156 functional categories. The expression profiles of genes indicated a reprogramming pattern of previously known and unknown genes and transcription factors that provided clues to the possible functional mechanism of DHA. An average of (ratios from triplicate experiments) 504 out of 3,800 genes expressed after 48 h of DHA treatment. Altered expression on the transcription factors includes down regulation of nine members of the RNA II polymerases, transcription co-repressor associated protein and enhancer binding proteins such as AP2, in addition to changes in the expression of zinc finger group of transcription factors. Activation of cytochrome c which triggers caspases was associated with the elevated expression of pro-apoptotic caspases 10, 13, 8, 5 and 9 in DHA treated cells. Activation of cyclin-dependent kinase inhibitors such as p21 (waf1/cip1), p27, p57, p19 and growth arrest specific proteins by more than 2-fold is consistent with the induction of apoptosis and inactivation of antiapototic Bcl-2 family of genes. Inactivation of prostaglandin family of genes, lipoxygenases and altered expression of peroxisome proliferators (PPARalpha and gamma) by DHA seem to indicate a lipid peroxidation-induced apoptosis in addition to effect reflected on the modification of cell cycle regulatory genes. These findings support the conclusion that a genomewide expression profiling of human colon cancer precursor genes and transcription factors provides a set of novel regulatory mechanism(s) to determine the chemopreventive efficacy of DHA and thus to prevent the inflammation and neoplasia.
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PMID:Docosahexaenoic acid regulated genes and transcription factors inducing apoptosis in human colon cancer cells. 1171 97

Peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed largely in adipose tissues and plays an important role in adipocyte differentiation. Several studies have recently shown that ligands of PPARgamma could lead to growth inhibition in some malignancies. In our study, we focused on pancreatic cancers, because the prognosis of advanced pancreatic cancer has not significantly improved due to its resistance to various chemotherapeutic regimens, so that a novel strategy should be required. We show here that PPARgamma is expressed in 5 pancreatic cancer cell lines detected in both mRNA and protein level as well as in human primary and metastatic pancreatic carcinomas examined by immunohistochemical studies. A specific ligand of PPARgamma, troglitazone, led to G1 accumulation with the increase in p27(Kip1), but not p21(Waf1/Cip1) and inhibited cellular proliferation in a pancreatic cancer cell line, Panc-1. The overexpression of PPARgamma in a pancreatic cancer cell line, KMP-3, caused lipid accumulation, which suggested cell growth in some cancers might be inhibited, at least in part, through terminal differentiation in the adipogenic lineage. In addition, implanted Panc-1 tumors in nude mice showed significant inhibition of tumor growth, when treated with pioglitazone, another specific ligand of PPARgamma. Our results suggest that ligands of PPARgamma may be a novel therapeutic agent for the treatment of pancreatic carcinomas.
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PMID:Ligands for peroxisome proliferator-activated receptor gamma inhibit growth of pancreatic cancers both in vitro and in vivo. 1174 16

In human androgen-independent prostate cancer (PCa), epidermal growth factor receptor (EGFR) regulates angiogenesis, tumor growth, and progression. In this study, we evaluated whether the blockade of EGFR by the anti-EGFR antibody ImClone C225 (IMC-C225) inhibited tumor growth and metastasis by inhibiting angiogenesis, and whether paclitaxel enhanced the results of therapy in androgen-independent PCa. PC-3M-LN4 PCa cells were implanted orthotopically in athymic nude mice and treated with i.p. IMC-C225 (1 mg twice a week) and/or paclitaxel (200 microg once a week). In vitro treatment of PC-3M-LN4 with IMC-C225 inhibited EGFR autophosphorylation without any significant antiproliferative effect. In contrast, in vivo therapy with IMC-C225 alone (P < 0.05) or in combination with paclitaxel (P < 0.005) significantly inhibited PCa growth and metastasis. Serum levels of interleukin (IL) 8 were lower after therapy, and IL-8 mRNA expression was down-regulated within the tumors after therapy. The down-regulation of IL-8 correlated with reduced microvessel density. IMC-C225 reduced tumor cell proliferation, enhanced p27(kip1) expression, and induced tumor and endothelial cell apoptosis. These studies indicate that IMC-C225 has significant antitumor effect in this murine model, mediated in part by inhibition of cellular proliferation and angiogenesis, and by enhancement of apoptosis. The simultaneous administration of paclitaxel enhanced this effect.
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PMID:Inhibition of angiogenesis by the antiepidermal growth factor receptor antibody ImClone C225 in androgen-independent prostate cancer growing orthotopically in nude mice. 1200 46

