Clinical review 132: The sodium iodide symporter and its potential role in cancer therapy.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
J C Morris
Publications and source records attributed to J C Morris.
Pathologic correlates of nondemented aging, mild cognitive impairment, and early-stage Alzheimer's disease.
The results of studies from the Washington University Alzheimer Disease (AD) Research Center and those from other centers and investigators regarding the neuropathologic correlates of normal aging and early-stage AD are reviewed. We conclude that widespread amyloid plaques in the neocortex best distinguishes very early stage AD, including "MCI" stage, and preclinical stages, from healthy brain aging. Other AD lesions, including increased formation of neurofibrillary tangles and neuronal degeneration appear to result from the amyloid-initiated pathologic process, although they may have a more immediate effect on expression and severity of dementia. These data provide strong support for anti-amyloid intervention as a preventive therapy for AD. It is now critical to develop methods to detect preclinical AD during life.
Aged↗
Cholinesterase inhibitors for Alzheimer's disease.
Alzheimer's disease (AD) is the most common age-related neurodegenerative disease and has become an urgent public health problem in most areas of the world. Substantial progress has been made in understanding the basic neurobiology of AD and, as a result, new drugs for its treatment have become available. Cholinesterase inhibitors (ChEIs), which increase the availability of acetylcholine in central synapses, have become the main approach to symptomatic treatment. ChEIs that have been approved or submitted to the US Food and Drug Administration (FDA) include tacrine, donepezil, metrifonate, rivastigmine and galantamine. In this review we discuss their pharmacology, clinical experience to date with their use and their potential benefits or disadvantages. ChEIs have a significant, although modest, effect on the cognitive status of patients with AD. In addition to their effect on cognition, ChEIs have a positive effect on mood and behaviour. Uncertainty remains about the duration of the benefit because few studies of these compounds beyond one year have been published. Although ChEIs are generally well tolerated, all patients should be followed closely for possible adverse effects. There is no substantial difference in the effectivenes of the various ChEIs, however, they may have different safety profiles. We believe the benefits of their use outweigh the risks and costs and, therefore, ChEls should be considered as primary therapy for patients with mild to moderate AD.
Alzheimer Disease↗
Inhibition of Trypanosoma brucei gene expression by RNA interference using an integratable vector with opposing T7 promoters.
RNA interference is a powerful method for inhibition of gene expression in Trypanosoma brucei (Ngo, H., Tschudi, C., Gull, K., and Ullu, E. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 14687-14692). Here we describe a vector (pZJM) for in vivo tetracycline-inducible synthesis of double-stranded RNA (dsRNA) in stably transformed cells. The dsRNA is synthesized from opposing T7 promoters. We tested the vector with genes involved in processes such as kinetoplast DNA replication, mitochondrial mRNA synthesis, glycosyl phosphatidylinositol biosynthesis, glycosome biogenesis, and polyamine biosynthesis. In most cases the induction of dsRNA caused specific and dramatic loss of the appropriate mRNA, and in many cases there was growth inhibition or cell death. One striking phenotype was the loss of kinetoplast DNA after interference with expression of a topoisomerase II. The gene being analyzed by this procedure need not even be fully sequenced. In fact, many of the genes we tested were derived from partial sequences in the T. brucei genome data base that were identified by homology with known proteins. It takes as little as 3 weeks from identification of a gene sequence in the data base to the appearance of a phenotype.
Animals↗
Early DAT is distinguished from aging by high-dimensional mapping of the hippocampus. Dementia of the Alzheimer type.
OBJECTIVE: To determine the feasibility of using high-dimensional brain mapping (HDBM) to assess the structure of the hippocampus in older human subjects, and to compare measurements of hippocampal volume and shape in subjects with early dementia of the Alzheimer type (DAT) and in healthy elderly and younger control subjects. BACKGROUND: HDBM represents the typical structures of the brain via the construction of templates and addresses their variability by probabilistic transformations applied to the templates. Local application of the transformations throughout the brain (i.e., high dimensionality) makes HDBM especially valuable for defining subtle deformities in brain structures such as the hippocampus. METHODS: MR scans were obtained in 18 subjects with very mild DAT, 18 healthy elderly subjects, and 15 healthy younger subjects. HDBM was used to obtain estimates of left and right hippocampal volume and eigenvectors that represented the principal dimensions of hippocampal shape differences among the subject groups. RESULTS: Hippocampal volume loss and shape deformities observed in subjects with DAT distinguished them from both elderly and younger control subjects. The pattern of hippocampal deformities in subjects with DAT was largely symmetric and suggested damage to the CA1 hippocampal subfield. Hippocampal shape changes were also observed in healthy elderly subjects, which distinguished them from healthy younger subjects. These shape changes occurred in a pattern distinct from the pattern seen in DAT and were not associated with substantial volume loss. CONCLUSIONS: Assessments of hippocampal volume and shape derived from HDBM may be useful in distinguishing early DAT from healthy aging.
