Several types of cellular responses to ionizing radiation, such as the adaptive response or the bystander effect, suggest that low-dose radiation may possess characteristics that distinguish it from its high-dose counterpart. Accumulated evidence also implies that the biological effects of low-dose and high-dose ionizing radiation are not linearly distributed. We have investigated, for the first time, global gene expression changes induced by ionizing radiation at doses as low as 2 cGy and have compared this to expression changes at 4 Gy. We applied cDNA microarray analyses to G1-arrested normal human skin fibroblasts subjected to X irradiation. Our data suggest that both qualitative and quantitative differences exist between gene expression profiles induced by 2 cGy and 4 Gy. The predominant functional groups responding to low-dose radiation are those involved in cell-cell signaling, signal transduction, development and DNA damage responses. At high dose, the responding genes are involved in apoptosis and cell proliferation. Interestingly, several genes, such as cytoskeleton components ANLN and KRT15 and cell-cell signaling genes GRAP2 and GPR51, were found to respond to low-dose radiation but not to high-dose radiation. Pathways that are specifically activated by low-dose radiation were also evident. These quantitative and qualitative differences in gene expression changes may help explain the non-linear correlation of biological effects of ionizing radiation from low dose to high dose.

No abstract

No abstract

Elevated fatty acid synthase (FASN) has been reported in both androgen-dependent and -independent prostate cancers. Conventional treatment for prostate cancer is radiotherapy (RT); however, the following radiation-induced radioresistance often causes treatment failure. Upstream proteins of FASN such as Akt and NF-κB are found increased in the radioresistant prostate cancer cells. Nevertheless, whether inhibition of FASN could improve RT outcomes and reverse radiosensitivity of prostate cancer cells is still unknown. Here, we hypothesised that orlistat, a FASN inhibitor, could improve RT outcomes in prostate cancer. Orlistat treatment significantly reduced the S phase population in both androgen-dependent and -independent prostate cancer cells. Combination of orlistat and RT significantly decreased NF-κB activity and related downstream proteins in both prostate cancer cells. Combination effect of orlistat and RT was further investigated in both LNCaP and PC3 tumour-bearing mice. Combination treatment showed the best tumour inhibition compared to that of orlistat alone or RT alone. These results suggest that prostate cancer treated by conventional RT could be improved by orlistat via inhibition of FASN.

In our previous studies using combined radioisotopes with chemotherapeutic liposomal drugs (i.e., 111 In-labeled polyethylene glycol (PEG)ylated liposomal vinorelbine) we have reported possible therapeutic efficiency in tumor growth suppression. Nevertheless, the challenge remains as to whether this chemotherapy has a therapeutic effect as good as that of combination therapy. The goal of this study was to investigate the real therapeutic effectiveness of 6 mol% PEG 111 In-vinorelbine liposomes via the elevation of the radiation dosage and reduction in the concentration of chemotherapeutic agents. Methods: Murine colon carcinoma cells transfected with dual-reporter genes (CT-26/tk-luc) were xenografted into BALB/c mice. The biodistribution was estimated to determine the drug profile and targeting efficiency of 111 In-vinorelbine liposomes. Bioluminescence imaging and 18 F-FDG small-animal PET were applied to monitor the therapeutic response after drug administration. The survival in vivo was estimated and linked with the toxicologic and histopathologic analyses to determine the preclinical safety and feasibility of the nanomedicine. Results: Effective long-term circulation of radioactivity in the plasma was achieved by 6 mol% PEG 111 In-vinorelbine liposomes, and this dose showed significantly lower uptake in the reticuloendothelial system than that of 0.9 mol% PEG 111 In-vinorelbine liposomes. Selective tumor uptake was represented by cumulative deposition, and the maximum accumulation was at 48 h after injection. The combination therapy exhibited an additive effect for tumor growth suppression as tracked by caliper measurement, bioluminescence imaging, and small-animal PET. Furthermore, an improved survival rate and reduced tissue toxicity were closely correlated with the toxicologic and histopathologic results. Conclusion: The results demonstrated that the use of 6 mol% PEG 111 In-vinorelbine liposomes for passively targeted tumor therapy displayed an additive effect with combined therapy, not only by prolonging the circulation rate because of a reduction in the phagocytic effect of the reticuloendothelial system but also by enhancing tumor uptake. Thus, this preclinical study suggests that 6 mol% PEG 111 In-vinorelbine liposomes have the potential to increase the therapeutic index and reduce the toxicity of the passively nanotargeted chemoradiotherapies.

