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)

This study sought to determine if pretreatment with low-dose tumor necrosis factor-alpha (TNF-alpha) can enhance the effects of radiation in an NCI-H441 human lung tumor xenograft model. In vitro assays were performed on spleen cells, blood leukocytes, and plasma from the animals, as well as on cultured tumor cells. Tumors in animals given only TNF-alpha grew as well as, or better than, tumors in their untreated counterparts at all time-dose regimens employed. In contrast, early treatment with a total radiation dose of 16 Gy resulted in complete tumor inhibition, whereas 8 Gy modestly (but significantly, P < 0.05) slowed tumor progression. However, the administration of TNF-alpha (4 x 10(4) total units/mouse) 16-18 h prior to irradiation (8 Gy total dose) enhanced the antitumor effects of radiation when treatment was initiated early (P < 0.05). Oxygen radical production and response to mitogenic stimulation by splenocytes were greatest in untreated tumor-bearing animals. Total leukocyte counts in mice given radiation or TNF-alpha + radiation were low, and treatment-related changes were found in percentages of neutrophils and lymphocytes. In vitro assays of tumor cells showed that TNF-alpha + radiation resulted in greater suppression of clonogenic survival and incorporation of [3H]TdR and [3H]UdR incorporation than either agent alone. These results suggest that the use of low-dose TNF-alpha together with radiation may be beneficial in the clinical setting and so warrant further investigation.
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PMID:Evaluation of TNF-alpha effects on radiation efficacy in a human lung adenocarcinoma model. 916 Mar 52

Leukocyte infiltration and necrosis are two biological phenomena associated with the development of neovascularization during the malignant progression of human astrocytoma. Here, we demonstrate expression of interleukin (IL)-8, a cytokine with chemotactic and angiogenic properties, and of IL-8-binding receptors in astrocytoma. IL-8 expression is first observed in low grade astrocytoma in perivascular tumor areas expressing inflammatory cytokines. In glioblastoma, it further localizes to oxygen-deprived cells surrounding necrosis. Hypoxic/anoxic insults on glioblastoma cells in vitro using anaerobic chamber systems or within spheroids developing central necrosis induced an increase in IL-8 messenger RNA (mRNA) and protein expression. mRNA for IL-8-binding chemokine receptors CXCR1, CXCR2, and the Duffy antigen receptor for chemokines (DARC) were found in all astrocytoma grades by reverse transcription/PCR analysis. In situ hybridization and immunohistochemistry localized DARC expression on normal brain and tumor microvascular cells and CXCR1 and CXCR2 expression to infiltrating leukocytes. These results support a model where IL-8 expression is initiated early in astrocytoma development through induction by inflammatory stimuli and later in tumor progression increases due to reduced microenvironmental oxygen pressure. Augmented IL-8 would directly and/or indirectly promote angiogenesis by binding to DARC and by inducing leukocyte infiltration and activation by binding to CXCR1 and CXCR2.
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PMID:Upregulation of interleukin 8 by oxygen-deprived cells in glioblastoma suggests a role in leukocyte activation, chemotaxis, and angiogenesis. 933 59

Numerous natural and synthetic quinone compounds possess significant antitumor properties. Various mechanisms have been proposed to account for these properties, including scission and degradation of tumor cell DNA, intracellular "redox cycling" to cogenerate semiquinone free radicals and reactive oxygen intermediates, and the interaction of semiquinone radicals with tumor cell surface flavoenzymes. However, no evidence has been presented to explain adequately the preferential attack on tumor cells by semiquinone radicals, as opposed to normal cells. To address this question, a synergistic interaction was examined. A therapy consisting of a mixture of L-ascorbate and 2,6-dimethoxy-p-benzoquinone, was used for in vivo evaluation. BALB/c mice were depleted of functional T-lymphocytes by xenogeneic monoclonal antibody pretreatment, challenged with Ehrlich ascites tumor, and administered the semiquinone radical-generating therapy. Mice depleted of CD4+ T-lymphocytes responded with rapidly fatal tumor progression, with significantly decreased mean survival times over controls, whereas less severe responses were observed in mice devoid of CD8+ T-lymphocytes. Mice depleted of both T-lymphocyte subpopulations responded with uninhibited tumor growth and rapid mortalities. When tumor challenge occurred after therapy, tumor growth was significantly delayed in mice enriched for CD4+ T-lymphocytes, with demonstrable increases in mean survival time over controls. This reagent combination had no significant effect on T-lymphocyte profiles in secondary lymphoid organs. These data suggest a synergistic phenomenon of semiquinone radical-induced cytostasis coupled with T-lymphocyte helper activity for optimal tumor suppression.
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PMID:Synergism of dimethoxybenzosemiquinone free radicals and CD4+ T-lymphocytes to suppress Ehrlich ascites tumor. 942 Dec 11

