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)

Rapamycin and its derivatives are promising anticancer agents, but the exact mechanisms by which these drugs induce cell cycle arrest and inhibit tumor growth are unknown. A biochemical analysis of human mammary tumor cell lines indicated that rapamycin-induced antiproliferative effects correlated with down-regulation of cellular p21 levels and the levels of p21 in cyclin-dependent kinase (Cdk) 2 and 4 complexes. Cyclin D1 overexpression reversed rapamycin action and this reversal correlated with increased levels of cellular p21, higher levels of p21 associated with Cdk2, and stabilization of cyclin D1/Cdk2/p21/proliferating cell nuclear antigen (PCNA) complexes. Experiments using a novel cyclin D1-Cdk2 fusion protein or a kinase-dead mutant of the fusion protein indicated that reversal of rapamycin action required not only the formation of complexes with p21 and PCNA but also complex-associated kinase activity. Similar results were observed in vivo. The rapamycin derivative RAD001 (everolimus) inhibited the growth of mouse mammary tumors, which correlated with the disruption of cyclin D1/Cdk2 complexes. The potential implications of these results with respect to the use of rapamycin derivatives in breast cancer therapy are discussed.
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PMID:Rapamycin disrupts cyclin/cyclin-dependent kinase/p21/proliferating cell nuclear antigen complexes and cyclin D1 reverses rapamycin action by stabilizing these complexes. 1642 43

Squamous cell carcinoma (SCC) is an invasive malignancy of epidermal keratinocytes. Surgical excision is currently the main treatment; however, this can cause scarring and disfigurement. There is accordingly, an acute need for alternative strategies to treat SCC. The transcription factor c-Jun is expressed in human SCC and another common form of invasive skin cancer, basal cell carcinoma together with the mitogenic marker-proliferating cell nuclear antigen. Here, we have employed DNAzymes (catalytic DNA molecules) targeting c-Jun (Dz13) to inhibit c-Jun expression in SCC cells. Dz13 inhibits SCC proliferation and suppresses solid SCC tumor growth and tumor angiogenesis in severe combined immunodeficient mice. We further demonstrate that Dz13 inhibits c-Jun, together with matrix metalloproteinase (MMP)-2 and MMP-9 expression in the tumors, consistent with DNAzyme inhibition of MMP-2 and MMP-9 gelatinolytic activity by zymography. Dz13 also suppressed the expression of vascular endothelial growth factor and fibroblast growth factor-2 in the tumors. These findings demonstrate that c-Jun regulates SCC growth and suggest that DNAzymes targeting this transcription factor may potentially be useful as inhibitors of cutaneous carcinoma.
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PMID:Squamous cell carcinoma growth in mice and in culture is regulated by c-Jun and its control of matrix metalloproteinase-2 and -9 expression. 1678 94

In this review are presented various lead compounds bearing a polyphenolic moiety and their biological targets. The relevance of these targets to develop the desired compounds as potential anti-cancer agents is discussed. For instance, caffeic acid phenethyl ester (CAPE) has preliminary been studied in our group to hold various biochemical responses. When C6 glioma cells were grown as xenografts in nude mice, treatment with CAPE (1-10 mg/kg; ip) induced a significant dose dependent decrease in tumor growth by evaluating tumor volume and tumor weight. Histochemical and immunohistochemical analysis revealed that CAPE treatment significantly reduced the number of mitotic cells and proliferating cell nuclear antigen (PCNA)-positive cells in C6 glioma. Moreover, the ability of flavonoids to scavenge free-radicals and block lipid peroxidation raises the possibility that they may act as protective factors against carcinogenesis. Furthermore, protocatechuic acid (PCA) seems to be a promising compound regarded as a candidate group for cancer preventive agents. We have isolated and investigated Hibiscus protocatechuic acid from Hibiscus sabdariffa L. Hibiscus PCA showed against oxidative damage induced by t-butyl hydroperoxide in rat primary hepatocytes, and inhibitory effect on tumor promotion in mouse skin. Finally, we review here recent progress with the analogs of natural and synthetic lead compounds in Asiatic folk medicine. Since phenolic dimmers or trimers are significantly more potent than monomer in vitro and in vivo, a large number of phenolic dimmers or trimers with linker lengths and their pharmacological properties have been investigated.
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PMID:Evaluation of natural and synthetic compounds from East Asiatic folk medicinal plants on the mediation of cancer. 1684 35

