Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The thiol N-acetyl-L-cysteine (NAC), an analogue and precursor of reduced glutathione, has cancer chemopreventive properties attributable to its nucleophilicity, antioxidant activity, and a variety of other mechanisms. We demonstrated recently that NAC has anti-invasive, antimetastatic, and antiangiogenic effects in in vitro and in vivo test systems. In the present study, s.c. transplantation of KS-Imm cells in (CD-1)BR nude mice resulted in the local growth of Kaposi's sarcoma, a highly vascularized human tumor. The daily administration of NAC with drinking water, initiated after the tumor mass had become established and detectable, produced a sharp inhibition of tumor growth, with regression of tumors in half of the treated mice along with a markedly prolonged median survival time. The production of vascular endothelial growth factor (VEGF) and certain proliferation markers (proliferating cell nuclear antigen and Ki-67) were significantly lower in Kaposi's sarcomas from NAC-treated mice than from control mice. Treatment of KS-Imm cells with NAC in vitro resulted in a dose-dependent inhibition of chemotaxis and invasion through inhibition of gelatinase-A (matrix metalloproteinase-2, MMP-2) activity without altering MMP-2 or MMP-9 mRNA levels. NAC also significantly inhibited VEGF production but did not affect proliferation markers in vitro. Reverse transcription-PCR analysis indicated that total VEGF mRNAs were reduced by 10 mM NAC. Taken together, these findings provide evidence that NAC, the safety of which even at high doses has been established in almost 40 years of clinical use, in addition to its chemopreventive action, has a strong antiangiogenic potential that could be exploited for preventing cancer progression as well as used in cancer adjuvant therapy.
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PMID:Inhibition of angiogenesis-driven Kaposi's sarcoma tumor growth in nude mice by oral N-acetylcysteine. 1171 47

Increased cellular activity of ornithine decarboxylase (ODC), the first and rate-limiting enzyme in polyamine (PA) synthesis, is an independent adverse prognostic factor for overall survival in human breast cancer, thus suggesting an important role for PA in tumor progression. The experiments presented here were designed to investigate the role of PA in invasion and metastasis, using the highly aggressive MDA-MB-435 and MDA-MB-231 human breast cancer cell lines. Administration of alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC, significantly reduced, in a dose-dependent manner, the invasiveness in matrigel of both MDA-MB-435 and MDA-MB-231 cells by approximately 70%. DFMO treatment also inhibited (P < 0.0001) 'stellate' colony formation (an indicator of aggressive phenotype) by MDA-MB-435 cells plated in the matrigel outgrowth assay. Administration of DFMO (2% in drinking water) reduced the growth rate of both cell lines implanted orthotopically in nude mice. To evaluate metastasis while minimizing effects on proliferation, DFMO-treated mice were sacrificed later to allow their tumors to reach the same size of the tumors in the control mice. The most striking finding was that DFMO, while ineffective in reducing local invasion, nearly totally abolished (P = 0.0152) pulmonary metastasis in mice bearing MDA-MB-435 xenografts. These results support a role of PA in promoting breast cancer aggressiveness, particularly with regard to the development of distant metastasis. Furthermore, the data suggest that PA involvement is distal to local invasion in the metastatic cascade.
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PMID:Influence of polyamines on in vitro and in vivo features of aggressive and metastatic behavior by human breast cancer cells. 1196 84

