Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bexarotene (Targretin), is a synthetic high-affinity RXR receptor agonist with limited affinity for RAR receptors. Bexarotene has shown efficacy in a phase I/II trial of non-small-cell lung cancers. However, the chemopreventive efficacy of bexarotene has not been determined in mouse lung cancer models. In this study, we have investigated the ability of bexarotene to inhibit lung tumor progression in the mutant A/J mouse models with genetic alterations in p53 or K-ras, two of the most commonly altered genes in human lung tumorigenesis. Mice were administered vinyl carbamate (VC), a carcinogen, by a single intraperitoneal injection (i.p.) at 6 weeks of age. Bexarotene was given by gavage starting at 16 weeks after VC and was continued for 12 weeks. Although all mice developed lung tumors, only 7% of lung tumors were adenocarcinomas in wild-type mice, whereas 22 and 26% of lung tumors were adenocarcinomas in p53 transgenic or K-ras heterozygous deficient mice. Bexarotene inhibited both tumor multiplicity and tumor volume in mice of all three genotypes. Furthermore, bexarotene reduced the progression of adenoma to adenocarcinoma by approximately 50% in both p53(wt/wt)K-ras(ko/wt) and p53(wt/wt)K-ras(wt/wt) mice. Thus, bexarotene appears to be an effective preventive agent against lung tumor growth and progression.
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PMID:Prevention of lung cancer progression by bexarotene in mouse models. 1624 46

The objective of this investigation was to determine the efficacy of several novel agents in preventing lung tumorigenesis in mice. We evaluated polyphenon E, red ginseng, and rapamycin in A/J mice treated with the tobacco-specific carcinogen benzo(a)pyrene for their ability to inhibit pulmonary adenoma formation and growth. We found that treatment with polyphenon E exhibited a significant reduction on both tumor multiplicity and tumor load (tumor multiplicity x tumor volume) in a dose-dependent fashion. Polyphenon E (2% wt/wt) in the diet reduced tumor multiplicity by 46% and tumor load by 94%. This result provided key evidence in support of a phase II clinical chemoprevention trial of lung cancer. Administration of red ginseng in drinking water decreased tumor multiplicity by 36% and tumor load by 70%. The mammalian target of rapamycin inhibitor rapamycin showed significant efficacy against lung tumor growth in the tumor progression protocol and reduced tumor load by 84%. The results of these investigations demonstrate that polyphenon E, red ginseng, and rapamycin significantly inhibit pulmonary adenoma formation and growth in A/J mice.
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PMID:Efficacy of polyphenon E, red ginseng, and rapamycin on benzo(a)pyrene-induced lung tumorigenesis in A/J mice. 1653 26

Pregnancy in acromegaly is a rather rare event since the fertility is reduced in acromegalic women. Besides, metabolic complications of acromegaly are harmful to both mother and fetus. Little is known about the outcome of pregnancy in acromegalic women. Here, we report seven cases of pregnancy out of 48 acromegalic women followed for 16 years. At diagnosis, five patients had macroadenoma, one patient had microadenoma and the size of the tumor was not documented in one patient. In one patient, acromegaly was initially diagnosed during pregnancy at 29 weeks. When she was 33 weeks, she developed pituitary apoplexy and had an emergency transsphenoidal resection of her macroadenoma during which she also had a cesarian section and delivered a healthy baby girl. In the remaining six patients, pregnancy occurred 6 to 64.5 months after the adenoma resection. Three patients received radiotherapy before getting pregnant. In three patients, pregnancy occurred during bromocriptine treatment and the drug was withdrawn. In one patient, pregnancy occurred during chronic octreotide treatment and therapeutic abortion was performed. In another patient, therapeutic abortion was performed because of uncontrolled disease. In the remaining four patients, there were neither worsening of symptoms nor tumor growth. All four patients gave birth to full-term healthy infants. Out of our seven patients, two developed gestational diabetes mellitus which was controlled with diet. None of the patients had coronary artery disease, hypertension or dyslipidemia. These cases show that pregnancy might be uneventful in acromegalic women when the disease is controlled with prior surgery and radiotherapy.
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PMID:Follow-up of pregnancy in acromegalic women: different presentations and outcomes. 1663 80