Aged↗
Effect of APOE genotype and promoter polymorphism on risk of Alzheimer's disease.
OBJECTIVE: To verify the association between APOE gene promoter polymorphisms and the development of AD and to determine whether the effect of promoter polymorphisms on AD is independent of the APOE epsilon4 allele. BACKGROUND: Three polymorphisms in the APOE promoter have been shown to modify APOE expression in vitro. Several studies have suggested that these polymorphisms may also modulate risk for AD, either independently or by modifying the effect of the APOE coding polymorphism. METHODS: The authors analyzed allele and genotype distributions for APOE and all three known APOE promoter polymorphisms (-491 A/T, -427 T/C, and -219 G/T) in a study group consisting of 237 subjects with AD and 274 age-matched controls. They then used log-linear and logistic regression analyses to test for possible interactions between APOE genotype and the promoter polymorphisms on risk of AD. CONCLUSION: A strong association between the APOE epsilon 4 allele and AD was detected regardless of promoter polymorphism status. In addition, the -491 AA genotype appears to be an independent genetic risk factor for AD. The -427 T/C polymorphism and the -219 T/G polymorphism were not directly associated with AD.
Aged↗
The value of informant versus individual's complaints of memory impairment in early dementia.
Self-reported versus informant-reported memory problems in nondemented elderly adults and in individuals with very mild and mild dementia of the Alzheimer type (DAT) were correlated with cognitive outcomes. No significant correlations were found between self-reported memory complaints and cognitive performance or (in controls) later development of dementia. In contrast, informant-reported memory loss distinguished nondemented from demented individuals and predicted future diagnosis of DAT.
Aged↗
Treatment of prostate cancer by radioiodine therapy after tissue-specific expression of the sodium iodide symporter.
Causing prostate cancer cells to express functionally active sodium iodide symporter (NIS) by targeted NIS gene transfer might offer the possibility of radioiodine therapy of prostate cancer. Therefore, we investigated radioiodine accumulation and therapeutic effectiveness of 131I in NIS-transfected prostate cancer cells in vitro and in vivo. The human prostatic adenocarcinoma cell line LNCaP was stably transfected with NIS cDNA under the control of the prostate-specific antigen promoter. The stably transfected LNCaP cell line NP-1 showed perchlorate-sensitive, androgen-dependent iodide uptake in vitro that resulted in selective killing of these cells by 131I in an in vitro clonogenic assay. Xenografts were established in athymic nude mice and imaged using a gamma camera after i.p. injection of 500 microCi of 123I. In contrast to the NIS-negative control tumors (P-1) which showed no in vivo uptake of 123I, NP-1 tumors accumulated 25-30% of the total 123I administered with a biological half-life of 45 h. In addition, NIS protein expression in LNCaP cell xenografts was confirmed by Western blot analysis and immunohistochemistry. After a single i.p. application of a therapeutic 131I dose (3 mCi), significant tumor reduction was achieved in NP-1 tumors in the therapy group compared with P-1 tumors and tumors in the control group. In conclusion, a therapeutic effect of 131I has been demonstrated in prostate cancer cells after induction of tissue-specific iodide uptake activity by prostate-specific antigen promoter-directed NIS expression in vitro and in vivo. This study demonstrates the potential of NIS as a novel therapeutic gene for nonthyroidal cancers, in particular prostate cancer.
Adenocarcinoma↗
Misleading results with the 14-3-3 assay for the diagnosis of Creutzfeldt-Jakob disease.
The definitive diagnosis of Creutzfeldt-Jakob disease (CJD) requires brain tissue analysis. A positive assay for the 14-3-3 protein in CSF has been suggested to be highly sensitive and specific in patients with CJD. The authors describe three patients for whom CSF 14-3-3 assays were falsely positive or falsely negative. Caution against overreliance on this putative biomarker is suggested in the diagnosis of CJD.
14-3-3 Proteins↗
The role of the E1B 55 kDa gene product in oncolytic adenoviral vectors expressing herpes simplex virus-tk: assessment of antitumor efficacy and toxicity.
