Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.1.21 (thymidine kinase)
7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The use of intrathecal, retroviral-mediated transfer of the herpes simplex thymidine kinase (HStk) gene and subsequent ganciclovir (GCV) administration has recently been shown to improve survival in a rat model of leptomeningeal carcinomatosis. Clinical application of this approach is attractive because access to the cerebrospinal fluid (CSF) space is relatively noninvasive and distribution of producer cells and vectors may be facilitated by circulation of CSF, overcoming distribution problems inherent in solid tumors. However, meningeal inflammation, transduction and injury to normal CNS tissue, proliferation of the xenogeneic producer cells in the subarachnoid space, immune-mediated injury, and development of hydrocephalus are possible complications of intraventricular or intrathecal administration of vector-producer cells. In addition, the dynamics of producer cell and vector distribution in the CSF are unknown. To address these issues, we evaluated the safety of this approach for gene delivery and assessed the dynamics of distribution of producer cells and retroviral vectors in rats and non-human primates. In rats, transduction of normal central nervous system (CNS) structures surrounding the subarachnoid space was evaluated after intrathecal and intraventricular injections of beta-galactosidase and HStk vector-producer cells, with and without GCV. In primates, beta-galactosidase and HStk vector-producer cells were injected intraventricularly and GCV was administered either intrathecally or intravenously. Toxicity was evaluated by neurologic examination, serial gadolinium-enhanced MRI scans of the brain, and blood and CSF profiles. A subgroup of monkeys received repeated intraventricular injection of vector-producer cells and intravenous GCV. The titer of retroviral-vector was measured in cisternal and lumbar CSF samples after repeated producer cell injection.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Toxicity studies and distribution dynamics of retroviral vectors following intrathecal administration of retroviral vector-producer cells. 762 Dec 61

Total regression of malignant brain tumors was observed in Wistar rats after retrovirus-mediated gene therapy. Tumors were induced by inoculation of C6 rat glioblastoma cells to a specific location in the rat brain and the tumors that developed were visualized by magnetic resonance imaging (MR). Retroviral vectors were constructed from a defective murine retrovirus to which the thymidine kinase (tk 1) gene from herpes simplex was added (HSV1tk). The vectors produced therapeutic viruses upon their introduction into retrovirus packaging cells. Delivery of the producer cells to the tumor mass and subsequent antiherpetic treatment eradicated the tumors completely, as observed using MRI. Some of the treated animals have been followed for over 8 months and show no signs of recurrence.
...
PMID:Long-term rat survival after malignant brain tumor regression by retroviral gene therapy. 771 34

Primary CNS malignancies are responsible for approximately 12,000 deaths annually in the United States. There has been little change in the outcome for adults with malignant brain tumors over the past few decades, despite improvements in surgical techniques and advances in radiation therapy. These tumors are uniformly fatal one to two years after diagnosis. The morbidity and mortality of this disease arise from the effects of a locally invasive, non-metastasizing lesion. The patients may suffer from seizures, paralysis, incoordination, aphasia, confusion, memory loss, sensory deficits or visual loss, depending on the regions of the brain affected. In addition, they usually require large doses of corticosteroids early and late in their illness, and may experience disabling side effects of this treatment, such as edema, proximal myopathy, diabetes, fungal infections or deep vein thrombosis. Few patients in the older age group are able to work after the diagnosis. Most of the patients are incapable of self-care for several months before death. The localized transfer of new genes into cancer cells potentially permits the expression of proteins with specific biologic functions that may provide a means to alter the biology of tumor growth through a variety of mechanisms including increasing tumor immunogenicity, inducing the local expression of toxic agents, and sensitization of tumors to chemotherapeutic agents. Gene therapy with the transfer of the drug susceptibility gene Herpes virus thymidine kinase (HSV-TK) has shown promise in a number of animal models, including CNS tumors. This study will evaluate the use of adenovirus-mediated transfer of the HSV-TK gene into primary human brain tumors followed by systemic treatment with ganciclovir. The goals of this phase I study are to evaluate the overall safety and efficacy of this treatment and to gain insight into the parameters that may limit the general applicability of this approach. In this phase I study, patients with recurrent gliomas will receive stereotactic-guided injections of the virus into the brain tumor, followed by intravenous ganciclovir for 14 days. Patients eligible to undergo a palliative debulking procedure will receive the same treatment followed by resection on day 7. At the time of resection a second dose of virus will be administered intra-operatively into the residual, unresectable portion of the tumor, and intravenous ganciclovir will be continued for additional 14 days. Tissue removed at the time of resection will be analyzed for evidence of adenovirus infection, thymidine kinase expression and signs of inflammation. The size and metabolic activity of all tumors will be followed by volumetric MRI scans and Position Emission Tomography Scans, respectively. Patients will be enrolled in groups of three, with each group receiving successively larger doses of adenovirus. This study will quantify the toxicity of this therapy, and provide evidence as to the duration of transgene expression and virus induced inflammation.
...
PMID:Treatment of advanced CNS malignancies with the recombinant adenovirus H5.010RSVTK: a phase I trial. 884 6

