Biomedical subjects

B L Davidson

Publications and source records attributed to B L Davidson.

At least 127 records · Page 7Linked to original sources

PubMed1995

Evaluation of rhesus rotavirus monovalent and tetravalent reassortant vaccines in US children. US Rotavirus Vaccine Efficacy Group.

OBJECTIVE: To determine the safety and relative efficacy of two reassortant rhesus rotavirus vaccines over two rotavirus seasons. DESIGN: A prospective, double-masked, placebo-controlled trial. SETTING: Twenty-three centers in the United States. PARTICIPANTS: A total of 1006 healthy infants between 4 and 26 weeks of age were enrolled, and 898 received three doses of vaccine or placebo. MAIN OUTCOME MEASURES: Reactogenicity was determined by comparing the incidence of fever, diarrhea, and/or vomiting for 5 days after each dose of vaccine. Rotavirus IgA and neutralizing antibody to rhesus rotavirus and four rotavirus serotypes were measured in a subset of subjects. Relative efficacy was determined by comparing the incidence of rotavirus gastroenteritis after three doses of vaccine or placebo over two rotavirus seasons. RESULTS: Adverse reactions were mild and limited to a small but significant increase in the incidence of fever after the first dose of tetravalent but not monovalent vaccine. The relative efficacy against rotavirus disease over the 2 years of observation was 40% (98.3% confidence interval, 7% to 62%) for the monovalent and 57% (98.3% confidence interval, 29% to 74%) for the tetravalent vaccine. In post hoc analyses, the relative efficacy against very severe rotavirus gastroenteritis was 73% and 82% for monovalent and tetravalent vaccine recipients, respectively. Also, a 67% and 78% reduction in medical visits for rotavirus gastroenteritis was observed. Both vaccines protected against disease caused by serotype 1 rotavirus, but only the tetravalent vaccine reduced the incidence of disease caused by non-serotype 1 rotavirus infection detected in the second season. It is unclear, however, whether this result represents serotype-specific protection or a difference in the duration of protection. CONCLUSIONS: Vaccination with both vaccines was safe and significantly reduced the incidence of rotavirus gastroenteritis, but only the tetravalent vaccine provided protection against disease caused by non-serotype 1 rotaviruses during the second year of follow-up.

Antibodies, Viral↗

PubMed1995

Treatment of deep venous thrombosis with low-molecular-weight heparins. A meta-analysis.

BACKGROUND: An intravenous course of unfractionated heparin adjusted on the basis of the activated partial thromboplastin time is the initial treatment of choice for most patients with venous thromboembolism. Recently introduced low-molecular-weight heparin preparations can be administered subcutaneously, once or twice daily, without laboratory monitoring. We quantitatively assessed the relative efficacy and safety of low-molecular-weight heparin vs standard heparin for the initial treatment of deep venous thrombosis. METHODS: English-language reports of randomized trials were identified through a MEDLINE search (1984 through 1994) and a complementary extensive manual search. Reasons for exclusion from the analysis were no heparin dosage adjustments, the lack of use of objective tests for deep venous thrombosis, duplicate reports, preliminary reports of data later presented in full, dose-ranging studies that used higher doses of low-molecular-weight heparin than are currently in use, and the failure to provide blind end-point assessment. We assessed the incidence of symptomatic recurrent venous thromboembolic disease, the incidence of clinically important bleeding, and mortality. RESULTS: Ten of the 19 identified trials satisfied the predetermined criteria. The relative risk reductions for symptomatic thromboembolic complications (53% [95% confidence interval, 18% to 73%]), clinically important bleeding (68% [95% confidence interval, 31% to 85%]), and mortality (47% [95% confidence interval, 10% to 69%]) were all statistically significantly in favor of low-molecular-weight heparin. CONCLUSIONS: Low-molecular-weight heparins administered subcutaneously in fixed doses adjusted for body weight and without laboratory monitoring are more effective and safer than adjusted-dose standard heparin. Since low-molecular-weight heparins may not be interchangeable and the conclusions of our meta-analysis are based mainly on the findings of three trials that used two different low-molecular-weight heparins, definitive randomized controlled trials for the other low-molecular-weight heparins are required.