In this study, we evaluated three herpes simplex virus-1 thymidine kinase (HSV-tk) carrying replication-competent adenoviral vectors with and without the Ad5 E1B 55 kDa gene to assess whether this gene product has an influence on their antitumor efficacy, replication kinetics, and potential hepatotoxicity. Furthermore, we assessed the efficacy of these vectors in combination with ganciclovir (GCV). When compared with wild-type adenovirus, the recombinant vectors, in particular the E1B 55 kDa-deleted vector Ad.TK(RC)(II), generated a more efficiently cytopathic effect in proliferating cells, independently of their p53 phenotype. In a s.c. A549 lung cancer xenograft model, the cytoreductive effect of Ad.TK(RC)(II) was enhanced when followed by GCV treatment. In contrast, the efficacy of both E1B 55 kDa-positive vectors could not be further improved by GCV. In an i.p. MDAH 2774 ovarian cancer xenograft tumor model, the survival of animals treated with a prototypical replication-deficient adenovirus expressing HSV-tk (Ad.TK) was improved compared to controls when followed by GCV. In contrast, the cytoreductive efficacy of the replication-competent vectors was diminished when combined with the virostatic GCV. However, the antitumor effect of all replication-competent vectors was superior to combination chemotherapy with paclitaxel and carboplatin. In both tumor models, the oncolytic effect of the E1B 55 kDa-positive vectors was greater than that of Ad.TK(RC)(II). In an attempt to assess the toxicity of these vectors in a nonpermissive host, the viruses were administered systemically to immunocompetent and immunodeficient mice. Greater hepatotoxicity was seen with i.v. administration of the replication-competent viruses than with Ad.TK and in immunocompetent hosts, suggesting involvement of the immune system in the induction of tissue damage. The E1B 55 kDa gene had no significant influence on the liver toxicity of the vectors in this system. At therapeutic doses, intratumoral or i.p. injection of all vectors was well tolerated. Importantly, these replication-competent HSV-tk-expressing vectors were highly susceptible to GCV, representing an effective fail-safe mechanism to abolish viral replication in a clinical setting. Controllable intratumoral viral replication holds promise as a new treatment modality for cancer.
Adenovirus E1B Proteins↗
A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group.
OBJECTIVE: To investigate the efficacy and tolerability of galantamine, using a slow dose escalation schedule of up to 8 weeks, in 978 patients with mild to moderate AD. METHODS: A 5-month multicenter, placebo-controlled, double-blind trial. Following a 4-week placebo run-in, patients were randomized to one of four treatment arms: placebo or galantamine escalated to final maintenance doses of 8, 16, or 24 mg/day. Outcome measures included the cognitive subscale of the AD Assessment Scale (ADAS-cog), the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus), the AD Cooperative Study Activities of Daily Living inventory, and the Neuropsychiatric Inventory. Standard safety evaluations and adverse event monitoring were carried out. RESULTS: After 5 months, the galantamine-placebo differences on ADAS-cog were 3.3 points for the 16 mg/day group and 3.6 points for the 24 mg/day group (p < 0.001 versus placebo, both doses). Compared with placebo, the galantamine 16- and 24-mg/day groups also had a significantly better outcome on CIBIC-plus, activities of daily living, and behavioral symptoms. Treatment discontinuations due to adverse events were low in all galantamine groups (6 to 10%) and comparable with the discontinuation rate in the placebo group (7%). The incidence of adverse events in the galantamine groups, notably gastrointestinal symptoms, was low and most adverse events were mild. CONCLUSIONS: Galantamine 16 and 24 mg/day significantly benefits the cognitive, functional, and behavioral symptoms of AD as compared with placebo. Slow dose escalation appears to enhance the tolerability of galantamine, minimizing the incidence and severity of adverse events.
Activities of Daily Living↗
Tau polymorphisms are not associated with Alzheimer's disease.
Alzheimer's disease (AD) is one of a number of neurodegenerative conditions including frontotemporal dementia and progressive supranuclear palsy that are associated with abnormal tau protein aggregates in neurons. Mutations in the tau gene cause familial forms of frontotemporal dementia and alleles of the tau gene have been associated with risk for progressive supranuclear palsy. However, studies evaluating whether polymorphic variation in tau is associated with AD have produced conflicting results. We investigated the role of the tau exon 2 polymorphism in a large sample of AD cases and controls and found no evidence that polymorphic variation in tau is associated AD.
Aged↗
A phase I study of intralesional administration of an adenovirus vector expressing the HSV-1 thymidine kinase gene (AdV.RSV-TK) in combination with escalating doses of ganciclovir in patients with cutaneous metastatic malignant melanoma.
