Murine retroviral vectors can infect a wide variety of proliferating mammalian cell types (e.g. lymphocytes). Non-proliferating tissues (e.g. neurons) are not transduced by murine retroviral vectors. These findings suggest that this type of vector may be useful for the selective introduction of genes into growing tumors in the brain, since the tumor is essentially the only tissue that will integrate and express the vector genes. We have investigated the possibility of direct in vivo gene transfer into growing brain tumors in animals. Rats with a malignant brain tumor were given an intratumoral stereotaxic injection of murine retroviral vector-producer cells (VPC) that were producing vectors containing the Herpes Simplex-thymidine kinase (HS-tk) gene or a control VPC line containing the β-galactosidase gene. The animals were rested 5 days to allow time for the HS-tk retroviral vectors that were produced in situ to transduce the neighboring proliferating gliosarcoma. The animals were then treated with the anti-herpes drug ganciclovir (GCV). Tumors injected with the HS-tk VPC regressed completely with GCV therapy while the tumors injected with β-galactosidase VPC developed large tumors. Staining for β-galactosidase (+) cells in control animal brain revealed transduction of 10–50% of the tumor cells without evidence of transduction of the surrounding normal brain tissue. No significant toxicity was observed in toxicity studies in mice, rats and non-human primates. Based upon these findings, we have proposed a human clinical trial to determine if the direct implantation of the GlTkSvNa VPC line into growing human brain tumors will induce regression with GCV therapy. The patient population primarily consists of individuals with recurrent malignant tumors who are currently considered ineligible for the approved NIH trial due to the size of the tumor. The RAC has previously approved an initial trial at NIH involving the stereotaxic injection of brain tumors. In this protocol, patients will undergo surgical debulking of the tumor followed by repeated treatments of HS-tk VPC into the tumor bed in an attempt to induce complete regression of the tumor with GCV therapy. These are patients who have failed standard therapy for their tumor and are expected to survive for several weeks to a few months. Project Title: Gene Therapy for the Treatment of Malignant Brain Tumors with In Vivo Tumor Transduction with the Herpes Thymidine Kinase Gene/Ganciclovir System. Principal Investigators: Kenneth W. Culver, M.D. and John Van Gilder, M.D. We have investigated the possibility of transferring a “sensitivity” gene into a growing brain tumor. The purpose is to make the tumor sensitive to a type of chemotherapy that is relatively nontoxic to the rest of the body. The gene we have selected is the Herpes Simplex-thymidine kinase (HS-tk) gene. Herpes Simplex is a virus that can be killed by a drug called ganciclovir (GCV). By transferring the HS-tk gene into the tumor, using a disabled mouse virus called a “vector,” we then essentially convert the tumor to be like a herpes virus and now the tumor can be killed with GCV. Experiments in rats have shown that the direct injection of mouse cells producing a HS-tk vector into a growing brain tumor can result in complete destruction of the tumor with GCV therapy. We found no evidence of spread of the virus to the normal brain tissue or to other parts of the body. Based upon these findings, an initial trial is underway at the National Institutes of Health (NIH). To date, five patients have been treated without evidence of toxicity. We now proposed a second human clinical trial for patients who are currently ineligible for treatment in the NIH trial due to the large size of their tumor. In this study, patients will undergo surgery to remove as much of the tumor as possible followed by repeated treatments of HS-tk vector-producer cells (VPC) into their growing human brain tumors in an attempt to induce regression of the tumor with GCV therapy. The patient population consists of individuals who have failed standard therapy and have recurrent primary brain tumors with an expected survival of weeks to a few months.
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This chapter discusses the molecular biology of gene therapy and its application to the clinical research on treatments for primary and metastatic brain tumors. Gene therapy as a potential treatment of cancer has exploded onto the forefront of medicine. Depending upon the mode of action of the gene that is inserted into the tumor, a different treatment approach may be indicated. glioblastoma multiforme (GBM) tumors infiltrate into the surrounding brain parenchyma, successfully avoiding complete surgical resection and complicating radiotherapy. The number and type of metastatic brain tumors generally follow the incidence of systemic cancers in the general population, with lung, breast, and colorectal cancers being the most common. In the brain, the tumor is the most mitotically active cell; macrophage-derived cells, blood cells, and endothelial cells are only minimally mitotic. There are several disadvantages to the use of adenoviral vectors in the brain.
A betweenness semigroup is a semigroup possessing a ternary relation, ‘ b lies between a and c ’, which is invariant under the semigroup operation. We take as our axioms of betweenness those suggested by Shepperd in (2) and given below in 1·01–1·04. It was shown in (2) that these axioms lead to just two types of betweenness; namely a linear betweenness corresponding to the order of points on an undirected straight line or a cyclic betweenness of just four points on a circle. In (3), Shepperd characterized betweenness groups and we here generalize his results to betweenness semigroups.
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Sherman, Barry M.; Harris, Curtis E.; Schlechte, Janet; Duello, Teresa M.; Halmi, Nicholas S.; Gilder, John Van; Chapler, Frederick K.; Granner, Daryl K. Author Information
At the time of writing, second class stamps cost 12p and first class 17p. To minimise the amount of change in my pocket I have a preference for buying these stamps in ratios that cost a whole number of pounds.
