Cancer science
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Transforming growth factor (TGF)-beta signaling has been shown to promote tumor growth and metastasis in advanced cancer. Use of inhibitors of TGF-beta signaling may thus be a novel strategy for treatment of patients with such cancers. In this study, we investigated the effects of a novel TGF-beta type I receptor (TbetaR-I) kinase inhibitor, Ki26894, on bone metastasis of a highly bone-metastatic variant of human breast cancer MDA-MB-231 cells, termed MDA-MB-231-5a-D (MDA-231-D). ⋯ X-ray radiography revealed that systemic Ki26894 treatment initiated 1 day before the inoculation of MDA-231-D cells into the left ventricle of BALB/cnu/nu female mice resulted in decreased bone metastasis of breast cancer cells. Moreover, Ki26894 prolonged the survival of mice inoculated with MDA-231-D cells compared to vehicle-treated mice. These findings suggest that TbetaR-I kinase inhibitors such as Ki26894 may be useful for blocking the progression of advanced cancers.
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Comparative Study
Adaphostin has significant and selective activity against chronic and acute myeloid leukemia cells.
Adaphostin is a tyrphostin that was designed to inhibit Bcr/Abl tyrosine kinase by altering the binding site of peptide substrates rather than that of adenosine triphosphate, a known mechanism of imatinib mesylate (IM). However, it has been shown that adaphostin-mediated cytotoxicity is dependent on oxidant production and does not require Bcr/Abl. We have tested adaphostin against both Philadelphia chromosome (Ph)-positive (K562, KBM5, KBM5-R [IM resistant KBM5], KBM7, and KBM7-R [IM-resistant KBM7]) and Ph-negative (OCI/AML2 and OCI/AML3) cells, and against cells from patients with chronic myeloid leukemia (CML) and acute myeloid leukemia (AML). ⋯ Adaphostin selectively inhibited colony growth of cells from CML (IM-sensitive and IM-resistant) and AML patients. Analysis of tyrosine phosphorylated proteins after treatment with adaphostin revealed alternate effects in different cells consistent with the modulation of multiple targets. In conclusion, adaphostin showed significant and selective activity against CML and AML cells and its development for clinical testing is warranted.
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In adults, the vasculature is normally quiescent, due to the dominant influence of endogenous angiogenesis inhibitors over angiogenic stimuli. However, blood vessels in adults retain the capacity for brisk initiation of angiogenesis, the growth of new vessels from pre-existing vessels, during tissue repair and in numerous diseases, including inflammation and cancer. Because of the role of angiogenesis in tumor growth, many new cancer therapies are being conducted against tumor angiogenesis. ⋯ However, we have proposed a concept in which cells of the hematopoietic lineage are mobilized and then entrapped in peripheral tissues, where they function as accessory cells that promote the sprouting of resident EC by releasing angiogenic signals. Most recently we found that hematopoietic cells play major roles in tumor angiogenesis by initiating sprouting angiogenesis and also in maturation of blood vessels in the fibrous cap of tumors. Therefore, manipulating these entrapment signals may offer therapeutic opportunities to stimulate or inhibit angiogenesis.
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Comparative Study
High expression of ubiquitin carboxy-terminal hydrolase-L1 and -L3 mRNA predicts early recurrence in patients with invasive breast cancer.
The present study investigated the mRNA expression level of ubiquitin c-terminal hydrolase (UCH)-L1 and -L3 in breast cancer tissue and aimed to elucidate its association with tumor characteristics and patient prognosis. UCH-L1 and UCH-L3 mRNA levels in invasive breast cancer (n = 100) were determined by a real-time polymerase chain reaction (PCR) assay and their relationship with various clinicopathological characteristics of breast tumors as well as patient prognosis were studied. UCH-L3 mRNA level was significantly upregulated in breast cancer tissue compared to adjacent normal breast tissue (P < 0.005), and UHC-L1 mRNA level also showed a non-significant increase in tumor tissue compared to adjacent normal breast tissue. ⋯ High UCH-L1 mRNA level was significantly associated with negative estrogen receptor status (P < 0.05) and negative progesterone receptor status (P < 0.05). Patients with both UCH-L1 and UCH-L3 mRNA high tumors showed a significantly poorer prognosis than those in the UCH-L1 or UCH-L3 mRNA low group (P < 0.005). These observations that UCH-L3 mRNA level is upregulated in breast cancer tissue, and breast tumors with both UCH-L1 and UCH-L3 mRNA high expression are associated with a poor prognosis, suggest the possible involvement of UCH-L1 and UCH-L3 in the pathogenesis and progression of breast cancer.
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UFT is an oral 5-fluorouracil derivative drug that may improve postoperative survival in non-small cell lung cancer (NSCLC), and experimental studies have shown that UFT inhibits tumor angiogenesis. In the present study, therefore, the correlation between tumor angiogenesis (intratumoral microvessel density, IMVD) and the efficacy of UFT in 162 patients with pathologic stage I NSCLC was examined. For higher IMVD tumors (IMVD > or = 20, n = 80), the 5-year survival rate of UFT-treated patients (82.5%) was significantly higher than that of surgery-alone patients (61.8%, P = 0.032). ⋯ For tumor showing strong VEGF expression (n = 63), UFT administration improved the survival (5-year survival rates of UFT-treated patients and surgery-alone patients, 84.6% and 60.0%, respectively; P = 0.048); for weakly VEGF-expressing tumors (n = 99), UFT administration did not influence the survival (5-year survival rates, 83.4% and 79.1%, respectively; P = 0.455). Multivariate analyses demonstrated that UFT administration seemed to be effective for strong VEGF tumors (P = 0.063; RR and the 95% CI, 0.234 [0.051-10.81]), but not for weak VEGF tumors (P = 0.456; 0.673 [0.293-1.900]). In conclusion, the efficacy of postoperative UFT administration in NSCLC was correlated with tumor angiogenesis.