Hemorrhage↗

PubMed1995

Accuracy of ultrasound for the diagnosis of deep venous thrombosis in asymptomatic patients after orthopedic surgery. A meta-analysis.

OBJECTIVE: To evaluate, by meta-analysis, the accuracy of ultrasound screening for deep venous thrombosis in patients after orthopedic surgery. DATA SOURCES: The MEDLINE database from January 1982 to October 1993. Bibliographies of retrieved articles and recent journal publications were searched independently and using Current Contents. STUDY SELECTION: All articles evaluating the use of venous ultrasound imaging (B-mode, duplex, and color Doppler) compared with standard contrast venography for detecting deep venous thrombosis. We excluded abstracts, early reports of studies later reported in full, and studies in which venography was not done in all patients. Seventeen of 30 identified studies were eligible. DATA EXTRACTION: Eligible articles were reviewed for the presence of three key criteria necessary for evaluating the accuracy of the diagnostic tests: 1) previously established objective criteria for venography and ultrasound, 2) independent blinded comparisons of venography and ultrasound, and 3) prospective evaluations of consecutive patients. Studies including all three key criteria were defined as level 1 (minimized bias) studies; otherwise, they were defined as level 2 studies. DATA SYNTHESIS: In level 1 studies, ultrasonography had a sensitivity of 62% (95 of 153; 95% CI, 54% to 70%), a specificity of 97% (CI, 96% to 98%), and a positive predictive value of 66% (95 of 144; CI, 58% to 74%) for detecting proximal thrombi. For level 2 studies, the sensitivity was 95% (CI, 87% to 99%), the specificity was 100% (CI, 99% to 100%), and the positive predictive value was 100% (CI, 94% to 100%). Differences between level 1 and level 2 studies appeared to be related to bias in study design. CONCLUSIONS: Venous ultrasound imaging has only moderate sensitivity and a moderate positive predictive value when used to screen for deep venous thrombosis in patients after orthopedic surgery; thus, ultrasound imaging may have limitations as a screening test.

Aged↗

PubMed1995

Economic impact of immunization against rotavirus gastroenteritis. Evidence from a clinical trial.

OBJECTIVE: To estimate the economic impact of immunization against rotavirus gastroenteritis in an infant population in the United States. DESIGN: Cost identification and break-even analyses from the perspective of society, nested within a phase 3, randomized, double-blind, placebo-controlled trial. PATIENTS: Infants (N = 1278), aged 6 to 22 weeks, enrolled during the summer and fall of 1991 and followed up until July 1, 1992. INTERVENTION: Immunization schedule of three doses of orally administered tetravalent or serotype 1 rhesus rotavirus vaccine, or placebo. MAIN OUTCOME MEASURES: Incidence of rotavirus gastroenteritis, total direct medical costs, direct nonmedical costs, and indirect costs of rotavirus and nonrotavirus gastroenteritis for the duration of the study and of any illness during 5 days after each dose. The cost of the vaccine was not included. RESULTS: Median total cost per infant among the 1187 infants who completed the immunization schedule was $9 in the tetravalent vaccine group, $9 in the serotype 1 vaccine group, and $49 in the placebo group (P = .01). Rotavirus gastroenteritis occurred in 195 infants (16%): 13% (51/398) in the tetravalent group, 12% (47/404) in the serotype 1 group, and 25% (97/385) in the placebo group (P < .0001). Of infants with an episode of rotavirus gastroenteritis, the proportion who incurred cost during the episode and the median cost during the episode did not differ by treatment group. The baseline net cost savings for treatment of rotavirus gastroenteritis and break-even cost of immunization were $11 per infant for the tetravalent vaccine and $12 for the serotype 1 vaccine. In sensitivity analysis, savings ranged from $40 to -$6, because of a large variance in the costs of rotavirus gastroenteritis. CONCLUSION: The results of the baseline analysis suggest that society should be willing to pay between $11 and $12 for immunization against rotavirus. It might be willing to pay an additional amount for the intangible benefits of reduced parental inconvenience or anxiety associated with this illness in infants.