Knowledge of the role of cell-cycle regulators in the pathogenesis of acquired immune deficiency syndrome-related non-Hodgkin's lymphomas (AIDS-NHLs) is scarce. Here we analyzed 86 systemic AIDS-NHLs and 20 AIDS-primary central nervous system lymphomas for expression of p27(Kip1), a negative regulator of cell-cycle progression belonging to the Kip family of cyclin-dependent kinase inhibitors. In parallel, we investigated the relationship between p27(Kip1), the lymphoma proliferation index, Epstein-Barr virus status, expression of cellular cyclin D3 and cyclin D1, and B-cell differentiation stage. We report that AIDS-immunoblastic lymphomas (AIDS-IBLs), either systemic or primarily localized to the central nervous system, consistently express p27(Kip1) protein (19 of 24 and 10 of 14, respectively) despite the high proliferative rate of the lymphoma clone, suggesting a failure of p27(Kip1) to inhibit the cell cycle in AIDS-IBL. Conversely, the remaining systemic AIDS-NHLs and AIDS-primary central nervous system lymphomas preferentially fail to express p27(Kip1). Expression of p27(Kip1) in Epstein-Barr virus-positive AIDS-NHLs generally associates with latent membrane protein 1 (LMP1) expression and is related to a late stage of B-cell differentiation, characterized by the BCL-6-/MUM1+/syn-1+/- phenotypic profile, whereas it seems to be unrelated to the expression of cellular cyclins. In B cells in vitro, induction of LMP-1 expression under the control of inducible promoters up-regulates expression of p27(Kip1), thus providing a putative mechanistic explanation for the association between LMP1 and p27(Kip1) observed in vivo. Overall, these data show that AIDS-IBL pathogenesis is characterized by loss of the inverse relationship between p27(Kip1) positivity and tumor growth fraction that is otherwise generally observed in normal lymphoid tissues and in most other types of NHLs.
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PMID:Expression of cyclin-dependent kinase inhibitor p27(Kip1) in AIDS-related diffuse large-cell lymphomas is associated with Epstein-Barr virus-encoded latent membrane protein 1. 1210 1

The cyclin-dependent kinase (CDK) inhibitors p21(Cip1) and p27(Kip1) are induced in response to anti-proliferative stimuli and block G(1)/S-phase progression through the inhibition of CDK2. Although the cyclin E-CDK2 pathway is often deregulated in tumors the relative contribution of p21(Cip1) and p27(Kip1) to tumorigenesis is still unclear. The MYC transcription factor is an important regulator of the G(1)/S transition and its expression is frequently altered in tumors. Previous reports suggested that p27(Kip1) is a crucial G(1) target of MYC. Our study shows that in mice, deficiency for p27(Kip1) but not p21(Cip1) results in decreased survival to retrovirally-induced lymphomagenesis. Importantly, in such p27(Kip1) deficient lymphomas an increased frequency of Myc activation is observed. p27(Kip1) deficiency was also shown to collaborate with MYC overexpression in transgenic lymphoma models. Thus, in vivo, the capacity of MYC to promote tumor growth is fully retained and even enhanced upon p27(Kip1) loss. We show that in lymphocytes, MYC overexpression and p27(Kip1) deficiency independently stimulate CDK2 activity and augment the fraction of cells in S phase, in support of their distinct roles in tumorigenesis.
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PMID:Loss of p27(Kip1) but not p21(Cip1) decreases survival and synergizes with MYC in murine lymphomagenesis. 1211 May 86