We examined the effects of epidermal growth factor (EGF) on tumor progression of a weakly malignant rat mammary carcinoma cell line, ER-1. In vitro treatment with EGF enhanced tumorigenicity, metastatic capacity and in vitro invasive capacity of ER-1 cells. The increased malignancy of ER-1 cells was reversible, when the cells were pretreated with EGF for 24 h, whereas it was irreversible when pretreated with EGF for 1 month. EGF treatment elevated the intracellular peroxide level in ER-1 cells. When ER-1 cells were treated with EGF in the presence of N-acetylcysteine, a chemical antioxidant, the reversible or irreversible EGF-induced progression was inhibited. These results suggest that the reversible or irreversible tumor progression in ER-1 cells occur in accordance with the duration of exposure to EGF, and that reactive oxygen species may be involved in the progression.
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PMID:Reversible and irreversible tumor progression of a weakly malignant rat mammary carcinoma cell line by in vitro exposure to epidermal growth factor. 945 5

Hypoxia occurs to a variable extent in a vast majority of rodent and human solid tumors. It results from an inadequate and disorganized tumor vasculature, and hence an impaired oxygen delivery. A probe for the non-invasive detection of tumor hypoxia could find important utility in the selection of patients for therapy with bioreductive agents, anti-angiogenic/anti-vascular therapies and hypoxia-targeted gene therapy. In addition, tumor hypoxia has been shown to predict for treatment outcome following radio- or chemotherapy in human cancers, the underlying mechanism for which may involve hypoxia driving genetic instability and resulting tumor progression. Beyond oncology, utility can also be envisaged in stroke, ischemic heart disease, peripheral vascular disease, arthritis and other disorders. Design, validation, preclinical development and current status of a fluorinated 2-nitroimidazole, N-(2-hydroxy-3,3,3-trifluoropropyl)-2-(2-nitro-l-imidazolyl) acetamide (SR 4554, CRC 94/17), which has been rationally designed for the measurement of tumor hypoxia by magnetic resonance spectroscopy (MRS) and imaging (MRI), are reviewed. Application in positron emission tomography (PET) detection is also proposed. Design goals were: (i) a nitro group with appropriate redox potential for selective reduction and binding in hypoxic tumor cells; (ii) hydrophilic/hydrogen bonding character in the side chain to limit nervous tissue penetration and prevent neurotoxicity; and (iii) three equivalent fluorine atoms to enhance MRS/MRI detection, located in a metabolically stable position. Reduction of SR 4554 by mouse liver microsomes was dependent on oxygen content, with a half-maximal inhibition at 0.48 +/- 0.06%. SR 4554 underwent nitroreduction by hypoxic but not oxic tumor cells in vitro and electron energy loss spectroscopic analysis showed selective retention in the hypoxic regions of multicellular tumor spheroids. Pharmacokinetic design goals were met. In particular, low brain tissue concentrations were seen in contrast to excellent tumor levels, as measured by high performance liquid chromatography. The extent of this restricted entry to brain tumor was surprising given the overall octanol/water partition coefficient and was attributed to the hydrophilic/hydrogen bonding character of the side chain. Quantitative MRS was used to assess the retention of 19F signal in murine tumors and human tumor xenografts. The 19F retention index (FRI; ratio of 19F signal levels at 6 h relative to that at 45 min) ranged from 0.5 to 1.0 and 0.2 to 0.9 for murine tumors and human xenografts respectively. The correlation between SR 4554 retention and pO2 was not a linear one, but when FRI was > 0.5, the % pO2 < or = 5 mmHg was always > 60%, indicating that high FRI was associated with low levels of oxygenation. Finally, whole body 19F-MRI in mice demonstrated that SR 4554 and related metabolites localized mainly in tumor, liver and bladder regions. A selective MRS signal was readily detectable in tumors at doses at least 7-fold lower than those likely to cause toxicity in mice. We conclude that proof of principle is established for the use of SR 4554 as a non-invasive MRS/MRI probe for the detection of tumor hypoxia. Based on these promising studies, SR 4554 has been selected for clinical development.
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PMID:Preclinical development and current status of the fluorinated 2-nitroimidazole hypoxia probe N-(2-hydroxy-3,3,3-trifluoropropyl)-2-(2-nitro-1-imidazolyl) acetamide (SR 4554, CRC 94/17): a non-invasive diagnostic probe for the measurement of tumor hypoxia by magnetic resonance spectroscopy and imaging, and by positron emission tomography. 975 26