Developing novel mechanism-based chemopreventive approaches for lung cancer through the use of dietary substances which humans can accept has become an important goal. In the present study, employing normal human bronchial epithelial cells (NHBE) and human lung carcinoma A549 cells, we first compared the growth inhibitory effects of pomegranate fruit extract (PFE). Treatment of PFE (50-150 microg/ml) for 72 h was found to result in a decrease in the viability of A549 cells but had only minimal effects on NHBE cells as assessed by the MTT and Trypan blue assays. PFE treatment of A549 cells also resulted in dose-dependent arrest of cells in G0-G1 phase of the cell cycle (as assessed by DNA cell cycle analysis). We further found that PFE treatment also resulted in (i) induction of WAF1/p21 and KIP1/p27, (ii) decrease in the protein expressions of cyclins D1, D2 and E, and (iii) decrease in cyclin-dependent kinase (cdk) 2, cdk4 and cdk6 expression. The treatment of cells with PFE inhibited (i) phosphorylation of MAPK proteins, (ii) inhibition of PI3K, (iii) phosphorylation of Akt at Thr308, (iv) NF-kappaB and IKKalpha, (v) degradation and phosphorylation of IkappaBalpha, and (vi) Ki-67 and PCNA. We also found that PFE treatment to A549 cells resulted in inhibition of NF-kappaB DNA-binding activity. Oral administration of PFE (0.1 and 0.2%, wt/vol) to athymic nude mice implanted with A549 cells resulted in a significant inhibition in tumor growth. Our results provide a suggestion that PFE can be a useful chemopreventive/chemotherapeutic agent against human lung cancer.
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PMID:Pomegranate fruit extract inhibits prosurvival pathways in human A549 lung carcinoma cells and tumor growth in athymic nude mice. 1692 Jul 36

Interferon (IFN)-beta is a multifunctional cytokine. Our previous studies revealed that intratumoral transfer of the murine interferon (IFN)-beta gene inhibited the growth of human and mouse prostate cancer cells in mice. Since IFN-beta activity is species-restricted, we investigated the efficacy and mechanisms of forced expression of human IFN-beta in suppressing the growth of human prostate cancer cells in mice. Orthotopic tumors of PC-3MM2 human prostate cancer cells were forced to express human IFN-beta by intratumoral injection of an adenoviral vector (AdhIFN-beta). Tumor growth and survival of tumor-bearing mice were determined. Cell proliferation and apoptosis were evaluated by immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). Angiogenesis and angiogenic molecule expression were evaluated by IHC and quantitative real-time reverse-transcriptional PCR (qRT-PCR). We found that forced expression of human IFN-beta inhibited tumor growth in a dose-dependent manner. An injection of 2 x 10(9) PFU (plaque-forming units) of AdhIFN-beta retarded tumor growth by 90% and prolonged the survival of tumor-bearing mice. Control tumors contained more proliferating cells (PCNA(+)) and fewer apoptotic cells (TUNEL(+)) than did AdhIFN-beta treated-tumors. Treatment with AdhIFN-beta downregulated the expression of interleukin-8 and vascular endothelial cell growth factor-A. Taken together, our data indicated that forced expression of human IFN-beta in human prostate cancer cells significantly inhibited their prostatic growth, which correlated with downregulation of angiogenic molecules and suggested that adenoviral vector-mediated IFN-beta gene therapy could be an effective approach for the management of human prostate cancer.
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PMID:Adenovirus-mediated interferon-beta gene transfer inhibits angiogenesis in and progression of orthotopic tumors of human prostate cancer cells in nude mice. 1708 78

