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Biomedical subjects

A H Baker

Publications and source records attributed to A H Baker.

At least 19 recordsLinked to original sources
PubMed2002

Adenovirus-mediated overexpression of extracellular superoxide dismutase improves endothelial dysfunction in a rat model of hypertension.

Gene transfer may be appropriate for therapeutic protocols targeted at the vascular endothelium. Endothelial dysfunction is the principal phenotype associated with atherosclerosis and hypertension. Oxidative stress has been implicated in the development of endothelial dysfunction. We have explored the ability of overexpressing anti-oxidant genes (superoxide dismutases; SODs) in vitro and in vivo to assess their potential for reversing endothelial dysfunction in a rat model, the stroke-prone spontaneously hypertensive rat (SHRSP). Western blotting and immunofluorescence assays in vitro showed efficient overexpression of MnSOD and ECSOD with respect to localisation to the mitochondria and extracellular surface, respectively. Transgene functional activity was quantified with SOD activity assays. MnSOD and ECSOD overexpression in intact SHRSP vessels in vivo led to endothelial and adventitial overexpression. Pharmacological assessment of transduced vessels following in vivo delivery by basal NO availability quantification demonstrated that the "null" adenovirus and MnSOD adenovirus did not significantly increase NO availability. However, AdECSOD-treated carotid arteries showed a significant increase in NO availability (1.91 +/- 0.04 versus 0.75 +/- 0.08 g/g, n = 6, P = 0.029). In summary, efficient overexpression of ECSOD, but not MnSOD in vivo, results in improved endothelial function in a rat model of hypertension and has important implications for the development of endothelial-based vascular gene therapy.

Adenoviridae↗
PubMed2001

Paradoxical effects of tissue inhibitor of metalloproteinases 1 gene transfer in collagen-induced arthritis.

OBJECTIVE: The imbalance between matrix metalloproteinases (MMPs) 1, 3, and 9 and their specific inhibitor, tissue inhibitor of metalloproteinases 1 (TIMP-1), is a critical step in cartilage injury and angiogenesis in arthritis. To explore the therapeutic potential of TIMP-1 gene transfer in erosive arthritis, the effects of an adenoviral vector (Ad-TIMP-1) were assessed in DBA/1 mice with collagen-induced arthritis (CIA). METHODS: DBA/1 mice with CIA received an intravenous injection of replication-deficient adenovirus containing the human TIMP-1 gene or a control LacZ gene on day 28 postimmunization. The efficiency of gene transfer was determined by serum TIMP-1 detection, measurements of paw swelling, as well as radiologic and histologic examination of the paws. RESULTS: A single administration of Ad-TIMP-1 resulted in detectable serum levels of the exogenous protein for at least 13 days. The incidence and onset of arthritis were not statistically modified after human TIMP-1 gene transfer in DBA/1 mice compared with control mice. However, the severity of inflammation was statistically significantly increased in Ad-TIMP-1-treated mice and a similar trend was observed in the histologic and radiologic scores. With regard to the mechanisms of the worsened effect in the Ad-TIMP-1-treated mice, we observed 1) higher serum levels of anti-type II collagen IgG2a, 2) a significant increase in endogenous soluble tumor necrosis factor receptor I (TNFRI) in sera, and 3) increased labeling of mouse tumor necrosis factor alpha and TNFRI within arthritic joints. CONCLUSION: These findings show that overexpression of TIMP-1 does not prevent osteochondral injury in a mouse model of arthritis. Since MMPs have overlapping properties in terms of their roles in extracellular matrix degradation, angiogenesis, and shedding of cell surface adhesion molecules, cytokines, and cytokine receptors, the paradoxical results obtained suggest that TIMP-1 is probably not the main inhibitor to target.

Adenoviridae↗
PubMed2001

Efficient and selective AAV2-mediated gene transfer directed to human vascular endothelial cells.