Tumor progression necessitates the induction of blood vessels that converge upon the tumor and enhance the diffusibility of oxygen and nutrients. Approaches to treat cancer by antiangiogenic therapy are therefore straightforward, and there is a great need for suitable in vitro systems to test antiangiogenic agents. In the present study, embryoid bodies (EBs) differentiated from totipotent mouse embryonic stem (ES) cells and cultivated using the spinner flask technique are introduced as an in vitro system for antiangiogenesis research. ES cells effectively differentiated endothelial cells within the three-dimensional tissue of EBs. The total area of capillary-like structures, which were positive for CD31 (platelet endothelial cell adhesion molecule, PECAM-1), was assessed by confocal laser scanning microscopy and image analysis of a series of optical sections. Endothelial differentiation occurred between Day 4-5 and Day 8 of EB development. Within 7 days, 100% of EBs contained capillary-like structures. Suramin, tamoxifen, tetrahydrocortisol, and a combination of tetrahydrocortisol and heparin were tested for their antiangiogenic capacity in the EB system and were found to efficiently inhibit endothelial differentiation. Diffusion studies of a 10-kd 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF)-dextran and the fluorescent, amphiphilic agent doxorubicin in avascular and vascularized EBs revealed that the endothelial structures formed functional vessels that facilitated diffusion. The diffusion coefficient D for doxorubicin was 296 x 10(-9) cm2 s(-1) in vascularized 8-day-old EBs, ie, about 10-fold larger than in avascular 3-day-old EBs (18 x 10(-9) cm2 s(-1)) and EBs treated with suramin (14 x 10(-9) cm2 s(-1)), tamoxifen (13.5 x 10(-9) cm2 s(-1)), and tetrahydrocortisol/heparin (18.5 x 10(-9) cm2 s(-1)). Consequently, avascular EBs treated with antiangiogenic agents developed central necrosis, which was absent in vascularized EBs. Our findings indicate that EBs are a suitable in vitro model system to study the effects of antiangiogenic agents in a three-dimensional tissue context. Furthermore, EBs provide a unique model to investigate the diffusion of anticancer agents in a tissue in both the avascular and vascularized states.
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PMID:The embryoid body as a novel in vitro assay system for antiangiogenic agents. 980 Sep 56

In many cases, solid tumors exhibit numerous and highly permeable blood vessels. For a long time, this observation drew little attention. In the early 70's, however, Folkman proposed for the first time the potential relevance of tumor angiogenesis (formation of new vessels) for tumor growth and metastasis (6). He realized that tumors up to a diameter of 1-2 mm could be nurtured with oxygen and energy simply by diffusion (prevascular phase). Further growth, however, would require newly formed blood vessels. He hypothesized that (assuming the formation of new vessels was essential for tumor growth) pharmacological inhibition of angiogenesis could be developed as a new, more specific form of tumor treatment. In recent years, several groups have investigated the pathophysiology of tumor angiogenesis. Folkman's hypothesis that tumor growth is dependent on the formation of new vessels was supported by several experiments: Implants of different tumors into an avascular cornea initially have a slow growth rate that increases exponentially after infiltration of new vessels into the tumors (9). Inversely, the growth rate of solid tumors decreases with increasing distance to the supplying capillaries (27). The onset of neovascularization at the bases of human melanomas is directly associated with tumor growth and metastasis (25). Experiments with transgenic mice have demonstrated that the transition from hyperplastic to malignant cell growth occurs parallel to the onset of angiogenesis (7). Tumor vessel density has been shown to be associated with tumor progression and the clinical course in many human tumors (e.g. of the breast, lung, colon, cervix, prostate and bladder). Aside from the basic research on the formation of new (tumor) vessels, it is the therapeutic potential of various inhibitors of angiogenesis, some of which are currently tested in clinical (phase I/II) studies, that deserves special scientific attention. This review gives an overview of the relevance of angiogenesis for tumor growth, especially for renal cancers. It also discusses the potential advantages and disadvantages of different anti-angiogenic therapeutic approaches.
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PMID:Pathophysiology of tumor angiogenesis and its relevance in renal cell cancer. 1036 45

