Cancer research
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Flavopiridol, a cyclin-dependent kinase (cdk) inhibitor, can cause cell cycle arrest, induce apoptosis in cancer cells, and inhibit tumor cell growth in vivo. The present study investigated the in vitro radiosensitizing effect of flavopiridol and the underlying molecular mechanisms in a murine ovarian cancer cell line, OCA-I. Flavopiridol inhibited cell growth in a dose-dependent manner and enhanced cell radiosensitivity assessed by the clonogenic cell survival assay. ⋯ Furthermore, flavopiridol on its own induced apoptosis in the OCA-I cells, whereas in combination with radiation, exerted no additional increase in apoptosis. Taken together, our data show that flavopiridol strongly augmented the response of ovarian carcinoma cells to radiation and that the underlying mechanisms included inhibition of sublethal DNA damage repair and cell cycle redistribution. At the molecular level, transcriptional regulation by flavopiridol may have been involved.
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Interactions between the Bcr/Abl kinase inhibitor STI571 (Gleevec, imatinib mesylate) and histone deacetylase inhibitors (HDIs) have been examined in STI571-sensitive and -resistant Bcr/Abl(+) human leukemia cells (K562 and LAMA 84). Cotreatment of K562 cells with 250 nM imatinib mesylate and 2.0 micro M suberoylanilide hydroxamic acid (SAHA) for 24 h, exposures that were minimally toxic alone, resulted in a marked increase in mitochondrial damage (e.g., cytochrome c, Smac/DIABLO, and apoptosis-inducing factor release), caspase activation, and apoptosis. Similar events were observed in other Bcr/Abl(+) cells (i.e., LAMA 84), and in cells exposed to STI571 in combination with the HDI sodium butyrate. ⋯ Lastly, inducible expression of a constitutively active MEK1/2 construct significantly attenuated SAHA/STI571-mediated apoptosis in K562 cells, implicating disruption of the Raf/MEK/ERK axis in synergistic antileukemic effects of this drug combination. Together, these findings indicate that combined exposure of Bcr/Abl(+) cells to the kinase inhibitor STI571 and HDIs leads to diverse perturbations in signaling and cell cycle-regulatory proteins, associated with a marked increase in mitochondrial damage and cell death. They also raise the possibility that this strategy may be effective in some Bcr/Abl(+) cells that are resistant to STI571 through increased Bcr/Abl expression.
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Prostate cancer is a common malignancy affecting men, which is often associated with skeletal metastases resulting in significant morbidity and mortality. In this hormone-dependent cancer, low levels of a prostate secretory protein of 94 amino acids (PSP-94) are associated with advanced disease stage. In the current study, we have examined the effect of PSP-94 on prostate cancer growth and experimental metastases to the skeleton. ⋯ Whereas the highest dose of PSP-94 caused a modest but statistically significant delay in the development of hind-limb paralysis, a marked dose-dependent decrease in primary tumor volume was seen in experimental animals receiving PSP-94 due to its ability to promote tumor cell apoptosis. Furthermore, whereas control animals routinely developed hypercalcemia due to PTHrP production, treatment with PSP-94 led to a near normalization of plasma calcium and a marked reduction in PTHrP production as determined by radioimmunoassay and immunohistochemistry. Collectively, these results demonstrate the ability of PSP-94 to be an effective treatment modality for prostate cancer, where decrease in plasma PTHrP and calcium levels can serve as useful biochemical markers for monitoring the efficacy of this novel antitumor agent.
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Photodynamic therapy is an effective and often curative treatment for certain solid tumors. The porphyrin-based photosensitizer Photofrin, the only Food and Drug Administration-approved drug for this therapy, suffers from certain disadvantages: its complex chemical nature; retention by skin (leading to protracted cutaneous photosensitivity); and less than optimal photophysical properties. In this study, we examine the population pharmacokinetics and cutaneous phototoxicity of 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH), a chlorin-type photosensitizer with more favorable photophysical properties. ⋯ Whereas low concentrations of HPPH can be detected in plasma several months after a single infusion, no instances of cutaneous photosensitivity have been noted in these patients. In general, HPPH pharmacokinetic profiles are readily predictable from the global population model. This is the first comprehensive human population pharmacokinetic/pharmacodynamic study of a clinical anticancer photodynamic therapy agent.
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Vascular endothelial growth factor (VEGF) is thought to promote tumor growth and angiogenesis. Whereas VEGF is up-regulated in only a portion of anaplastic astrocytoma (AA), it is overexpressed in most glioblastoma multiforme (GBM), and the level of expression is correlated with grade of glioma. To explore the possibility that VEGF may act as a driving force in the progression of AA to GBM, the VEGF isoforms VEGF(121) and VEGF(165) were overexpressed in genetically modified, mutant H-Ras-transformed human astrocytes that on intracranial implantation form AA-like tumors. ⋯ Whereas these modest levels of VEGF overexpression were insufficient to drive oxygenation and GBM formation, an additional 8-fold increase in VEGF expression mediated by retroviral infection with constructs encoding either VEGF (121) or VEGF (165) resulted in cells which, after intracranial implantation, formed tumors that were larger, more vascular, and better oxygenated than those formed by the mutant H-ras parental cells. However, the tumors formed by the cells expressing exogenous VEGF (121) or VEGF (165) retained the phenotype of AA, lacking areas of necrosis that are the hallmark of the GBM phenotype. These results suggest that whereas the VEGF(121) and VEGF(165) isoforms can contribute to glioma vascularization, oxygenation, and growth, they do not in and of themselves drive the formation of the GBM phenotype.