The bystander effect (BSE) is an interesting and important communication. We confirmed that mixtures of tumor cells property of the herpes thymidine kinase/ganciclovir resistant to the BSE did not show dye transfer from cell to (hTK/GCV) system of gene therapy for cancer. With the cell while bystander-sensitive tumor cells did. Dieldrin, a BSE, not only are the hTK expressing cells killed upon gandrug known to decrease GJ communication, diminished ciclovir (GCV) exposure but also neighboring wild-type dye transfer and also inhibited the BSE. Forskolin, an uptumor cells. On testing a large number of tumor cell lines regulator of cAMP did increase GJ, but directly inhibited in vitro, a wide range of sensitivity to bystander killing was hTK and therefore its effect on BSE could not be deterfound. Since transfer of toxic GCV metabolites from hTKmined. We conclude that these observations further supmodified to wild-type tumor cells via gap junctions (GJ) port the concept that functional GJ play an important role seemed to be a likely mechanism of the BSE, we tested in the BSE and further suggest that pharmacological GJ function in these various tumors with a dye transfer manipulation of GJ may influence the outcome of cancer technique and pharmacological agents known to affect GJ therapy with hTK/GCV.
Apigenin, a flavinoid, and lovastatin, an HMG-CoA reductase inhibitor, upregulated gap junction (GJ) function and dye transfer in tumors expressing GJ and were inactive in the GJ-negative tumor line N2a. N2a cells transfected with the connexin 43 gene showed restored cell-to-cell dye transfer, which could then be improved nearly fourfold by addition of apigenin. To test the drugs in HSV thymidine kinase/ganciclovir (HSV-tk/GCV) tumor killing, mixtures of 90% wild-type (WT) with 10% HSV-tk gene-modified MCA38 adenocarcinoma cells were exposed in vitro to GCV +/- apigenin or lovastatin. A significant bystander effect (BSE) was seen following GCV treatment alone, while neither apigenin or lovastatin alone had any effect on the recovery of viable tumor colonies. However, GCV-treated cultures also exposed to apigenin or lovastatin showed an increased BSE and reduced tumor cell recovery. Thirty percent of mice bearing tumors from the same mixture of 90% WT and 10% HSV-tk MCA38 cells treated with GCV alone became tumor free. Tumor-bearing mice given only two or three injections of lovastatin or apigenin during GCV treatment had a doubling of the antitumor response rate, with 60-70% of the mice achieving complete remission. These results support the hypothesis that the transfer of phosphorylated GCV from HSV-tk gene-expressing cells to neighboring WT tumor cells is a major component of the BSE and that pharmacological manipulation of GJ function with lovastatin or apigenin can result in striking improvement in the antitumor response in mice with tumors modified to contain as few as 10% HSV-tk cells.
The occurrence of liver tumours in the course of Fanconi anaemia (FA) has been well documented. We present a case, review the literature and conclude that androgen therapy would increase the risk of developing tumours, most of which appear to be benign (adenomas or peliosis) and androgen-dependent, generally decreasing in size after cessation of treatment. Survival of patients is poor, mostly because of the rapid evolution of the tumour. In the absence of an allogenic bone marrow transplantation, administration of haematopoietic growth factors might be effective. As a preventive measure, other types of unsubstituted androgens may be used.
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