Cost Savings↗

PubMed1995

Simultaneous administration of oral rhesus-human reassortant tetravalent (RRV-TV) rotavirus vaccine and oral poliovirus vaccine (OPV) in Thai infants.

Rhesus-human reassortant tetravalent (RRV-TV) oral rotavirus vaccine was given at the same time as oral poliovirus vaccine (OPV) or inactivated parenteral poliovirus vaccine (IPV) to Thai infants at 2, 4 and 6 months of age. Sera for rotavirus antibody studies were taken prior to and one month after each vaccination. After the first dose of vaccine at 2 months of age, 37% of the infants receiving rotavirus vaccine with IPV but only 10% of those receiving it with OPV showed a seroconversion by rotavirus IgA ELISA antibody test (p < 0.001). Likewise, neutralizing antibody seroconversion rates in initially seronegative subjects to rhesus rotavirus type 3 (RRV-3) after the first dose of RRV-TV vaccine were higher if the vaccine was given with IPV (74%) than if given with OPV (39%) (p = 0.0069). After the second and third doses of vaccine, the rotavirus IgA ELISA and RRV-3-neutralizing antibody response rates were not different between groups. Development of neutralizing antibodies to human rotavirus serotypes 1, 2 and 4 in the first seven months of life in vaccinees receiving rotavirus vaccine with OPV tended to occur at a lower rate than in those receiving rotavirus vaccine with IPV but the antibody levels were not significantly different at 7 months of age. Poliovirus type 2 and type 3 antibody responses were not different in infants receiving the rotavirus vaccine with OPV as compared with infants receiving only OPV. The mean poliovirus type 1 antibody level was slightly but not significantly lower at 5 and 7 months of age in infants that received both rotavirus vaccine and OPV.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1995

Attenuation of stroke size in rats using an adenoviral vector to induce overexpression of interleukin-1 receptor antagonist in brain.

Adenoviruses have been proposed as potential vectors for gene therapy in the central nervous system, but there are no reports of their use in the treatment of a brain disease. Because central administration of interleukin-1 receptor antagonist protein (IL-1ra) reduces ischemic brain damage, we determined whether a recombinant adenovirus vector carrying the human IL-1ra cDNA (Ad.RSVIL-1ra) could be used to ameliorate brain injury in permanent focal ischemia. Groups of six rats received intraventricular injections of Ad.RSVIL-1ra or a control adenovirus containing the Escherichia coli beta-galactosidase gene (Ad.RSVlacZ). Histochemical staining for beta-galactosidase 5 days after virus injection indicated that transgene expression was confined primarily to the cells lining the ventricle. The concentrations of IL-1ra injected animals, achieving levels of 9.1 +/- 3.3 ng/g in brain and 23.7 +/- 22.5 ng/ml in CSF. In these animals, cerebral infarct volume resulting from 24 h of permanent middle cerebral artery occlusion was reduced 64%. These studies demonstrate that adenoviral vectors can be used to deliver genes that attenuate brain injury.

Adenoviridae↗

PubMed1995

Pulmonary inflammation induced by incomplete or inactivated adenoviral particles.

One of the major obstacles to pulmonary-directed gene therapy using adenoviral vectors is the induction of inflammation. We investigated whether the adenoviral particles that constitute the initial inoculum can serve as an inflammatory stimulus, independent of their ability to express genes that they contain. Viral particles were prepared that are defective in gene expression by (i) isolating particles that have incomplete genomes by selecting those that have buoyant densities on CsCl density gradients lighter than complete viruses; and (ii) cross-linking viral DNA by exposure to ultraviolet light in the presence of 8-methoxypsoralen. The defective particles retained their icosahedral appearance when viewed by electron microscopy but lost their plaque-forming ability on 293 cells. High doses of intact, incomplete, or inactivated viral particles were instilled intratracheally into CBA/J mice, and after 6 days the amount of inflammation was quantified by counting inflammatory cells contained within lung tissue. We found that the inflammatory responses induced by the incomplete or inactivated viral vectors were quantitatively similar to those caused by intact, competent viral vectors. We conclude that high doses of adenoviral vectors that are used for gene therapy can induce pulmonary inflammation, independent of expressing the genes they contain.