BackgroundTo compare the RapidArc plan for primary hepatocellular carcinoma (HCC) with 3-D conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT) plans using dosimetric analysis.MethodsNine patients with unresectable HCC were enrolled in this study. Dosimetric values for RapidArc, IMRT, and 3DCRT were calculated for total doses of 45~50.4 Gy using 1.8 Gy/day. The parameters included the conformal index (CI), homogeneity index (HI), and hot spot (V107%) for the planned target volume (PTV) as well as the monitor units (MUs) for plan efficiency, the mean dose (Dmean) for the organs at risk (OAR) and the maximal dose at 1% volume (D1%) for the spinal cord. The percentage of the normal liver volume receiving ≥ 40, > 30, > 20, and > 10 Gy (V40 Gy, V30 Gy, V20 Gy, and V10 Gy) and the normal tissue complication probability (NTCP) were also evaluated to determine liver toxicity.ResultsAll three methods achieved comparable homogeneity for the PTV. RapidArc achieved significantly better CI and V107% values than IMRT or 3DCRT (p < 0.05). The MUs were significantly lower for RapidArc (323.8 ± 60.7) and 3DCRT (322.3 ± 28.6) than for IMRT (1165.4 ± 170.7) (p < 0.001). IMRT achieved a significantly lower Dmean of the normal liver than did 3DCRT or RapidArc (p = 0.001). 3DCRT had higher V40 Gy and V30 Gy values for the normal liver than did RapidArc or IMRT. Although the V10 Gy to the normal liver was higher with RapidArc (75.8 ± 13.1%) than with 3DCRT or IMRT (60.5 ± 10.2% and 57.2 ± 10.0%, respectively; p < 0.01), the NTCP did not differ significantly between RapidArc (4.38 ± 2.69) and IMRT (3.98 ± 3.00) and both were better than 3DCRT (7.57 ± 4.36) (p = 0.02).ConclusionsRapidArc provided favorable tumor coverage compared with IMRT or 3DCRT, but RapidArc is not superior to IMRT in terms of liver protection. Further studies are needed to establish treatment outcome differences between the three approaches.

No abstract

Development of nonimmunogenic and specific reporter genes to monitor gene expression in vivo is important for the optimization of gene therapy protocols. We developed a membrane-anchored form of mouse b-glucuronidase (mbG) as a reporter gene to hydrolyze a nonfluorescent glucuronide probe (fluorescein di-b-D-glucuronide, (FDGlcU) to a highly fluorescent reporter to assess the location and persistence of gene expression. A functional b-glucuronidase (bG) was stably expressed on the surface of murine CT26 colon adenocarcinoma cells where it selectively hydrolyzed the cell-impermeable FDGlcU probe. FDGlcU was also preferentially converted to fluorescent probe by (bG) on CT26 tumors. The fluorescent intensity in bG-expressing CT26 tumors was 240 times greater than the intensity in control tumors. Selective imaging of gene expression was also observed after intratumoral injection of adenoviral bG vector into carcinoma xenografts. Importantly, mbG did not induce an antibody response after hydrodynamic plasmid immunization of Balb/c mice, indicating that the reporter gene product displayed low immunogenicity. A membraneanchored form of human bG also allowed in vivo imaging, demonstrating that human bG can be employed for imaging. This imaging system therefore, displays good selectivity with low immunogenicity and may help assess the location, magnitude and duration of gene expression in living animals and humans.