Recently, nanoparticles have been considered as a method of providing radiation dose enhancement in tumors. In order to quantify this affect, a dose enhancement factor (DEF) is defined that represents the ratio of the dose deposited in tumor with nanoparticles, divided by the dose deposited in the tumor without nanoparticles. Materials with atomic numbers (Z) ranging from 25 to 90 are considered in this analysis. In addition, the energy spectrum for a number of external beam x-ray sources and common radionuclides are evaluated. For a nanoparticle concentration of 5 mg/ml, the DEF is < 1.05 for Co-60, Ir-192, Au-198, Cs-137, 6, 18, and 25 MV x-rays for all materials considered. However, relatively large increases in the DEF are observed for 50, 80, 100, and 140 KVp x-rays as well as Pd-103 and I-125. The DEF increases for all sources as Z varies from 25-35. From Z = 40-60, the DEF plateaus or slightly decreases. For higher Z materials (Z>70), the DEF increases and is a maximum for the highest Z materials. High atomic number nanoparticles coupled with low energy external beam x-rays or brachytherapy sources offer the potential of significantly enhancing the delivered dose.
BackgroundVascular endothelial cells contribute to the pathogenesis of numerous human diseases by actively regulating the stromal inflammatory response; however, little is known regarding the role of endothelial inflammation in the growth of human tumors and its influence on the prognosis of human cancers.MethodsUsing an experimental model of tumor necrosis factor-alpha (TNF-α)-mediated inflammation, we characterized inflammatory gene expression in immunopurified tumor-associated endothelial cells. These genes formed the basis of a multivariate molecular predictor of overall survival that was trained and validated in four types of human cancer.ResultsWe report that expression of experimentally derived tumor endothelial genes distinguished pathologic tissue specimens from normal controls in several human diseases associated with chronic inflammation. We trained these genes in human cancer datasets and defined a six-gene inflammatory signature that predicted significantly reduced overall survival in breast cancer, colon cancer, lung cancer, and glioma. This endothelial-derived signature predicted outcome independently of, but cooperatively with, standard clinical and pathological prognostic factors. Consistent with these findings, conditioned culture media from human endothelial cells stimulated by pro-inflammatory cytokines accelerated the growth of human colon and breast tumors in immunodeficient mice as compared with conditioned media from untreated endothelial cells.ConclusionsThis study provides the first prognostic cancer gene signature derived from an experimental model of tumor-associated endothelial inflammation. These findings support the notion that activation of inflammatory pathways in non-malignant tumor-infiltrating endothelial cells contributes to tumor growth and progression in multiple human cancers. Importantly, these results identify endothelial-derived factors that could serve as potential targets for therapy in diverse human cancers.
PurposeTo determine the mechanisms of Signal Transducer and Activator of Transcription 1 (Stat1)-associated radioresistance developed by nu61 tumour selected in vivo by fractionated irradiation of the parental radiosensitive tumour SCC61.Materials and methodsRadioresistence of nu61 and SCC61 in vitro was measured by clonogenic assay. Apoptotic response of nu61 and SCC61 cells to genotoxic stress was examined using caspase-based apoptotic assays. Co-cultivation of carboxyfluorescein diacetate, succinimidyl ester (CFDE-SE)-labeled nu61 with un-labeled SCC61 was performed at 1:1 ratio. Production of interleukin-6, interleukin-8 and soluble receptor of interleukin 6 (IL6, IL8 and sIL6R) was measured using Enzyme-Linked Immunosorbent Assay (ELISA).ResultsRadioresistant nu61 was also resistant to interferon-gamma (IFNγ) and the death ligands of tumour necrosis factor alpha receptor (TNFR) family when compared to SCC61. This combined resistance is due to an impaired apoptotic response in nu61. Relative to SCC61, nu61 produced more IL6, IL8 and sIL6R. Using Stat1 knock-downs we demonstrated that IL6 and IL8 production is Stat1-dependent. Treatment with neutralising antibodies to IL6 and IL8, but not to either cytokine alone sensitised nu61 to genotoxic stress induced apoptosis.ConclusionNu61, which over-expresses Stat1 pathway, is deficient in apoptotic response to ionising radiation and cytotoxic ligands. This resistance to apoptosis is associated with Stat1-dependent production of IL6 and IL8 and suppression of 8, 9 and 3.
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