Adenoviridae↗

PubMed1995

Inhibition of interleukin-1-induced effects in synoviocytes transduced with the human IL-1 receptor antagonist cDNA using an adenoviral vector.

In this report, we present data showing that a recombinant adenoviral vector (Ad.RSVIL-1ra) containing the cDNA for human interleukin-1 receptor antagonist protein (IL-1ra) can genetically modify synoviocytes both in vitro and in vivo. Human synoviocytes infected with Ad.RSVIL-1ra in vitro expressed and secreted high levels of human IL-1ra that were detected by ELISA of tissue culture supernatants. New Zealand White rabbits that received intra-articular injections of Ad.RSVIL-1ra expressed transgenic IL-1ra in synoviocytes, and secretion was detected for at least 4 weeks post-infection. Further, biological activity of the transgenic IL-1ra was demonstrated by its ability to inhibit IL-1-induced prostaglandin E2 (PGE2) synthesis in vitro and IL-1-induced glycosaminoglycan (GAG) degradation in vivo. These data demonstrate that recombinant adenoviral vectors can mediate the intra-articular expression of anti-inflammatory proteins and may be a reasonable method to deliver therapeutically relevant proteins for the regional treatment of synovial inflammation.

Adenoviridae↗

PubMed1995

Monitoring the anticoagulant effects of a low molecular weight heparin preparation. Correlation of assays in orthopedic surgery patients receiving ardeparin sodium for prophylaxis of deep venous thrombosis.

This prospective, uncontrolled trial explored the relationship between varying dosages of a low molecular weight heparin (LMWH) preparation, ardeparin sodium (Normiflo, Wyeth-Ayerst, Philadelphia, PA), and anticoagulant effects, monitored by an amidolytic anticoagulation factor Xa (aXa) assay and by global coagulometric methods, including the activated partial thromboplastin time (APTT) and the Heptest (Haemachem, St. Louis, MO). Thirty-three patients undergoing elective unilateral total hip or knee replacement received subcutaneous ardeparin prophylaxis initiated 12 to 18 hours following surgery, administered at a fixed 40-mg dose twice daily, 50 aXa U/kg twice daily or 90 aXa U/kg once daily for up to 14 days. The target antithrombotic aXa levels, determined by amidolytic assay in plasma 6 hours after each ardeparin injection, were most optimally attained and maintained by twice-daily dosing based on body weight and correlated well with incremental increases in Heptest values measured chronometrically. The Heptest results at 12 hours after ardeparin administration indicated that the global anticoagulant effects produced by LMWH are sustained for many hours after subcutaneous dosing.

Anticoagulants↗

PubMed1995

Treatment of experimental human mesothelioma using adenovirus transfer of the herpes simplex thymidine kinase gene.

OBJECTIVE: The authors demonstrate the ability of an adenovirus vector expressing the herpes simplex thymidine kinase (HSVtk) gene to treat human malignant mesothelioma growing within the peritoneal cavity of severe combined immunodeficient (SCID) mice. BACKGROUND DATA: Introduction of the HSVtk gene into tumor cells renders them sensitive to the antiviral drug ganciclovir (GCV). This approach has been used previously to treat experimental brain tumors. Although malignant mesothelioma is refractory to current therapies, its localized nature and the accessibility of the pleural space make it a potential target for a similar type of in vivo gene therapy using adenovirus. METHODS: An adenovirus containing the HSVtk gene (Ad.RSVtk) was used to transduce mesothelioma cells in vitro. These cells were then injected into the flanks of SCID mice. Ad.RSVtk was also injected directly into the peritoneal cavity of SCID mice with established human mesothelioma tumors. Mice were subsequently treated for 7 days with GCV at a dose of 5 mg/kg. RESULTS: Mesothelioma cells transduced in vitro with Ad.RSVtk formed nodules when injected in the subcutaneous tissue. These tumors could be eliminated by the administration of GCV, even when as few as 10% of cells were transduced to express HSVtk (bystander effect). Administration of Ad.RSVtk into the peritoneal space of animals with established multifocal human mesothelioma followed by GCV therapy resulted in the eradication of macroscopic tumor in 90% of animals and microscopic tumor in 80% of animals when evaluated after 30 days. The median survival of animals treated with Ad.RSVtk/GCV was significantly longer than that of control animals treated with similar protocols. CONCLUSION: These results indicate that an adenoviral vector containing the HSVtk gene is effective in treating established malignant mesothelioma in an in vivo setting and raise the possibility of using adenovirus transfer of HSVtk for clinical trials in mesothelioma and other localized tumors.

