Cancer research
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Hypoxia-inducible factor 1 (HIF-1) is a master regulator of the transcriptional response to oxygen deprivation. HIF-1 has been implicated in the regulation of genes involved in angiogenesis [e.g., vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase] and anaerobic metabolism (e.g., glycolytic enzymes). HIF-1 is essential for angiogenesis and is associated with tumor progression. ⋯ We show that concomitant with HIF-1 and VEGF inhibition, the activity of the Topo-I inhibitors tested is associated with induction of cyclooxygenase 2 mRNA expression. The luciferase-based high-throughput screen is a feasible tool for the identification of small molecule inhibitors of HIF-1 transcriptional activation. In addition, our results suggest that altered Topo-I function may be associated with repression of HIF-1-dependent induction of gene expression.
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Morphine is used to treat pain in several medical conditions including cancer. Here we show that morphine, in a concentration typical of that observed in patients' blood, stimulates human microvascular endothelial cell proliferation and angiogenesis in vitro and in vivo. ⋯ Consistent with these effects, morphine in clinically relevant doses promotes tumor neovascularization in a human breast tumor xenograft model in mice leading to increased tumor progression. These results indicate that clinical use of morphine could potentially be harmful in patients with angiogenesis-dependent cancers.
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We have shown previously that arsenic trioxide (ATO) preferentially shutsdown tumor blood flow, leading to pronounced cell death in the central part of the solid tumor with a minimal effect on the surrounding normal tissues. On the basis of the histopathological and tumor perfusion studies, we hypothesized that the tumor control rate of locally advanced solid tumors would increase after the combined treatment of ATO and radiation relative to either radiation or ATO alone. The antitumor action and quantitative tumor perfusion studies were carried out with locally advanced methylcholanthrene-induced fibrosarcoma grown in BALB/c mice. ⋯ Sustained reduction in tumor blood flow after the combined treatment measured using a rubidium uptake method paralleled enhanced tumor response. There was an immediate 10-fold increase in the production of tumor necrosis factor-alpha in the tumor tissue after the drug treatment, concomitant with the onset of prompt reduction of the tumor blood flow. The present results indicate that tumor response was better with combined treatment than with either treatment alone, suggesting that ATO has potential as an adjuvant to radiotherapy.