Summary and Discussion

We have presented for discussion a broad-based review of the utility of adenoviral vectors in animal models of lung cancer. Since this entire compilation is devoted to Ad-gene therapy, we have particularly embellished the sections on "animal models" of disease, especially as they pertain to lung and prostate cancer. These examples illustrate that the development of our approaches may need to be disease specific, especially with respect to targeting and mode of delivery. From this review, it is evident that to realize the full potential of cancer gene therapy, advances need to be made on a number of fronts. Not only do we need to construct better Ad-vectors or more relevant animal models, we also need to incorporate emerging technologies to a useful purpose within the experimental design. For example, the pathway to human clinical trials may be better paved by an improved ability to gather interim surrogate measures of gene transfer and expression in animal models.

The implementation of a quantitative and noninvasive method capable of monitoring transgene expression in living animals repetitively would be useful toward validating the efficacy of any gene therapy strategy. In this respect, a number of investigators, including those at UCLA, are developing sensitive technologies for imaging transgene expression using positron emission tomography (PET) and optical measurements. PET is a noninvasive, tomographic imaging modality that already has clinical applications for the diagnosis and management of several diseases including cancer. Newer high-resolution animal microPET technology developed at UCLA, is allowing for the study of smaller animal systems (mice, rats, small primates) previously difficult to image with a resolution approaching 2 mm [179]. With relevance to gene therapy for cancer, the herpes simplex virus 1 thymidine kinase (HSVl-tk) gene has been demonstrated to be an excellent "PET reporter gene" by virtue of trapping positron-emitting 8-[18F] fluoroganciclovir (FGCV) specifically only in cells expressing HSVl-tk[180]. Using FGCV, repetitive PET imaging of adenovirus-directed hepatic expression of the HSVl-tk reporter gene in living mice has been achieved [180-182], More importantly direct correlation between the retained PET reporter probe and the levels of HSVl-tk gene expression in the targeted organ have also been demonstrated [180-182]. Thus, PET is a sensitive and quantitative modality to image the location and magnitude of adenoviral vector-mediated gene expression in living animals which could be translated to clinical gene therapy application. Similarly, a charge-coupled device (CCD) camera is a highly sensitive camera for measuring photons. Advances in CCD technology can now enable investigators to quantitatively and reliably image low levels of luminescence (from the heterologous expression of the firefly luciferase gene) arising from within living animals [183], Although tomographic images are not possible, and the signal is dependent on the depth of tissue from which the light source emanates, it is possible to get reproducible and semiquantitative images. The simplicity and minimal background signal of optical CCD luciferase approach may complement the detailed tomographic imaging of MicroPET and the newer confocal microscopy techniques and, ultimately, be more predictive of gene transfer strategies in the treatment of human disease.

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