Gene therapy vectors based on adeno-associated virus-2 (AAV2) offer considerable promise for human gene therapy. Applications for AAV vectors are limited to tissues efficiently transduced by the vector due to its natural tropism, which is predominantly skeletal muscle, neurons, and hepatocytes. Tropism modification to elevate efficiency and/or selectivity to individual cell types would enhance the scope of AAV for disease therapies. The vascular endothelium is implicitly important in cardiovascular diseases and cancer, but is relatively poorly transduced by AAV vectors. We therefore genetically incorporated the peptide SIGYPLP, which targets endothelial cells (EC), into position I-587 of AAV capsids. SIGYPLP-modified AAV (AAVsig) showed enhanced transduction of human EC compared with AAV with a wild-type capsid (AAVwt), a phenotype independent of heparan sulphate proteoglycan (HSPG) binding. In contrast, AAVsig did not enhance transduction of primary human vascular smooth muscle cells or human hepatocytes, principal targets for AAV vectors in local or systemic gene delivery applications, respectively. Furthermore, infection of EC in the presence of bafilomycin A(2) indicated that intracellular trafficking of AAV particles was altered by targeting AAV by means of SIGYPLP. AAV vectors with enhanced tropism for EC will be useful for diverse gene therapeutics targeted at the vasculature.

Amino Acid Sequence↗
PubMed2001

Ablating adenovirus type 5 fiber-CAR binding and HI loop insertion of the SIGYPLP peptide generate an endothelial cell-selective adenovirus.

Adenovirus type 5 (Ad) based vectors transduce vascular endothelial cells (EC) and have been widely used for vascular gene transfer. However, many cell types express the Ad receptor (cox-sackievirus adenovirus receptor; CAR), preventing selective EC infection and precluding clinical use. We previously isolated the human EC-binding peptides SIGYPLP and LSNFHSS by phage display and demonstrated by means of a bispecific antibody that SIGYPLP directs efficient, high-level, EC-selective Ad-mediated gene transfer. We now generate genetically modified Ad fiber proteins with selective EC tropism by engineering these peptides into the HI loop of the Ad fiber. SIGYPLP, but not LSNFHSS, enhanced EC selectivity, demonstrating maintenance of peptide-cell binding fidelity upon incorporation into virions. Combining fiber mutations that block CAR binding (detargeting) with SIGYPLP insertion (retargeting) generated a novel Ad vector, AdKO1SIG, in a single component system. AdKO1SIG demonstrated efficient and selective tropism for EC compared with control Ad vectors. This is the first demonstration of genetic incorporation of a novel, mammalian, cell-selective ligand that retains its targeting fidelity in the Ad fiber HI loop, in combination with point mutations that abolish fiber-CAR interaction. This study demonstrates the potential for improving the cell-selectivity and safety of adenoviral vectors.

Adenoviridae↗
PubMed2001

Inhibition of transcription factor NF-kappaB reduces matrix metalloproteinase-1, -3 and -9 production by vascular smooth muscle cells.

OBJECTIVE: Matrix metalloproteinases (MMPs) contribute to the destruction of the extracellular matrix at the shoulder regions of atherosclerotic plaques that leads to plaque destabilisation and triggers clinical cardiovascular disease. There is therefore considerable interest in establishing the mechanisms responsible for increased MMP production. MMPs-1, -3 and -9 are upregulated by inflammatory cytokines and growth factors that are produced by plaque resident macrophages and smooth muscle cells. Our present studies focused on NF-kappaB, which regulates numerous inflammatory genes, and is activated in plaque smooth muscle cells. Moreover, an NF-kappaB binding site is present in the promoter of the MMP-9 gene and an NF-kappaB-like element in the promoter of the MMP-1 gene. METHODS: We used adenovirus mediated overexpression of its inhibitor, I kappaBalpha to investigate the role of NF-kappaB in regulation of MMP-1, -3 and -9 by isolated, cytokine stimulated rabbit aortic and human saphenous vein VSMC. RESULTS: IL-1alpha potently activated NF-kappa B in VSMCs and acted synergistically with growth factors to upregulate expression of MMP-1, -3 and -9. Overexpression of I kappaBalpha, almost completely inhibited expression of MMP-1, -3 and -9 in response to IL-1alpha alone or in combination with bFGF and PDGF. CONCLUSION: NF-kappaB is required for cytokine upregulation of MMP-1, -3 and -9 in VSMCs, which suggests that NF-kappaB inhibition may promote plaque stabilisation.