Squamous cancers of the oral cavity and esophagus are common worldwide, but no good genetically based animal model exists. A number of environmental factors as well as genetic alterations have been identified in these cancers, yet the specific combination of genetic events required for cancer progression remains unknown. The Epstein-Barr virus ED-L2 promoter (L2) can be used to target genes in a specific fashion to the oral-esophageal squamous epithelium. To that end, we generated L2-cyclin D1 (L2D1(+)) mice and crossbred these with p53-deficient mice. Whereas L2D1(+) mice exhibit a histologic phenotype of oral-esophageal dysplasia, the combination of cyclin D1 expression and p53 deficiency results in invasive oral-esophageal cancer. The development of the precancerous lesions was significantly reversed by the application of sulindac in the drinking water of the L2D1(+)/p53(+/-) mice. Furthermore, cell lines derived from oral epithelia of L2D1(+)/p53(+/-) and L2D1(+)/p53(-/-) mice, but not control mice, formed tumors in athymic nude mice. These data demonstrate that L2D1(+)/p53(+/-) mice provide a well-defined, novel, and faithful model of oral-esophageal cancer, which allows for the testing of novel chemopreventive, diagnostic, and therapeutic approaches.
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PMID:A mouse model of human oral-esophageal cancer. 1223 7

The ability of macrophages to produce reactive nitrogen species, particularly nitric oxide (NO) is correlated with an enhanced microbicidal or tumoricidal activity during pathogenic or tumoral invasion, respectively. NO reacts in water with oxygen and its reactive intermediates to yield, among others, nitrite and nitrate, which are relatively, stable anions. In this study, we show the varying concentrations of nitrite and nitrate present in different body fluids during AK-5 tumor growth and regression in Wistar rats. We have followed the tumor progression profile and the corresponding levels of nitrite and nitrate present in three major body compartments: the tumor mass; the serum which is the intermediary site; and the peritoneal compartment which is the priming ground for the macrophages. We are thus able to show that the status of the tumor has a direct correlation with macrophage activation and motility to different sites in the body. We also demonstrate after in vitro coculture, that the levels of nitrite and nitrate secreted by the macrophages correlate with their cytocidal capacity.
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PMID:Role of reactive nitrogen intermediates and protein nitration during immune response against a rat histiocytoma. 1227 May 52

Using an ICR mouse model bearing a syngeneic Ehrlich ascitis carcinoma, the present study was undertaken to examine the effects of crude, water-soluble propolis (CWSP) on tumor progression, chemotherapeutic efficacy, and hematopoiesis in the peripheral blood. It was demonstrated that CWSP, administered subcutaneously, resulted in marked regression of tumor growth in mice, at the early phase after tumor inoculation (CWSP, p < 0.05 vs. saline control). Molecular analysis indicated that the CWSP is composed of 8.4% protein, 4.2% quercetin plus a variety of saccharides with a molecular weight of 29 kDa. Orally administered CWSP did not produce any regression for the observation period (oral CWSP, p > 0.05 vs. saline control). Peritoneal injection of CWSP into neonatal mice resulted in an increased lymphocyte/polymorphonuclear leukocyte ratio activity, indicating the potential activation of lymphoid cell lineages. These observations suggest that subcutaneously injected CWSP could regulate the development of tumors by possibly stimulating multicellular immunity. In addition, oral administration of CWSP concurrently with 5-fluorouracil (5-FU) or mitomycin C (MMC), significantly increased tumor regression as compared with the respective chemotherapy alone, illustrating the adjuvant effect of orally administered CWSP for tumor regression when combined with chemotherapeutic agents. To examine further the potential usefulness of CWSP for chemotherapeutic regimens, which induce profound multilineage hematopoietic suppression, mice that received CWSP orally in addition to a 5-FU or MMC were followed for absolute numbers of platelets and white and red blood cells. The oral administration of CWSP significantly ameliorated the cytopenia induced by 5-FU, resulting in recovery of white as well as red blood cell counts (5-FU plus CWSP, p < 0.05 vs. 5-FU alone or water control; white blood cells on day 15, red blood cells on day 25), but no marked effects on platelet counts was observed (5-FU plus CWSP, p > 0.05 vs. 5-FU alone or water control). On the other hand, CWSP significantly reduced all three MMC-induced cytopenias, especially at the later stage of the chemotherapeutic course (after day 30), suggesting repetitive requirements of oral administration of CWSP. In summary, subcutaneous administration of an aqueous CWSP resulted in marked regression of transplanted tumors. Orally administered CWSP combined with chemotherapeutic agents significantly increased tumor regression and ameliorated the cytopenia induced by the chemotherapeutic agents alone. These results suggest the benefits of potential clinical trials using CWSP combined with chemotherapeutic agents in order to maximize enhanced immunity while potentially minimizing postchemotherapeutic deteriorated reactions.
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PMID:Antitumor and anticytopenic effects of aqueous extracts of propolis in combination with chemotherapeutic agents. 1247 Apr 25