Pituitary hyperplasia and tumor growth are regulated by various hormones and growth factors. Estrogen (E(2)) stimulates pituitary cell proliferation and prolactin (PRL) production. Estrogen also regulates transforming growth factor-B (TGF-B) effects in the pituitary. IGF-B in turn regulates various cell cycle proteins including p15 and p27(Kip1) (p27). To better understand the regulatory role of growth factors and hormones in the cell cycle we analyzed cyclin D(1), cyclin E, and p27 expression in normal and neoplastic rat pituitary cells. An in vitro analysis using cultured normal pituitary cells and GH(3) tumor cells and an in vivo analysis of estrogen-treated normal pituitary and implanted GH(3) cells were performed. Semiquantitative RT-PCR was used to analyze mRNA expression for cyclin D(1) cyclin E, and p27 in cultured pituitary cells and E(2)-treated pituitaries in vivo, Cyclin D(1) and p27 were localized in the nuclei of normal pituitary cells by immunocytochemistry (ICC). Very weak or absent immunostaining for cyclin D(1) and p27 was present in GH(3) cells. Both normal pituitary and GH(3) cells had strong nuclear staining for cyclin E. Normal pituitary had a 20-fold greater amount of cyclin D mRNA and a 3-fold greater amount of p27 mRNA compared to GH cells, whereas GH cells had slightly (1.5-fold) more cyclin E than normal pituitary cells. Treatment in vivo stimulated cell proliferation and decreased cyclin D(1) mRNA levels in normal pituitary. GH(3) tumor cells, implanted subcutaneously in the same animal, showed increased proliferation after E(2) treatment, but there was no change in cyclin B(1) mRNA in GH(3) cells. Cyclin E and p27 mRNA levels did not change significantly in normal pituitary or in GH(3) cells after E(2) treatment in vivo. Treatment of normal pituitary cells with 10(-9)M TGF-B1 for 3 d in vitro led to significant decreases in cyclin B(1) and p27 mRNAs (p < 0.05 ), whereas cyclin E levels were unchanged. These results indicate that cyclin B(1) and p27 mRNAs are present at significantly higher levels in normal pituitary compared to GH(3) cells, and that both E(2) and TGF-B1 can down-regulate cyclin B(1) mRNA levels in normal pituitary cells, suggesting that these factors regulate G1 to S phase transition in pituitary cells. The lower levels of specific cell cycle regulators in GH cells may explain the decreased regulatory control by E(2) in GH(3) tumor cells.
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PMID:TGF-B and Estrogen Regulate P27(Kip1) and Cyclin D(1) in Normal and Neoplastic Rat Pituitary Cells. 1211 29

Our previous studies demonstrated that the oral antifungal agent ketoconazole (KT) induces apoptosis and G0/G1 phase cell cycle arrest in human cancer cell lines. In this study, we first demonstrated that KT (1 microM) potentiated the apoptotic effects of nocodazole (ND, 1 nM) in COLO 205 cancer cells. We further demonstrated the therapeutic efficacy of a combined treatment of KT (50 mg/kg/three times per week) and ND (5 mg/kg/three times per week) in vivo by treating athymic mice bearing COLO 205 tumor xenografts. The antitumor effects of ND were significantly potentiated by KT in mice after 6 wk of treatment. No gross signs of toxicity were observed in mice receiving these treatment regimens. The apoptotic cells were detected in a microscopic view of the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining and by observation of DNA fragmentation in KT + ND-treated tumor tissues. The levels of cell cycle regulatory proteins were determined by Western blot analysis. Treatment with KT inhibits tumor growth through elevation of p53, p21/CIP1, and p27/KIP1 as well as inhibition of cyclin D3 and cyclin-dependent kinase 4 protein expression. Immunohistochemical staining analysis showed that p53, p21/CIP1, and p27/KIP1 immunoreactivity were induced in the tumor tissues. To clarify the roles of the p21/CIP1 and p27/KIP1 protein expression involved in G(0)/G(1) arrest and/or apoptosis induced by a combined treatment with KT and ND, antisense oligodeoxynucleotides (ODNs) specific to p21/CIP1 and p27/KIP1 were used. Our results demonstrated that apoptotic phenomena, including BAX induction and cytochrome C released from mitochondria induced by KT + ND, were significantly attenuated by pretreatment the cells with the p27/KIP1-specific antisense ODNs. These results indicate that p27/KIP1 protein does indeed play a critical role in the KT + ND-induced apoptosis. Our study revealed the molecular mechanism of KT + ND in regression of the tumor growth. The apoptotic effects of KT in a great variety of cancer cells make it a very attractive agent for cancer chemotherapy.
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PMID:Ketoconazole potentiates the antitumor effects of nocodazole: In vivo therapy for human tumor xenografts in nude mice. 1220 71