Despite extensive surgery for glioblastoma, residual tumor cells always lead to relapse. Gene therapy based on retrovirus-mediated gene transfer of herpes simplex virus type 1 thymidine kinase (HSV-1 TK), which specifically sensitizes dividing cells to ganciclovir (GCV) toxicity, may help eradicate such cells. During glioblastoma surgery, HSV-1 TK retroviral vector-producing cells (M11) were injected into the surgical cavity margins after tumor debulking. After a 7-day transduction period, GCV was administered for 14 days. Safety was assessed by clinical and laboratory evaluations, and efficacy was assessed by MRI-based relapse-free survival at month 4 and by overall survival. Twelve patients with recurrent glioblastoma were treated without serious adverse events related to M11 cell administration or GCV. Quality of life was not negatively influenced by this treatment. Overall median survival was 206 days, with 25% of the patients surviving longer than 12 months. At 4 months after treatment, 4 of 12 patients had no recurrence; their median overall survival was 528 days, compared with 194 days for patients with recurrence (p=0.03 by the log rank test). One patient is still free of detectable recurrence, steroid free and independent, 2.8 years after treatment. Thus, brain injections of M11 retroviral vector-producing cells for glioblastoma HSV-1 TK gene therapy were well tolerated and associated with significant therapeutic responses. These results warrant further development of this therapeutic strategy in brain tumor, including recurrent glioblastoma.
...
PMID:A phase I/II study of herpes simplex virus type 1 thymidine kinase "suicide" gene therapy for recurrent glioblastoma. Study Group on Gene Therapy for Glioblastoma. 985 26

Herpes simplex virus-thymidine kinase/ganciclovir (HSV-TK/GCV) gene therapy was performed in five cases of recurrent glioblastoma multiforme. The mean age of cases, three males and two females, was 60 +/- 5 years old. All of the tumors were confirmed pathologically as glioblastoma multiforme and recurred after the initial treatments (surgery and irradiation). A total number of 1 x 10(9) vector producer cells (VPCs), which produce retroviral vectors containing the HSV-TK gene, was inoculated into the tumor-bed spaces after removal of the recurrent tumors. From the following 14th day to the 27th day, GCV was transfused 5 mg/kg i.v. twice a day. The effect of the HSV-TK/GCV gene therapy was evaluated by the Karnofsky performance scale and MRI findings sequentially, before the therapy and in the 1st, 2nd, 4th and 6th month after the VPCs inoculation. During the follow-up period of 12 months, two cases died (survival period; 8.4 and 9.9 months), whereas the other three are still alive for over 12 months (1-year survival; 60%). Karnofsky performance scale showed the maximum at the 2nd and 4th month in all cases; the mean performance rating of living cases was 80% and that of dead cases was 70%. MRI revealed progression in none of the cases until the 2nd month. These results obtained in five cases suggest that the HSV-TK/GCV gene therapy may promise a feasible approach against glioblastoma multiforme.
...
PMID:[The HSV-TK/GCV gene therapy in five cases of recurrent glioblastoma multiforme]. 1107 Sep 6