Adenoid cystic carcinoma (ACC) is a generally slow-growing but highly malignant salivary gland neoplasm with remarkable capacities for local invasion and lung metastasis. The precise characteristics of ACC are not fully understood because there was no suitable animal model. We have successfully established a new human tumor line (ACCI) derived from ACC of the oral floor, which showed a cribriform pattern histologically and serially transplantable into nude mice. This tumor developed spontaneous metastasis to the neck at the second passage level, and the histological feature changed from ACC to undifferentiated carcinoma (ACCIM). ACCIM caused spontaneous metastasis to the lung at high incidence when transplanted subcutaneously in nude mice. In this study, we examined the characteristics of this interesting human ACC metastatic line. Tumor fragments were subcutaneously transplanted into nude mice and tumor growth was measured at 1-week intervals. Histological and immunohistochemical examinations were performed. As a result, the tumor growth rate of ACCIM increased as compared to that of ACCI, and the PCNA labeling index was elevated. Furthermore, ACCIM produced multiple metastases to lymph nodes and lungs 5 months after transplantation, and all mice died within 6 months. These multiple metastases were also confirmed in orthotopic transplantation to the tongue. RT-PCR analysis revealed that ACCIM expressed human beta-actin, indicating its human origin. From these findings, ACCIM transplanted into nude mice would provide a useful model for investigating the biological behaviour of ACC.
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PMID:Establishment of nude mouse transplantable model of a human adenoid cystic carcinoma of the oral floor showing metastasis to the lymph node and lung. 1714 80

Metronomic chemotherapy is the frequent administration of low doses of chemotherapeutic agents targeting tumor-associated endothelial cells. We examined the efficacy of metronomic taxanes alone and in combination with AEE788-a dual epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) inhibitor-in an orthotopic mouse model of ovarian cancer. Growth-modulating effects of metronomic and maximum tolerated dose (MTD) regimens on overall survival were tested in vivo using both chemotherapy-sensitive (HeyA8 and SKOV3ip1) and chemotherapy-resistant (HeyA8-MDR) models. Treated tumors were stained for microvessel density (CD31), proliferation index (proliferating cell nuclear antigen), and apoptosis (terminal deoxyribonucleotide transferase-mediated nick-end labeling). The cytotoxic effects of MTD and metronomic dosing were tested with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Effects of metronomic regimens on circulating endothelial precursors (CEP) and tumor-specific cell-free DNA levels were assessed. In vivo, metronomic docetaxel resulted in significant reduction of tumor growth in the taxane-sensitive cell lines, whereas metronomic docetaxel plus AEE788 had an additive effect resulting in significant prolongation in survival. Combination therapy was effective even in the taxane-resistant model. Metronomic chemotherapy alone and combined with AEE788 resulted in a decrease in the proliferative index and microvessel density of treated tumors, whereas combination therapy increased the apoptotic index (P < 0.001). In vitro, metronomic taxanes caused endothelial cell toxicity at 10- to 100-fold lower concentrations compared with MTD dosing. Metronomic regimens inhibited mobilization of CEPs (P < 0.05) and led to a decrease in cell-free DNA levels (P < 0.05). Our results suggest that metronomic taxane chemotherapy with dual EGFR and VEGFR inhibition is highly efficacious and should be considered for future clinical trials.
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PMID:Metronomic chemotherapy enhances the efficacy of antivascular therapy in ovarian cancer. 3001 59

The consumption of diets containing 5 to 10 servings of fruits and vegetables daily is the foundation of public health recommendations for cancer prevention, yet this concept has not been tested in experimental models of prostate cancer. We evaluated combinations of tomato and broccoli in the Dunning R3327-H prostate adenocarcinoma model. Male Copenhagen rats (n=206) were fed diets containing 10% tomato, 10% broccoli, 5% tomato plus 5% broccoli (5:5 combination), 10% tomato plus 10% broccoli (10:10 combination) powders, or lycopene (23 or 224 nmol/g diet) for approximately 22 weeks starting 1 month prior to receiving s.c. tumor implants. We compared the effects of diet to surgical castration (2 weeks before termination) or finasteride (5 mg/kg body weight orally, 6 d/wk). Castration reduced prostate weights, tumor areas, and tumor weight (62%, P<0.001), whereas finasteride reduced prostate weights (P<0.0001), but had no effect on tumor area or weight. Lycopene at 23 or 224 nmol/g of the diet insignificantly reduced tumor weights by 7% or 18%, respectively, whereas tomato reduced tumor weight by 34% (P<0.05). Broccoli decreased tumor weights by 42% (P<0.01) whereas the 10:10 combination caused a 52% decrease (P<0.001). Tumor growth reductions were associated with reduced proliferation and increased apoptosis, as quantified by proliferating cell nuclear antigen immunohistochemistry and the ApopTag assay. The combination of tomato and broccoli was more effective at slowing tumor growth than either tomato or broccoli alone and supports the public health recommendations to increase the intake of a variety of plant components.
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PMID:Combinations of tomato and broccoli enhance antitumor activity in dunning r3327-h prostate adenocarcinomas. 1721 56