Adenoviruses, Human↗

PubMed1995

Adenovirus-mediated gene transfer to normal and atherosclerotic arteries. A novel approach.

Previous studies of gene transfer to blood vessels in vivo have relied on intraluminal, catheter-based methods for delivery of adenoviral and other vectors. In this study, topical application of a replication-deficient adenoviral vector was used as an alternative method of gene transfer to the vessel wall. We administered recombinant adenovirus (1.0 x 1.5 x 10(10) pfu/mL) containing the nuclear targeted bacterial beta-galactosidase gene topically to arteries in normal and atherosclerotic cynomolgus monkeys. Topical administration was achieved by injection of adenoviral suspension within the periarterial sheath. Segments of femoral and carotid arteries were examined histochemically after staining with 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside 1 day after treatment with the adenovirus. After topical administration of virus, beta-galactosidase activity was observed in approximately 20% of cells in the adventitia in both normal and atherosclerotic arteries. There was no detectable beta-galactosidase activity in cells of the intima or media. Thus, topical application provides an alternative method for gene transfer to blood vessels in vivo. This approach, which does not require interruption of blood flow and does not disrupt the endothelium, may be useful for studies of vascular biology and perhaps gene therapy in both normal and atherosclerotic vessels.

Adenoviridae↗

PubMed1995

Adenovirus-mediated gene transfer in vivo to cerebral blood vessels and perivascular tissue.

Gene transfer to blood vessels in vivo generally requires interruption of blood flow. Thus, gene transduction to cerebral blood vessels in vivo has not yet been achieved. In this study, we injected replication-deficient adenovirus into cerebrospinal fluid in an attempt to transduce genes to cerebral blood vessels. Recombinant adenovirus (1 x 10(9) infectious units) expressing nuclear-targeted bacterial beta-galactosidase driven by the cytomegalovirus promoter was injected into the cisterna magna of Sprague-Dawley rats. The brains were examined histochemically after staining with 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside 1 to 7 days after injection of adenovirus. Leptomeningeal cells overlying the major arteries were efficiently transduced, and adventitial cells of large vessels and smooth muscle cells of small vessels were occasionally stained. beta-Galactosidase was expressed on days 1 and 3 after injection but was undetectable by day 7. Expression of the gene was 'targeted' by altering the position of the head. When viral suspension was injected while the rat was in a nose-down position, the reporter gene was expressed extensively on the ventral surface of the brain, especially along the circle of Willis. When the position was changed to the nose-up or lateral position, the inferior or lateral region of the brain was stained primarily. Administration of the virus into the lateral ventricle provided extensive expression in ependymal cells and leptomeninges with some transduction to cerebral blood vessels. Thus, adenovirus injected into cerebrospinal fluid provides gene transfer in vivo to cerebral blood vessels and, with greater efficiency, to perivascular tissue. Furthermore, cisternal delivery may target specific brain regions by positioning of the head.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoviridae↗

PubMed1995

Gene expression from recombinant viral vectors in the central nervous system after blood-brain barrier disruption.

Direct intracerebral injection of recombinant adenoviral vectors within the brain parenchyma or the ventricular system results in a limited volume of distribution of virus, as demonstrated by transgene expression. Global delivery to the central nervous system may increase the use of these vectors but only if the viral vectors can cross the blood-brain barrier and result in transduction of the underlying cells. This short-term study examines whether osmotic disruption with mannitol can result in sufficient opening of the vascular endothelium to allow for passage of replication-defective adenovirus containing the Escherichia coli beta-galactosidase gene (lacZ). Virus was injected into the carotid artery of rats after blood-brain barrier disruption with intracarotid hypertonic mannitol, and the animals were killed and analyzed after 4 days. Histochemical analysis and electron microscopy confirmed expression of the E. coli lacZ gene in the pericapillary astrocytes of the ipsilateral cerebral cortex and deep grey matter. Furthermore, the extent of gene transfer and expression correlated with the degree of barrier opening, as measured by Evans blue staining. Transgene expression was not seen in control animals that received intracarotid saline before recombinant virus injection. These data demonstrate, for the first time, that blood-brain barrier disruption can allow for the delivery of functional viral vectors to the central nervous system.