Herpes simplex virus thymidine kinase (HSV tk) gene therapy combined with ganciclovir (GCV) medication is a potential new method for the treatment of malignant glioma. We have used both retrovirus-packaging cells (PA317/tk) and adenoviruses (Adv/tk) for gene therapy for malignant glioma. Retrovirus-packaging cells were used for eight tumors in seven patients and adenoviruses were used for seven tumors in seven patients. As a control group, seven tumors in seven patients were transduced with lacZ marker gene 4-5 days before tumor resection. Safety and efficacy of the gene therapy were studied with clinical evaluation, blood and urine samples, MRI follow-up, and survival of the patients. Four patients with adenovirus injections had a significant increase in anti-adenovirus antibodies and two of them had a short-term fever reaction. Frequency of epileptic seizures increased in two patients. No other adverse events possibly related to gene therapy were detected. In the retrovirus group, all treated gliomas showed progression by MRI at the 3-month time point, whereas three of the seven patients treated with Adv/tk remained stable (p < 0.05). Mean survival times for retrovirus, adenovirus, and control groups were 7.4, 15.0, and 8. 3 months, respectively. The difference in the survival times between the adenovirus and retrovirus groups was significant (p < 0.012). It is concluded that HSV tk gene therapy is safe and well tolerated. On the basis of these results further trials are justified, especially with adenovirus vectors.
...
PMID:Thymidine kinase gene therapy for human malignant glioma, using replication-deficient retroviruses or adenoviruses. 1108 77

Somatic gene therapy with the herpes simplex virus type I thymidine kinase gene/ganciclovir (HSV-Tk/GCV) system and murine retroviral vector producer cells (VPCs) was introduced as a new adjuvant treatment modality to treat tumor bulk and to prevent tumor recurrence in patients harboring malignant glioma. The single-center experience after treatment of 27 patients undergoing tumor resection followed by intracerebral VPC injection for HSV-Tk suicide gene therapy will be presented focused on findings of systematic and close MRI follow-up and a few histological specimens. The data indicate that hemorrhagic necrosis due to endothelial cell transfection mediated vessel necrosis and that local inflammatory immune response occurs frequently after gene therapy. These phenomena seem to be specific because none of the patients of a control group showed any similar features. The prognosis (time to progression, survival) of the patients with "bystander effects" after gene therapy was better, but compared to those patients without bystander effects, they were also privileged by a favorable constellation of prognostic factors. Therefore, the appearance of these neuroradiologic features cannot serve as an indicator for treatment effectiveness and outcome.
...
PMID:Local inflammation and devascularization--in vivo mechanisms of the "bystander effect" in VPC-mediated HSV-Tk/GCV gene therapy for human malignant glioma. 1177 74

Adenovirus (Adv)-mediated herpes simplex virus thymidine kinase (adv/tk) gene therapy combined with ganciclovir (GCV) medication is a promising approach for the treatment of malignant glioma. However, optimal administration and the effect of possible adjuvant treatments have not been fully examined. In the present study, we examined the efficacy of adv/tk/GCV gene therapy in a syngeneic BT4C rat malignant glioma model, either as a single administration or given as three injections during three consecutive days. The effect of combined adv-mediated macrophage colony-stimulating factor (MCSF) and adv/tk gene transfer was also studied. BT4C malignant glioma cells were injected into the right corpus callosum of BDIX rats (n=112). Before gene therapy, the presence of tumors was verified by MRI. The rats were divided into eight groups as follows: group I (n=20) received a single adv/tk gene transfer (total dose 4x10(8) pfu) and GCV treatment for 14 days; group II (n=5) received the same gene transfer without GCV; group III (n=28) received three adv/tk injections (total dose 4x10(8) pfu) on three consecutive days and GCV for 14 days; group IV (n=5) received three similar adv/tk injections without GCV medication; group V (n=13) received three adv/MCSF injections (total dose 2x10(8) pfu) on three consecutive days and GCV medication; group VI (n=12) received three adv/tk and adv/MCSF (total dose 6x10(8) pfu) injections on three consecutive days followed by GCV medication; and group VII (n=12) the same treatment without GCV. Group VIII (n=17) consisted of wild-type BT4C malignant glioma tumors without any treatment. Treatment effect and tissue responses were characterized by general histology, immunohistochemistry, MRI, and survival of the study groups. The best treatment effect and survival was found in rats treated with adv/tk gene transfer once a day for three consecutive days (P<.05). No improvement of the treatment effect was seen after the combined adv/tk and adv/MCSF gene transfer compared with the repeated adv/tk gene transfer. The results show that 20% of the rats can be cured (survival >6 months) after optimized adv/tk gene therapy. It is concluded that repeated intratumoral administration of adv/tk is a promising approach for the treatment of malignant glioma tumors in vivo.
...
PMID:Adenovirus-mediated herpes simplex virus thymidine kinase gene therapy in BT4C rat glioma model. 1238 30