Herein, we report the case of a 28-year old woman clinically presenting with unclear weight gain over the last years. The patient displayed facial and neck edema in combination with unobtrusive striae distensae. Endocrinological examinations led to the diagnosis of Cushing's disease. Neuroradiological examination revealed an intrasellar tumor mass of 7 mm in diameter. Subsequently, transsphenoidal tumor resection was performed. Histological and immunohistochemical investigations revealed a pituitary gland adenoma showing a biphasic tumor growth pattern with two morphologically different tumor areas producing ACTH and prolactin respectively. Co-expression of ACTH and prolactin is exceedingly rare in pituitary adenoma. To our surprise, both tumor areas exhibited features of atypia consisting in elevated MIB-1 proliferation index in the ACTH-producing portion as well as p53 expression selectively in the prolactin-producing tumor parts. To our knowledge, this is the first case of an ACTH- and prolactin-producing pituitary gland adenoma exhibiting biphasic features of atypia.
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PMID:ACTH- and prolactin-producing pituitary gland microadenoma with biphasic features of atypia and intermediate filament expression. 1664 16

Increased expression of cyclooxygenase-2 (COX-2) and subsequent prostaglandin production is an important event in several human malignancies, including colorectal cancer. COX-2 mediated prostanoid synthesis has been shown to play a key role in tumor progression with prostaglandin E(2) (PGE(2)) being shown to promote tumor growth, invasion and angiogenesis. The role of the other prostaglandins produced by COX-2 in tumors remains poorly understood. We have shown that colorectal tumor cells produce prostaglandin F(2alpha) (PGF(2alpha)) and provide evidence that PGF(2alpha) may play an important role in colorectal tumorigenesis. Our data show that PGF(2alpha) is secreted by both colorectal adenoma and carcinoma-derived cell lines at levels in excess of those detected for PGE(2). These cell lines were also found to express the PGF(2alpha) receptor (FP) indicating potential autocrine effects of PGF(2alpha). This finding is further supported by an in vivo immunohistochemical study of FP expression in resected colon tissue. These data show epithelial expression of FP in normal colorectal mucosa and also in colorectal adenomas and carcinomas. We compared the relative abilities of PGF(2alpha) and PGE(2) to induce cell motility in vitro in colorectal tumor cell lines and show the first evidence of prostaglandin-induced cell motility in colorectal adenoma cell lines. PGF(2alpha) induced cell motility with equivalent potency to PGE(2) in all the cell lines tested and was also shown to increase the invasion of carcinoma-derived cells into reconstituted basement membrane. These data show that PGF(2alpha) may play an important role in the malignant progression of colorectal tumors.
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PMID:Prostaglandin F(2alpha) stimulates motility and invasion in colorectal tumor cells. 1743 71

Anti-VEGF-A monoclonal antibodies, in combination with chemotherapy, result in a survival benefit in patients with metastatic colorectal and non-small cell lung cancer, but little is known regarding the impact of anti-VEGF-A therapy on benign or premalignant tumors. The Apc+/min mice have been widely used as a model recapitulating early intestinal adenoma formation. To investigate whether tumor growth in Apc+/min mice is mediated by VEGF-A-dependent angiogenesis, we used two independent approaches to inhibit VEGF-A: monotherapy with a monoclonal antibody (Mab) targeting VEGF-A and genetic deletion of VEGF-A selectively in intestinal epithelial cells. Short-term (3 or 6 weeks) treatment with anti-VEGF-A Mab G6-31 resulted in a nearly complete suppression of adenoma growth throughout the small intestine. Growth inhibition by Mab G6-31 was associated with a decrease in vascular density. Long-term (up to 52 weeks) treatment with Mab G6-31 led to a substantial increase in median survival. Deletion of VEGF-A in intestinal epithelial cells of Apc+/min mice yielded a significant inhibition of tumor growth, albeit of lesser magnitude than that resulting from Mab G6-31 administration. These results establish that inhibition of VEGF-A signaling is sufficient for tumor growth cessation and confers a long-term survival benefit in an intestinal adenoma model. Therefore, VEGF-A inhibition may be a previously uncharacterized strategy for the prevention of the angiogenic switch and growth in intestinal adenomas.
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PMID:Inhibition of VEGF-A prevents the angiogenic switch and results in increased survival of Apc+/min mice. 1755 57