The development of estrogen-induced pituitary prolactinoma in Fischer 344 (F344) rats is associated with enhanced neovascularization. Based on the significance of matrix metalloproteinases (MMPs) for tumor growth and angiogenesis, we have studied the effect of batimastat (BB-94), a synthetic MMPs inhibitor (MMPI) on the progression of prolactin-secreting pituitary adenoma in rats. Pituitary tumors were induced in male F344 rats by s.c. implantation of Silastic tubes containing diethylstilbestrol (DES). The effects of chronic treatment with BB-94 (30 mg/kg b.w.) on pituitary weight, cell proliferation, apoptosis and vascular density were evaluated. We have stated that chronic treatment with batimastat caused a significant reduction in the pituitary weight. Batimastat has been found to decrease cell proliferation evaluated by a number of PCNA-positive stained cell nuclei. A marked increase in the apoptotic index within the pituitary was observed in the study group. Moreover, the density of microvessels identified by CD31 was reduced in the group treated with BB-94. The results of our study provide evidence for an inhibitory effect of batimastat, a synthetic MMPI, on the growth and angiogenesis in an experimental model of human prolactinoma. The ability of BB-94 to suppress established pituitary tumor growth suggests a possible application of MMPIs in the treatment of pituitary adenomas.
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PMID:Inhibition of estrogen-induced pituitary tumor growth and angiogenesis in Fischer 344 rats by the matrix metalloproteinase inhibitor batimastat. 1723 67

Successful intrauterine transplantation (IUT) of stem cells for treatment of fetal defects in some animal models of human diseases has prompted us to study the mechanisms of transplantation, immunological tolerance and embryonic environment. The objective of this study was to determine whether intrauterine transplantation of tumor cells would affect the survival and growth of the tumor cells themselves as well as fetus development. A total of 2 x 10(6) H(22) cells or S(180) cells were transplanted into the amniotic or abdominal cavity of NIH mice on D9-D12 or D13-D18 of gestation. The adult and newborn NIH mice which were inoculated with the same number of H(22) cells and S(180) cells by intraperitoneal injection were used as positive controls for the cancer bearing control group while undisrupted fetuses of the same gestation were used as negative controls (i.e. for the normal development) group. The development of fetuses transplanted with tumor cells in utero was monitored by several developmental indices, and the tumor growth of them were observed by some distinctive bearing cancer index. The H(22) transplanted group was further assessed for minimal cancer bearing by detection of alpha-fetoprotein (AFP) using radioimmunoassay (RIA) and reverse transcription-polymerase chain reaction (RT-PCR). In addition, tumor burden and the development of the F1 generation of the mice by IUT were also investigated. Protein kinase C (PKC) and proliferating cell nuclear antigen (PCNA) of GFP-expressing H(22) cells transplanted in the uterus were analyzed under laser confocal microscopy. There was no significant difference in the developmental indices between the experimental and control groups. HE staining of the major organs, including liver, kidney, and lung, showed that these organs properly developed. No tumor ascites were found in those delivered mice after intrauterine transplantation with H(22) cells and S(180) cells. Furthermore, as minimal bearing cancer index for H(22) cells, AFP expression analyzed by RIA and RT-PCR indicated that no tumor cells were detected in the experimental groups. The F1 progenies developed normally without any signs of tumor development. Fluorescence analysis revealed that expression of PKC and PCNA was markedly reduced in the H(22) cells after injection for 24, 48, and 72 h. Our study showed that the tumor cells did not grow in the mice by intrauterine transplantation, whereas transplantation of the same number of tumor cells resulted in obvious ascites tumor in the adult and newborn mice. Furthermore, the differentiation and proliferation of H(22) cells changed dramatically after injection. Our results suggest that, while the embryonic transplantation of tumor cells does not affect fetal development, the survival and growth of implanted tumor cells may be significantly inhibited in the embryonic microenvironment.
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PMID:Effect of mid-late mouse fetus' microenvironment on the growth of tumor cells after intrauterine transplantation. 1727 3


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