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Ann Thorac Surg 1995;60:597-598
© 1995 The Society of Thoracic Surgeons
DR STEVEN J. MENTZER (Boston, MA): Doctor Smythe, the data you showed of the lac gene's staining of mesothelium suggested some tissue specificity. Before I would use the adenovirus vector in a patient, however, I would need significantly more evidence of tissue specificity. What evidence do you have that the virus is tropic for mesothelioma, and what explanation do you have for the mechanism of tumor elimination?
DR SMYTHE: There is absolutely no proof that it is specific for mesothelioma. We have shown in previous studies in addition to this that the adenovirus seems to be unable to traverse the mesothelial barrier in the chest and the peritoneal cavity. So its specificity is anatomic. This is one of the reasons we chose mesothelioma as our initial tumor to study rather than an intraparenchymal lung cancer, where the issues of gene transfer and lack of toxicity in surrounding parenchyma would be much less.
DR MENTZER: So the virus had to come into direct contact with the tumor?
DR SMYTHE: Yes, that is right. In this case the virus is just simply instilled into the pleural cavity. In our previous experiments with immune-deficient mice it was placed in the peritoneal cavity.
In answer to your second question about why the majority of the tumor is eradicated, there is a ``bystander effect.'' Cells that are not infected with the HSVtk gene are killed if they are in the vicinity of a cell that has received the new gene. This has been a significant question for many researchers in regard to how this occurs. We recently submitted work for publication showing that the majority of the effect is seemingly dependent on gap junctional transfer of metabolites from cell to cell. You do not have to resect the entire tumor to eradicate the tumor. Otherwise there would be no effective gene therapy for any sort of tumor at this point.
DR MENTZER: I was hoping that you were going to tell me that the tumor was the only cell that would allow expression of the tk gene so that you could treat any tumor.
DR SMYTHE: No, it does not seem to be that specific. However, it does certainly seem that cells that are rapidly synthesizing DNA are affected to a much greater degree. We have done a series of toxicity studies in rats and baboons leading up to an eventual clinical trial that we have received approval for by the NIH DNA Recombinant Advisory Committee, and we have not shown that there is significant damage to the normal mesothelium in the system. Although it is metabolically active, the normal mesothelium is probably not actually synthesizing large amounts of DNA as opposed to tumor cells.
DR HANI SHENNIB (Montreal, Quebec, Canada): What happens if you give the ganciclovir alone? Do you have another control in which you examine at the effects of ganiciclovir alone?
DR SMYTHE: Actually, I can harken back to our initial work in immunodeficient animals, which will shortly be published in the Annals of Surgery. In that study we had every control you could possibly think of-ganciclovir without virus, ganciclovir with marker virus, ganciclovir with therapeutic virus, therapeutic virus alone, marker virus alone-and the answer to your question is there is virtually no effect of ganciclovir alone, and virtually no effect of viral infection alone. There is a thousandfold difference in effect when you combine the two.
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