Dichloroacetic acid (DCA) is carcinogenic to the B6C3F(1) mouse and the F344 rat. Given the carcinogenic potential of DCA in rodent liver and the known concentrations of this compound in drinking water, reliable biologically based models to reduce the uncertainty of risk assessment for human exposure to DCA are needed. Development of such models requires identification and quantification of premalignant hepatic lesions, identification of the doses at which these lesions occur, and determination of the likelihood that these lesions will progress to cancer. In this study we determined the dose response of histopathologic changes occurring in the livers of mice exposed to DCA (0.05-3.5 g/L) for 26-100 weeks. Lesions were classified as foci of cellular alteration smaller than one liver lobule (altered hepatic foci; AHF), foci of cellular alteration larger than one liver lobule (large foci of cellular alteration; LFCA), adenomas (ADs), or carcinomas (CAs). Histopathologic analysis of 598 premalignant lesions revealed that (a)) each lesion class had a predominant phenotype; (b)) AHF, LFCA, and AD demonstrated neoplastic progression with time; and (c)) independent of DCA dose and length of exposure effects, some toxic/adaptive changes in non-involved liver were related to this neoplastic progression. A lesion sequence for carcinogenesis in male B6C3F(1) mouse liver has been proposed that will enable development of a biologically based mathematical model for DCA. Because all classes of premalignant lesions and CAs were found at both lower and higher doses, these data are consistent with the conclusion that nongenotoxic mechanisms, such as negative selection, are relevant to DCA carcinogenesis at lower doses where DCA genotoxicity has not been observed.
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PMID:A 2-year dose-response study of lesion sequences during hepatocellular carcinogenesis in the male B6C3F(1) mouse given the drinking water chemical dichloroacetic acid. 1251 79

Gap junctions, or connexons, are formed by connexin proteins and connect most cells in the body to form water-filled channels directly linking the cytoplasm. Among the molecules known to be transferred via junctions are cAMP, ATP, IP3 and glucose. Tumor cells are in general deficient in functional gap junctions either as a result of gene silencing, or failure to correctly process and assemble connexons. Tumor promoters inhibit function whereas certain cancer preventive agents increase junctional communication. When connexin expression in tumor cells is forced by introduction of exogenous genes or is increased by pharmacological agents, connexin expression reduces growth in suspension and growth as xenografts in nude mice. It is as yet unclear if in tumor cells these actions depend on junctional transfer of signal molecules or reflect some other function of these genes. Restoration of connexin function offers an exciting opportunity to delay tumor progression and inhibit metastasis.
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PMID:Cancer chemoprevention by connexins. 1254 61