Induction of apoptosis in malignant cells is a major goal of cancer therapy in general and of certain cancer gene therapy strategies in particular. Numerous apoptosis-regulating genes have been evaluated for this purpose. Besides the most prominent p53 gene others include p16, p21, p27, E2F genes, FHIT, PTEN and CASPASE genes. Recently, the potential for therapy of an adenoviral gene, E1A, known for a long time for its apoptosis-inducing activity, has been discovered. In experimental settings, these genes have proven their tumor-suppressive and apoptosis-inducing activity. Clinical trials are currently being performed with selected genes. By far the most studies transfer the p53 gene using retro- or adenoviral vectors. Disease stabilization or other benefits were observed in a limited number of patients when p53 was applied alone or in combination with cytotoxic drugs. A second proapoptotic gene that has entered clinical trials is adenovirus E1A. Here, too, disease stabilization as well as/or local regression in one case have been demonstrated in selected patients. In all cases, side effects were tolerable. To further improve E1A as a therapeutic transgene, we have deleted transforming domains from the adenovirus 5 and 12 13S cDNAs. Mutants were derived which had completely lost their transforming activity in combination with the E1B oncogene but retained a pronounced tumor-suppressive activity. Cells transduced with these constructs showed a highly reduced ability to grow in soft agar, and tumor growth in nude mice could be substantially suppressed. Outgrowing tumors had lost E1A expression when analyzed in Western blots. These E1A constructs may represent valuable tools for cancer gene therapy in the future.
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PMID:Apoptotic genes in cancer therapy. 1242 89

A high tumor interstitial fluid pressure (TIFP) is a pathologic characteristic distinguishing the stroma of carcinomas from normal interstitial loose connective tissues. The role of TGF-beta1 and -beta3 in generating a high TIFP was investigated in xenografted experimental anaplastic thyroid carcinoma (ATC) derived from the human ATC cell line KAT-4. A single intravenous injection of a soluble recombinant TGF-beta receptor type II-murine Fc:IgG(2A) chimeric protein that specifically inhibits TGF-beta1 and -beta3, significantly lowered TIFP in a time and concentration dependent manner but did not change total tissue water content in the tumors. Tumor growth rate was higher in tumors treated with the TGF-beta1 and -beta3 inhibitor compared to control tumors during the first 10 days after administration of the inhibitor. The apoptotic index of carcinoma cells, and expression of the cell cycle inhibitor p27(Kip1), were, however, increased in TGF-beta1 and -beta3 inhibitor-treated tumors. Prolonged treatment periods and administration of a second dose of the inhibitor decreased tumor growth rate. The TGF-beta1 and -beta3 inhibitor did not affect proliferation or expression of phosphorylated Smad2 protein in KAT-4 cells cultured in vitro. Our results indicate that members of the TGF-beta family are potential targets for novel anti-cancer treatment directed to the stroma. First by controlling TIFP and by that potentially the uptake of anticancer drugs into tumors and second by their suggested role in maintaining a supportive tumor stroma.
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PMID:Interference with TGF-beta1 and -beta3 in tumor stroma lowers tumor interstitial fluid pressure independently of growth in experimental carcinoma. 1243 46

Events that contribute to tumor formation include mutations in the ras gene and loss or inactivation of cell cycle inhibitors such as p21(Cip1) and p27(Kip1). In our previous publication, we showed that mice expressing the MMTV/v-Ha-ras transgene developed tumors earlier and at higher multiplicities in the absence than in the presence of p21(Cip1). To further evaluate the combinatorial role of genetic alterations and loss of cell cycle inhibitors in tumorigenesis, we performed two companion studies. In the first study, wild type and p21(Cip1)-null mice were exposed to the chemical carcinogen, urethane. Similar to its effects in v-Ha-ras mice, loss of p21(Cip1) accelerated tumor onset and increased tumor multiplicity in urethane-treated mice. Lung tumors were the predominant tumor type in urethane-treated mice regardless of p21(Cip1) status. In the second study, tumor formation was monitored in v-Ha-ras mice expressing or lacking p27(Kip1). Unlike p21(Cip1), the absence of p27(Kip1) had no effect on the timing or multiplicity of tumor formation, which was largely restricted to mammary and salivary glands. However, once tumors appeared, they grew faster in p27(Kip1)-null mice than in p27(Kip1)-wild type mice. Increases in growth rate were particularly striking for salivary tumors in ras/p27(-/-) mice. Loss of p21(Cip1), on the other hand, had no effect on tumor growth rate in v-Ha-ras mice. Collectively, our data suggest that p21(Cip1) suppresses tumor formation elicited by multiple agents and that p21(Cip1) and p27(Kip1) suppress tumor formation in different ways.
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PMID:Loss of the cell cycle inhibitors p21(Cip1) and p27(Kip1) enhances tumorigenesis in knockout mouse models. 1246 68


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