Adenoviridae↗

PubMed1995

Comparison of intracerebral inoculation and osmotic blood-brain barrier disruption for delivery of adenovirus, herpesvirus, and iron oxide particles to normal rat brain.

Delivery of adenovirus, herpes simplex virus (HSV), and paramagnetic monocrystalline iron oxide nanoparticles (MION) to rat brain (n = 64) was assessed after intracerebral inoculation or osmotic disruption of the blood-brain barrier (BBB). After intracerebral inoculation, the area of distribution was 7.93 +/- 0.43 mm2 (n = 9) for MION and 9.17 +/- 1.27 mm2 (n = 9) for replication-defective adenovirus. The replication-compromised HSV RH105 spread to 14.00 +/- 0.87 mm2 (n = 8), but also had a large necrotic center (3.54 +/- 0.47 mm2). No infection was detected when virus was administered intra-arterially without hyperosmotic mannitol. After osmotic BBB disruption, delivery of the viruses and MIONs was detected throughout the disrupted cerebral cortex. Positive staining was found in 4 to 845 cells/100 microns thick coronal brain section (n = 7) after adenovirus administration, and in 13 to 197 cells/section (n = 8) after HSV administration. Cells of glial morphology were more frequently stained after administration of adenovirus, whereas neuronal cells were preferentially stained after delivery of both HSV vectors and MION. In a preliminary test of vector delivery in the feline, MION was detected throughout the white matter tracts after inoculation into normal cat brain. Thus MION may be a tool for use in vivo, to monitor the delivery of virus to the central nervous system. Additionally, BBB disruption may be an effective method to globally deliver recombinant viruses to the CNS.

Adenoviridae↗

PubMed1995

Expression of human interleukin-1 receptor antagonist in mouse lungs using a recombinant adenovirus: effects on vector-induced inflammation.

Pulmonary inflammation is a major obstacle to using adenovirus-based vectors for gene transfer to the lung. Since the pro-inflammatory cytokine, interleukin-1 (IL-1), is expressed early following adenovirus infection, we hypothesized that inhibition of IL-1 might block the inflammation caused by adenoviral vectors. To inhibit IL-1 activity at the site of infection continuously, we employed a recombinant adenovirus that contained the cDNA for human IL-1 receptor antagonist protein (IL-1ra) designated as Ad.RSVIL-1ra. When Ad.RSVIL-1ra was instilled intratracheally into CBA/J mice, human IL-1ra was recovered in lung tissue and bronchoalveolar lavage fluid for up to 30 days. Human IL-1ra is known to bind to murine IL-1 receptors and inhibit IL-1-mediated responses. To measure pulmonary inflammation, the number of inflammatory cells contained within suspensions of protease-digested lung tissue were counted 6 days after virus administration. Ad.RSVIL-1ra failed to reduce the number of inflammatory cells below that induced by a control vector that lacked an expression cassette (Ad.BgIII). Light microscopy showed that the lung tissue from Ad.RSVIL-1ra and Ad.BgIII-treated mice contained qualitatively similar amounts of inflammatory infiltrate. We conclude that adenovirus-based vectors can be used to induce high levels of IL-1ra expression within the lung, but such expression was unable to prevent adenoviral vector-induced inflammation.

Adenoviridae↗

PubMed1995

A recombinant adenoviral vector expressing a soluble form of VCAM-1 inhibits VCAM-1/VLA-4 adhesion in transduced synoviocytes.

