Gene therapy using adenovirus carrying the herpes simplex-thymidine kinase gene to treat in vivo models of human malignant mesothelioma and lung cancer.

Abstract

Previous studies have shown adenoviral transfer of the herpes simplex virus thymidine kinase (HSVtk) gene followed by the anti-viral drug ganciclovir (GCV) can be used to successfully treat established human mesothelioma tumors growing within the peritoneal cavities of severe combined immune deficient (SCID) mice. These findings raised a number of questions important to the applicability, efficiency, and safety of this treatment strategy. In this report, we have further characterized the use of recombinant adenovirus carrying the HSVtk gene to treat mesothelioma and other localized malignancies. Our results indicate that the Ad.RSVtk/GCV system is effective in causing tumor regression in animals inoculated with another mesothelioma cell line and a lung cancer cell line and that animals with bulky disease can be successfully treated. Effects are seen at a wide range of virus doses and significant anti-tumor activity is present at doses of ganciclovir that are clinically achievable. Finally, this treatment approach appears safe, with limited dissemination of virus using a sensitive RT-PCR detection system. These studies further characterize the use of adenoviral transfer of the HSVtk gene to treat experimental mesothelioma and suggest that clinical trials using this approach may be feasible.

Decoy against nuclear factor-kappa B attenuates myocardial cell infiltration and arterial neointimal formation in murine cardiac allografts

“…This contrasts with other methodology, eg in vivo injection of genes using adenovirus, in which viral dissemination is revealed using RT-PCR. 30 These results further characterize the use of HVJ-AVE-liposome ex vivo transfer into transplant organs and suggest that clinical trials using this approach may be feasible.…”

Inclusion of the herpes simplex thymidine kinase gene in a replicating adenovirus does not augment antitumor efficacy

“…These results are similar to our previous studies of mesothelioma and lung cancer. 27 Delivery of Ad.wt.tk led to a slightly different type of survival profile. In these animals, there was evidence of some early toxicity (at about 1 week after viral injection), but surviving animals had an increase in survival (median survival 52 days) with some animals living to 95-105 days.…”

Use of protamine to augment adenovirus-mediated cancer gene therapy

“…8,9 Accordingly, adenoviral vectors encoding HSVtk (Ad.HSVtk) in combination with GCV have been used in several pre-clinical and clinical suicide gene studies directed against a variety of cancers including brain tumors, 10 head and neck tumors, 11 melanoma, 12,13 ovarian cancer, [14][15][16] and malignant mesothelioma. [17][18][19][20][21] Many of these animal studies have shown some therapeutic effects; however, one of the major shortcomings of adenoviral gene therapy has been the relatively low efficiency of recombinant gene transfer to target tumor tissues in vivo, thus, significantly limiting treatment efficacy. This occurs despite the presence of a 'bystander effect' where transfection of only a small percentage of malignant tumor cells is sufficient to achieve near complete tumor eradication in some animal studies.…”