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors with essential functions in regulating lipid metabolism. Both the PPARbeta (also referred to as PPARdelta) and PPARgamma subtype have been reported to either attenuate or potentiate tumorigenesis in a number of different models of intestinal and skin carcinogenesis. In the present study, we have addressed the role of PPARbeta and PPARgamma in lung tumorigenesis in a transgenic mouse model of RAF-induced lung adenoma using two different strategies: i) crossing with PPARbeta null mice, and ii) chronic treatment with the PPARgamma agonist rosiglitazone. Histological examination revealed a significant enhancement of tumor growth in mice lacking one or both alleles of Pparb, but no significant effect in response to rosiglitazone. These observations indicate i) that RAF-induced lung tumorigenesis is attenuated in mice with a disrupted Pparb gene, and ii) that chronic PPARgamma activation does not affect lung adenoma growth. These results are relevant with respect to the clinical application of drugs modulating the activity of PPARbeta or PPARgamma.
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PMID:Growth of transgenic RAF-induced lung adenomas is increased in mice with a disrupted PPARbeta/delta gene. 1767 88

The cyclooxygenase (COX) is a key enzyme in the conversion of arachidonic acid to prostaglandins. COX-1 is constitutively expressed and is a critical housekeeping gene, whereas COX-2 is rapidly upregulated by growth factors and cytokines and thus responsible for inflammation. COX-2 is frequently overexpressed in colonic adenoma and carcinoma. Specific inhibitors of COX-2 have been shown to induce apoptosis in tumor cells and to inhibit tumor growth in animal models and in humans. Long-standing IBD patients have increased risk of developing colorectal cancer compared to general population. IBD-associated colorectal carcinogenesis is probably promoted by chronic inflammation and closely related to COX-2. In a recent study, powerful chemopreventive ability of selective COX-2 inhibitor was observed in colitis-related colon carcinogenesis in mouse model. But it was reported that even selective COX inhibitors aggravated the DSS-induced colonic inflammation. It is assumed that endogenous PGs are involved in the mucosal defense against DSS-induced colonic ulcerations which are produced by COX-1 at early phase and by COX-2 at late phase. Long-term use of COX-2 inhibitors for the chemoprevention of colitic cancer is needed to define their mechanism of action, that reduce side effects and have specific tumor target.
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PMID:[COX-2 inhibitors in inflammatory bowel disease: friends or foes?]. 1815 71

From the conditioned medium of the human colon carcinoma cells, HT-29 5M21 (CM-5M21), expressing a spontaneous invasive phenotype, tumor-associated trypsin inhibitor (TATI) was identified and characterized by proteomics, cDNA microarray approaches and functional analyses. Both CM-5M21 and recombinant TATI, but not the K18Y-TATI mutant at the protease inhibitor site, trigger collagen type I invasion by several human adenoma and carcinoma cells of the colon and breast, through phosphoinositide-3-kinase, protein kinase C and Rho-GTPases/Rho kinase-dependent pathways. Conversely, the proinvasive action of TATI in parental HT29 cells was alleviated by the TATI antibody PSKAN2 and the K18Y-TATI mutant. Stable expression of K18Y-TATI in HT-29 5M21 cells downregulated tumor growth, angiogenesis and the expression of several metastasis-related genes, including CSPG4 (13.8-fold), BMP-7 (9.7-fold), the BMP antagonist CHORDIN (5.2-fold), IGFBP-2 and IGF2 (9.6- and 4.6-fold). Accordingly, ectopic expression of KY-TATI inhibited the development of lung metastases from HT-29 5M21 tumor xenografts in immunodeficient mice. These findings identify TATI as an autocrine transforming factor potentially involved in early and late events of colon cancer progression, including local invasion of the primary tumor and its metastatic spread. Targeting TATI, its molecular partners and effectors may bring novel therapeutic applications for high-grade human solid tumors in the digestive and urogenital systems.
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PMID:Autocrine induction of invasion and metastasis by tumor-associated trypsin inhibitor in human colon cancer cells. 1831 48

Although endocannabinoid signaling is important for certain aspects of gastrointestinal homeostasis, the role of the cannabinoid receptors (CB) in colorectal cancer has not been defined. Here we show that CB1 expression was silenced in human colorectal cancer due to methylation of the CB1 promoter. Our genetic and pharmacologic studies reveal that loss or inhibition of CB1 accelerated intestinal adenoma growth in Apc(Min/+) mice whereas activation of CB1 attenuated intestinal tumor growth by inducing cell death via down-regulation of the antiapoptotic factor survivin. This down-regulation of survivin by CB1 is mediated by a cyclic AMP-dependent protein kinase A signaling pathway. These results indicate that the endogenous cannabinoid system may represent a potential therapeutic target for prevention or treatment of colorectal cancer.
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PMID:Loss of cannabinoid receptor 1 accelerates intestinal tumor growth. 1867 72


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