Explore the source record for details and available documents.
Adenoviridae↗
Increased neocortical neurofibrillary tangle density in subjects with Alzheimer disease and psychosis.
BACKGROUND: Psychosis is common in patients with Alzheimer disease. While the relationship between psychosis and clinical variables has been examined frequently, few studies have examined the relationship between psychosis and the 2 major neuropathological hallmarks of Alzheimer disease: neurofibrillary tangles and senile plaques. We characterized the occurrence of psychosis in relation to dementia severity and determined if subjects with Alzheimer disease and psychosis had a greater neurofibrillary tangle or senile plaque burden than subjects with Alzheimer disease and no psychosis. METHODS: One hundred nine subjects with Alzheimer disease were followed longitudinally with semistructured assessments in order to assign a Clinical Dementia Rating and determine whether psychosis was present. After the subjects died, their brains were obtained for histological examination. Analysis of variance was used to compare the densities of neurofibrillary tangles, total senile plaques, and cored senile plaques in subjects with psychosis vs subjects without psychosis, in several neocortical regions, the hippocampus, and the entorhinal cortex. RESULTS: Psychosis occurred commonly in Alzheimer disease, affecting 63% of subjects. The frequency of psychosis increased with increasing dementia severity. More importantly, we found that subjects with psychosis had a 2.3-fold (95% confidence interval, 1.2-3.9) greater density of neocortical neurofibrillary tangles than did subjects without psychosis. The increase was independent of dementia severity. No similar relationship with psychosis was seen for total senile plaques or cored senile plaques. CONCLUSIONS: The increase in psychosis frequency that occurs with the progression of dementia severity and the independent association between psychosis and neurofibrillary tangle density suggest the possibility that some common underlying process or processes specific to Alzheimer disease may regulate both phenomena. Arch Gen Psychiatry. 2000;57:1165-1173.
Aged↗
Therapy of head and neck squamous cell carcinoma with an oncolytic adenovirus expressing HSV-tk.
Currently available therapeutic modalities for advanced head and neck squamous cell carcinoma (HNSCC), such as radical surgery, high-dose radiotherapy, and chemotherapy, are of limited efficacy. Overall survival has not significantly improved over the past 30 years; thus, HNSCC represents a promising target for new therapeutic approaches, such as gene therapy. A major obstacle to the development of effective suicide gene therapy strategies that rely on in situ transduction of tumor cells is the poor distribution of the vector throughout the tumor. To address this problem we evaluated the use of Ad.OW34, an Elb 55 kD and HSV-tk-carrying, replication-competent adenoviral vector that has a wild-type adenovirus phenotype in replicating cells, in combination with ganciclovir (GCV) as a treatment for HNSCC xenografts in nude mice and compared its efficacy with that of a standard replication-deficient adenovirus expressing HSV-tk (Ad.TK). In this model, Ad.OW34 had a significantly greater antitumor effect than the traditional Ad.TK vector, administered alone or in combination with GCV. Interestingly, GCV did not further enhance the oncolytic efficacy of Ad.OW34. GCV also aborts viral replication and thus represents a fail-safe feature of this vector not found in wild-type adenovirus.
Adenoviridae↗
The nosology of dementia.
The nosology of dementia has evolved from the simple distinctions between senility, degenerative dementia, and vascular insults that existed a few decades ago. The differentiation of normal cognitive aging from very mild dementia has sharpened considerably; however, appreciation of the heterogeneity of Alzheimer's disease (AD) and its clinical and pathologic overlap with other dementing disorders has blurred previous classification systems. Rather than viewing AD and vascular dementia, for example, as dichotomous entities, it may be more relevant to consider their additive or synergistic interactions producing dementia. Further elucidation of the nature and contribution of genetic factors in AD and related disorders will accelerate the use of genotype-phenotype correlations in dementia classification.
Aged↗
The immune response to the iodide transporter.
In addition to physiologic, diagnostic, and therapeutic implications, the recently cloned and characterized sodium iodide symporter (NIS) also may play an important role in the pathogenesis of autoimmune thyroid disease. Sodium iodide symporter expression patterns characteristically are changed in autoimmune thyroid disease, including Graves' disease and Hashimoto's thyroiditis, which may be caused, in part, by the regulation of sodium iodide symporter expression of cytokines involved in the pathogenesis of autoimmune thyroid disease. Further, there is increasing evidence that NIS-directed antibodies are present in sera from patients with autoimmune thyroid disease, and these antibodies also may affect NIS functional activity.
Animals↗