There is evidence that reactive oxygen species (ROS) are important mediators of tumor promotion and progression. The molecular mechanisms involved in ROS-mediated signaling, however, are unclear at present. Using ionizing radiation and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) as model physical and chemical carcinogens, we have malignantly progressed 308 cells, a papilloma-producing mouse keratinocyte cell line, and investigated the molecular alterations in the progressed phenotypes. In this study, we demonstrate that both MNNG and radiation-progressed malignant variants showed elevated ROS levels that contributed to their proliferative capacity in vitro as well as in vivo. We found increased Erk-1/2 and p38 MAP kinase activities to be important components of ROS-mediated signaling. The pro-oxidant state also contributed to constitutive elevation of AP-1, NFkappaB and cAMP response element transactivation in the malignant phenotype. Our data provide evidence for a functional role of elevated ROS levels in tumor progression and implicate Erk-1/2 and p38 MAP kinase activation in the malignant progression of mouse keratinocytes.
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PMID:Increased ROS levels contribute to elevated transcription factor and MAP kinase activities in malignantly progressed mouse keratinocyte cell lines. 1054 7

The switch to an angiogenic phenotype is a fundamental determinant of neoplastic growth and tumor progression. We demonstrate that homozygous deletion of the p53 tumor suppressor gene via homologous recombination in a human cancer cell line promotes the neovascularization and growth of tumor xenografts in nude mice. We find that p53 promotes Mdm2-mediated ubiquitination and proteasomal degradation of the HIF-1alpha subunit of hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor that regulates cellular energy metabolism and angiogenesis in response to oxygen deprivation. Loss of p53 in tumor cells enhances HIF-1alpha levels and augments HIF-1-dependent transcriptional activation of the vascular endothelial growth factor (VEGF) gene in response to hypoxia. Forced expression of HIF-1alpha in p53-expressing tumor cells increases hypoxia-induced VEGF expression and augments neovascularization and growth of tumor xenografts. These results indicate that amplification of normal HIF-1-dependent responses to hypoxia via loss of p53 function contributes to the angiogenic switch during tumorigenesis.
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PMID:Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. 1064 Feb 74

Mutatect MN-11 is a tumor line that can be grown subcutaneously in syngeneic C57BL/6 mice. The frequency of spontaneously arising mutants at the hypoxanthine phosphoribosyltransferase (Hprt) locus was observed to be elevated as a result of in vivo growth. The objective of the present study was to identify factors in the tumor microenvironment that might explain this increase in mutant frequency (MF). When tumors were examined histologically, neutrophils were found to be the predominant infiltrating cell type. Quantitative estimates of the number of neutrophils and MF of tumors in different animals revealed a statistically significant correlation (r = 0.63, P < 0.0001). Immunohistochemical analysis for inducible nitric oxide synthase (iNOS) demonstrated its presence, mainly in neutrophils. Biochemical analysis of tumor homogenates for nitric oxide synthase (NOS) activity indicated a statistically significant correlation with MF (r = 0.77, P < 0.0001). Nitrotyrosine was detected throughout the tumor immunohistochemically; both cytoplasmic and nuclear staining was seen. To increase the number of infiltrating neutrophils, tumors were injected with chemoattractant interleukin-8 and prostaglandin E2. This produced a statistically significant increase in neutrophil content (P = 0.005) and MF (P = 0.0002). As in control MN-11 tumors, neutrophil content and MF were strongly correlated (r = 0.63, P = 0. 003). Because neutrophils are a potential source of genotoxic reactive oxygen and/or nitrogen species, our results support the notion that these tumor-infiltrating cells may be mutagenic and contribute to the burden of genetic abnormalities associated with tumor progression.
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PMID:Neutrophils, nitric oxide synthase, and mutations in the mutatect murine tumor model. 1066 80


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