Dichloroacetic acid (DCA) is a major by-product of water disinfection by chlorination. Several studies have demonstrated that DCA exhibits hepatocarcinogenic effects in rodents when administered in drinking water. This chemical does not appear to be highly mutagenic, and the mechanism(s) involved in DCA induction of cancer are not clear. The present work was aimed at identifying changes in gene expression which may indicate critical alterations/pathways involved in this chemical's carcinogenic activities. We used cDNA microarray methods for analyses of gene expression in livers of mice treated with the tumorigenic dose of 2 g/l DCA in drinking water for 4 weeks. Total RNA samples obtained from livers of the control and DCA-treated mice were evaluated for gene expression patterns with Clontech Atlas Mouse 1.2 cDNA and Atlas mouse stress/toxicology arrays, and the data analyzed with AtlasImage 2.01 and one-way ANOVA in JMP4 software. From replicate experiments, we identified 24 genes with altered expression, of which 15 were confirmed by Northern blot analysis. Of the 15 genes, 14 revealed expression suppressed two- to five-fold; they included the following: MHR 23A, cytochrome P450 (CYP) 2C29, CYP 3A11, serum paraoxonase/arylesterase 1 (PON 1), liver carboxylesterase, alpha-1 antitrypsin, ER p72, glutathione S-transferase (GST) Pi 1, angiogenin, vitronectin precursor, cathepsin D (CTSD), plasminogen precursor (contains angiostatin), prothrombin precursor and integrin alpha 3 precursor (ITGA 3). An additional gene, CYP 2A4/5, had a two-fold elevation in expression. Further, in ancillary Northern analyses of total RNA isolated from DCA-induced hepatocellular carcinomas (from earlier reported studies of mice treated with 3.5 g/l DCA for 93 weeks), many of the same genes (11 of 15) noted above showed a similar alteration in expression. In summary, we have identified specific genes involved in the functional categories of cell growth, tissue remodeling, apoptosis, cancer progression and xenobiotic metabolism that have altered levels of expression following exposures to DCA. These findings serve to highlight new pathways in which to further probe DCA effects that may be critical to its tumorigenic activity.
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PMID:Altered gene expression in mouse livers after dichloroacetic acid exposure. 1264 86

In this study, we examined the unique relationship of maspin, a serine protease inhibitor (serpin), that plays a critical role in mammary gland development and is silenced during breast cancer progression, and nitric oxide (NO), a multifaceted water and lipid soluble free radical. The hypothesis tested was that there is a correlation between endothelial nitric oxide synthase and maspin in MCF-7 cells and that NO is capable of regulating maspin expression. An experimental system was developed in which cellular levels of NO in normal human mammary epithelial cells and the breast cancer cell line MCF-7 could be altered using NO modulators. The effect(s) of NO modulators on maspin was measured using reverse transcriptase-polymerase chain reaction and Western blot analysis of subcellular fractions of both cell types. The data revealed that NO induced maspin expression in MCF-7 cells, and the induced maspin resulted in diminished cell motility and invasion, concomitant with an increase in the apoptotic index. This novel finding provides new information regarding the molecular role of maspin in regulating mammary epithelial growth, remodeling, tumor progression, and the metastatic process. More significantly, these findings could have a potential impact on future therapeutic intervention strategies for breast cancer. Targeted delivery of NO within the tumor microenvironment could provide a feasible noninvasive approach for effective treatment.
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PMID:Nitric oxide regulation of maspin expression in normal mammary epithelial and breast cancer cells. 1270 24

Glioblastoma multiforme are infiltrative lesions that have a high degree of heterogeneity, both within and between different patients. Imaging is critical for all phases in the evaluation and treatment of these lesions, but has been limited in providing information that is reliable enough to stratify patients into groups with uniform behavior and to predict outcome. Although magnetic resonance imaging is the method of choice for visualizing anatomic features of the lesion, its results are ambiguous in terms of defining the functional characteristics of the lesion and distinguishing tumor from treatment induced necrosis. Recent advances in magnetic resonance have made possible the routine acquisition of physiological data such as perfusion- and diffusion-weighted images and of metabolic data such as water suppressed proton spectroscopic images. These provide quantitative measurements that are more closely related to the biological properties of the tumor and reflect changes in tumor vascularity, cellularity and proliferation that are associated with tumor progression. As the molecular properties that influence invasion and neoplastic transformation are elucidated, it is critical that noninvasive imaging techniques are available for investigating new therapies and tailoring treatment to individual patient characteristics. The data obtained from patients with glioblastoma multiforme have already demonstrated that these new magnetic resonance techniques are able to contribute to diagnosis, characterization of malignant potential, treatment planning and assessment of response to therapy.
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PMID:Imaging glioblastoma multiforme. 1278 79


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