Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.21 (thymidine kinase)
 7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant mesothelioma may prove to be an attractive candidate for somatic gene therapy with replication-deficient recombinant adenovirus transfer of a toxic, or drug sensitization gene. Transfer of the herpes simplex thymidine kinase type I gene (HSVtk), followed by exposure to the acyclic nucleoside drug ganciclovir, has been shown to be an effective tumor cell killing system. To study generalized applicability, we tested a number of thoracic malignant cell lines for their sensitivity to gancyclovir after infection with an adenoviral vector containing the HSVtk gene (Ad.RSVtk). Using the concentration of gancyclovir required to kill 50% of the cells (IC50) as a measure of sensitivity, we detected variable sensitivity among cell lines, with mesothelioma most sensitive (IC50 = 0.075 to 2.8 mumol/L gancyclovir), and non-small-cell carcinoma lines having an intermediate sensitivity (IC50 = 1.5 to 100 mumol/L). In contrast, an ovarian carcinoma line was extremely resistant (IC50 > 2000 mumol/L). To study the possible mechanisms for these differences, we studied cell lines with regard to their ability to be infected with an adenoviral vector containing a marker gene (Ad.CMVlacZ) and expression of the vitronectin receptor alpha v (an integrin cell adhesion molecule shown to be required for adenovirus internalization after initial binding). We found that the degree of lacZ transduction correlated with HSVtk sensitivity, whereas vitronectin receptor expression did not, suggesting that differences in initial viral binding ability, rather than internalization, may explain the sensitivity differences seen in vitro.
J Thorac Cardiovasc Surg 1995 Apr
PMID:Differential sensitivity of thoracic malignant tumors to adenovirus-mediated drug sensitization gene therapy. 753 80

Restenosis remains the main limitation of interventional cardiology. Restenosis is an important target for gene therapy since it is frequent (30% of patients), costly (estimated $2 billion annually), refractory to all pharmacological therapies, and related, at least in part, to smooth muscle cell proliferation which is an inviting target for antiproliferative molecular strategies. Because cell division is ultimately controlled by intranuclear events, the protein product of genes selected for their antiproliferative effects usually remains inside the cells. Consequently, the transfer of growth-inhibitory genes needs to be efficient-i.e., involve a large proportion of smooth muscle cells populating the angioplasty site. To date, adenoviral vectors are, by far, the most efficient vectors to perform in vivo arterial gene delivery. These vectors, as well as others, have been recently used to demonstrate that therapeutic genes encoding cytolytic (thymidine kinase) or cytostatic (hypophosphorylatable retinoblastoma protein, endothelial nitric oxide synthase, gax, etc.) products successfully inhibit smooth muscle cell proliferation and related intimal hyperplasia. Despite substantial progress, major technical issues remain to be addressed before gene therapy is applied to clinical restenosis. First-generation recombinant adenoviruses evoke both cellular and humoral immune responses leading to local toxicity and transient gene expression. Moreover, the low efficiency of gene transfer to atherosclerotic arteries may further impair the biological effect of antiproliferative genes. Finally, restenosis is a multifactorial phenomenon in which intimal hyperplasia plays an important but not exclusive role. Prevention of constrictive remodeling should also be taken into account in an integrated genetic strategy to prevent restenosis.
Cardiovasc Res 1996 Aug
PMID:Perspectives of arterial gene therapy for the prevention of restenosis. 879 5