Intra-articular injection of recombinant adenovirus has been shown to be a feasible approach to the introduction of genetic reagents into synovial tissues in vivo. Rheumatoid arthritis (RA) is an autoimmune disorder characterized by the infiltration of lymphocytes and monocytes into inflamed synovium. It has been hypothesized that the recruitment of T lymphocytes/monocytes into sites of chronic inflammation is mediated by enhanced binding of very late antigen-4 (VLA-4) to vascular cell adhesion molecule-1 (VCAM-1) expressed on microvascular endothelial cells. Additional evidence suggests that VLA-4 binding continues to be important within the inflamed synovial membrane, where it appears to play a role in T cell retention and activation. A feasible therapeutic strategy for RA could be to utilize a soluble congener of the VCAM-1 molecule to block VLA-4 binding. In order to test this concept, a recombinant serotype Ad5 human adenovirus encoding a secreted form of VCAM-1 (Ad.CBsVCAM) was constructed. Human synoviocytes were readily infected in vitro with Ad.CBsVCAM, and sVCAM-1 expression and processing were analyzed by immunoprecipitation studies. Secretion of transgenic sVCAM was identified by ELISA of tissue culture supernatants, and biological activity was demonstrated with cell adhesion assays. In vivo, transgenic sVCAM-1 expression was determined by immunohistochemical analysis and in situ hybridization of synovial tissue, and secretion of transgenic sVCAM-1 was demonstrated by ELISA of tidal knee lavage fluid. The results showed that recombinant adenovirus can mediate the expression of a biologically active sVCAM-1 by synoviocytes in vivo and suggest that this strategy may be useful for inhibiting T lymphocyte retention and activation within rheumatoid synovium.

Adenoviridae↗

PubMed1995

Assessment of ganciclovir toxicity to experimental intracranial gliomas following recombinant adenoviral-mediated transfer of the herpes simplex virus thymidine kinase gene by magnetic resonance imaging and proton magnetic resonance spectroscopy.

Magnetic resonance imaging and in vivo localized H magnetic resonance spectroscopy were used to evaluate a gene therapy approach for treating experimental brain tumors. This approach involved the use of an adenoviral vector to transfer the herpes simplex virus thymidine kinase (HSVtk) gene into intracerebral 9L gliosarcomas in rats followed by systemic administration of the antiherpetic agent ganciclovir. Magnetic resonance imaging quantitation of changes in intracranial 9L tumor doubling times revealed a significant variation in therapeutic response. Localized H magnetic resonance spectra of 9L tumors treated with Ad.RSVtk/ganciclovir revealed a dramatic increase in the resonance intensity at 0.9-1.3 ppm, corresponding to mobile lipids and/or lactate. Changes in intracranial tumor doubling times correlated with changes in H tumor magnetic resonance spectra, suggesting that specific changes in tumor metabolite levels may be predictive of the effectiveness of this gene therapy approach.

Animals↗

PubMed1994

Use of recombinant adenovirus to transfer the herpes simplex virus thymidine kinase (HSVtk) gene to thoracic neoplasms: an effective in vitro drug sensitization system.

Transfer of the herpes simplex virus thymidine kinase (HSVtk) gene into tumor cells using retroviral vectors followed by administration of ganciclovir provides a potential strategy for the treatment of malignancy. Because of the limitations of using retroviral vectors for clinical application, the feasibility of using a recombinant adenovirus containing HSVtk was examined. Cell lines derived from human malignant mesotheliomas and non-small cell lung cancers infected with a recombinant adenovirus containing HSVtk showed strong expression of HSVtk protein as determined by immunohistochemical staining. Infection with a recombinant adenovirus containing HSVtk rendered cells sensitive to doses of ganciclovir that were 2-3 logs lower than uninfected cells or those infected with a control virus. A strong "bystander effect" was noted in mesothelioma lines; there was no diminution in the efficacy of ganciclovir treatment until the ratio of infected:uninfected cells fell below 1:10. This study thus demonstrates in vitro efficacy of an adenovirus-transduced HSVtk drug sensitization gene therapy system in thoracic malignancies. Recombinant adenovirus transfer of the HSVtk gene followed by ganciclovir may have promise as an in situ treatment for tumors.

Adenoviridae↗