Oncolytic herpes simplex virus-1 (HSV-1) mutants possessing mutations in the ICP34.5 and ICP6 genes have proven safe through clinical trials. However, ICP34.5-null viruses may grow poorly in cells due to their inability to prevent host-cell shut-off of protein synthesis caused by hyperphosphorylation of eukaryotic initiation factor 2A. To increase tumor selectivity, glioma-selective expression of ICP34.5 in the context of oncolysis may be useful. Malignant gliomas remain an incurable disease. One molecular marker of malignant gliomas is expression of the intermediate filament nestin. Expression of nestin mRNA was confirmed in 6 of 6 human glioma lines and in 3 of 4 primary glioma cells. Normal human astrocytes were negative. A novel glioma-selective HSV-1 mutant (rQNestin34.5) was thus engineered by expressing ICP34.5 under control of a synthetic nestin promoter. Replication, cellular propagation, and cytotoxicity of rQNestin34.5 were significantly enhanced in cultured and primary human glioma cell lines compared with control virus. However, replication, cellular propagation, and cytotoxicity of rQNestin34.5 in normal human astrocytes remained quantitatively similar to that of control virus. In glioma cell lines infected with rQNestin34.5, the level of phosphoeukaryotic initiation factor 2A was lower than that of cells infected by control rHsvQ1, confirming selective ICP34.5 expression in glioma cells. In vivo, rQNestin34.5 showed significantly more potent inhibition of tumor growth compared with control virus. Treatment in the brain tumor model was instituted on animal's display of neurologic symptoms, which usually led to rapid demise. rQNestin34.5 treatment doubled the life span of these animals. These results show that rQNestin34.5 could be a potent agent for the treatment of malignant glioma. (Cancer Res 2005; 65(7): 2832-9)
Volumetric detection and accurate quantification of fluorescent proteins in entire animals would greatly enhance our ability to monitor biological processes in vivo. Here we present a quantitative tomographic technique for visualization of superficial and deep-seated (>2-3 mm) fluorescent protein activity in vivo. We demonstrate noninvasive imaging of lung tumor progression in a murine model, as well as imaging of gene delivery using a herpes virus vector. This technology can significantly improve imaging capacity over the current state of the art and should find wide in vivo imaging applications in drug discovery, immunology, and cancer research.fluorescence ͉ whole-body imaging ͉ imaging gene expression ͉ gene transfer ͉ multispectral imaging F luorescent proteins (FP) have become essential reporter molecules for the elucidation of the function of proteins within cells, the biodistribution of immune and stem cells, and evaluation of drug candidates in vivo (1, 2). Confocal and multiphoton microscopy have emerged as powerful methods for imaging superficial locations down to a few hundred micrometers and in limited field of views (typically 1-2 mm) (3). Alternative technologies to date use macroscopic epiillumination imaging using sensitive color cameras that obtain ''photographs'' of fluorescence activity emanating from up to a few millimeters under the skin surface of animals (4). Such images are often biologically informative, but they are surfaceweighted, i.e., they preferentially image superficial over deepseated activity because the intensity of the fluorescence signal recorded drops with a strong nonlinear dependence as a function of depth. In addition, photographic imaging yields a single projection that cannot resolve depth; signal quantification is complicated with varying tissue optical properties, for example because of angiogenesis; and superficial fluorescence signals or skin autofluorescence can reduce or even shield deep-seated contrast.To improve on imaging of FPs in whole animals, it is important to develop methods that account for the nonlinear propagation effects of photons into tissues and resolve depth. Such technology has been recently reported for tomographic imaging of extrinsically administered fluorescence probes in the nearinfrared (NIR) (5, 6). However, the FPs currently available absorb in the visible (Ͻ600 nm) and many also emit in the visible (7). The translation of tomographic methods for operation in the 450-600 nm spectral region comes with some unique challenges. These challenges arise because tissue offers significantly higher photon attenuation in the visible necessitating different instrumentation than implementations that have appeared so far for imaging in the NIR. Similarly, adept theoretical models are required to model the corresponding change of photon propagation patterns in highly absorbing media (8). We have recently developed a system and method for tomographic imaging in the visible (9) achieving 400-m resolution at 6-mm depth in homogenous slabs of 1.2-cm thickn...
We examined the radiological and histological features of, and the influences of the expression of VEGF and its two major receptors, Flt-1 and Flk-1, on the development of peritumoral brain edema (PTBE) in patients with intracranial meningiomas. The expressions of VEGF and VEGF receptors in the immunohistochemical study were analyzed in relation to several factors, including tumor size, location, vascularity, and blood supply, as seen on digital subtraction angiographic studies. The edema volume (P = 0.0003) and edema index (P < 0.0001) had a significantly positive relation to VEGF expression. The positivity of Flt-1 and Flk-1 was mainly observed in tumor vessels; 44 cases (37.2%) were positive for the Flt-1 antibody and 37 cases (31.4%) for the Flk-1 antibody. The mean value of the edema index of the positive-Flt-1 group (5.220 +/- 11.586) was significantly higher than that of the negative-Flt-1 group (1.782 +/- 2.559) (P < 0.0001). The mean value of the edema index of the positive-Flk-1 group (3.925 +/- 5.870) was slightly higher than that of the negative-Flk-1 group (2.671 +/- 8.136) (P < 0.0001). Our data suggest that the expressions of VEGF and VEGF receptors positively relate to each other and to the formation of PTBE in patients with meningiomas.
The success of cancer virotherapy depends on its efficacy versus toxicity profile in human clinical trials. Progress towards clinical trials can be hampered by the relatively elevated doses of oncolytic viruses administered in animal models to achieve an anticancer effect and by the even higher doses required in humans to approximate an animal bioequivalent dose. Such elevated doses of injected viral proteins may also lead to undesirable toxicities and are also very difficult to produce in a biotechnological setting. We report that a relatively potent herpes simplex virus type 1 oncolytic virus (rQNestin34.5) produces 45% survivors at a dose of 3 Â 10 4 plaque-forming units (pfu) in a 9-day-old mouse model of human glioma. Unlike our previous findings with less potent oncolytic viruses, though, the preadministration of cyclophosphamide did not enhance this survival or affect oncolytic virus tumor distribution and tumor volume. However, when oncolytic virus doses were reduced (3 Â 10 3 and 3 Â 10 2 pfu), cyclophosphamide significantly enhanced both animal survival and oncolytic virus tumor distribution and also reduced tumor volumes. These findings thus show that cyclophosphamide allows for dose reduction of doses of a relatively potent oncolytic virus, a finding with implications for the development of clinical trials. (Cancer Res 2005; 65(24): 11255-8)
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