Between November 1998 and December 2001, we treated 14 patients with advanced recurrent high-grade gliomas with a total dose of 4.6 x 10(8), 4.6 x 10(9), 4.6 x 10(10), or 4.6 x 10(11) viral particles (VP) of a replication-incompetent adenoviral vector harboring the herpes simplex virus thymidine kinase gene driven by the adenoviral major late promoter (IG.Ad.MLPI.TK), followed by ganciclovir (GCV) treatment. The VP-to-infectious-unit ratio was 40. The vector was administered by 50 intraoperative wound-bed injections of 0.2 ml each (total volume 10 ml). The study's primary objective was to determine the safety of this treatment and establish the maximum tolerated dose (MTD). Injection of all doses of IG.Ad.MLPI.TK followed by GCV was safely tolerated and MTD was not reached. All patients had recurrence or progression of the tumor 1-24 months (median 3.5 months) after gene therapy. The overall median survival was 4 months. Four patients survived longer than 1 year following gene therapy. One patient is still alive, with histologically confirmed progression of the tumor, 29 months after treatment. Ten patients died within 8 months of treatment, all from progression of the tumor. In 5 patients residual and measurable tumor was visible on the direct (<48 h) postoperative MRI. No objective radiological response was documented on subsequent MRI. None of the patients came to autopsy. In conclusion, the administration of 4.6 x 10(11) VP of IG.Ad.MLPI.TK by 50 injections into the wound bed following resection of recurrent malignant glioma, followed by GCV treatment, was well tolerated.
...
PMID:Treatment of relapsed malignant glioma with an adenoviral vector containing the herpes simplex thymidine kinase gene followed by ganciclovir. 1278 59

Spatial and temporal control of transgene expression is one of the major prerequisites of efficient gene therapy. Recently, a noninvasive, physical approach has been presented based on local heat in combination with a heat-sensitive promoter. This strategy requires tight temperature control in vivo. Here, we use MRI-guided focused ultrasound (MRI-FUS) with real-time feedback control on a whole-body clinical MRI system for a completely automatic execution of a predefined temperature-time trajectory in the focal point. Feasibility studies on expression control were carried out on subcutaneously implanted rat tumors. A stable modified C6 glioma cell line was used carrying a fused gene coding for thymidine kinase (TK) and green fluorescent protein (GFP) under control of the human heat-shock protein 70 (HSP70) promoter. In vitro studies showed strong induction of the TK-GFP gene expression upon heat shock under various conditions and localization of the protein product in the nucleus. In vivo tumors were subjected to a 3-min temperature elevation using MRI-FUS with a constant temperature, and were analysed 24 hr after the heat shock with respect to GFP fluorescence. Preliminary results showed strong local induction in regions heated above 40 degrees C, and a good correspondence between temperature maps at the end of the heating period and elevated expression of TK-GFP.
...
PMID:Image-guided control of transgene expression based on local hyperthermia. 1292 33


1 2 3 Next >>

---