Animals↗
PubMed2001

Combined transductional and transcriptional targeting improves the specificity of transgene expression in vivo.

The promise of gene therapy for health care will not be realized until gene delivery systems are capable of achieving efficient, cell-specific gene delivery in vivo. Here we describe an adenoviral system for achieving cell-specific transgene expression in pulmonary endothelium. The combination of transductional targeting to a pulmonary endothelial marker (angiotensin-converting enzyme, ACE) and an endothelial-specific promoter (for vascular endothelial growth factor receptor type 1, flt-1) resulted in a synergistic, 300,000-fold improvement in the selectivity of transgene expression for lung versus the usual site of vector sequestration, the liver. This combined approach should be useful for the design of other gene delivery systems.

Adenoviridae↗
PubMed2001

Wild-type p53 gene transfer inhibits neointima formation in human saphenous vein by modulation of smooth muscle cell migration and induction of apoptosis.

Patency of autologous human saphenous vein coronary artery bypass grafts (CABG) is compromised by intimal thickening and superimposed atherosclerosis, caused by migration of vascular smooth muscle cells (SMC) to the intima where they proliferate. Here, using adenoviral transfer, we have targeted SMCs using wild-type p53 (wt p53) overexpression. Initial in vitro analyses demonstrated that wt p53 overexpression had no effect on SMC proliferation but promoted apoptosis, which was inhibited by co-expression of bcl2 or crmA. Wt p53 inhibited SMC invasion through reconstituted matrices, a phenotype not affected by bcl2 or crmA. Overexpression of wt p53 in human saphenous vein before organ culture significantly induced apoptosis (P < 0.01, Student's t test) without affecting proliferation rates either in the media or in the intima. SMC migration was, however, significantly reduced by wt p53 (P < 0.01, Student's t test). Intimal thickening and the number of neointimal cells were reduced by 89% and 73%, respectively, after 14 days (P < 0.01 and P < 0.001, respectively, Student's t test). This study demonstrates that overexpression of wt p53 promotes apoptosis and inhibits migration of SMC leading to reduced intimal thickening. This maybe a useful approach for increasing patency rates in CABG procedures in the clinic.

Adenoviridae↗
PubMed2001

Identification of peptides that target the endothelial cell-specific LOX-1 receptor.

Current gene delivery vectors demonstrate inefficient and nonselective gene transfer to vascular endothelial cells, limiting their use in cardiovascular gene transfer and therapy. The lectinlike oxidized LDL receptor (LOX-1) is expressed selectively at low levels on endothelial cells but is strongly upregulated in dysfunctional endothelial cells associated with hypertension and atherogenesis. Using LOX-1 as a target receptor, we have sought to isolate peptide ligands that mediate binding to the extracellular domain of LOX-1 as a definitive step in the development of targeted gene transfer aimed at dysfunctional endothelium. To achieve this, we ectopically overexpressed LOX-1 in cells lacking endogenous LOX-1 by using an episomally maintained expression system and designed a novel subtractive phage display strategy to identify peptides selective for LOX-1. After extensive biopanning, we sequenced individual phage and identified 60 novel peptides. This population of peptides contained a number of potential consensus motifs. To define the selectivity of individual peptides for LOX-1 with the use of an independent gene transfer system, we developed a novel adenoviral vector to overexpress LOX-1 transiently in primary cells and cell lines. We then quantified recovery of each peptide from LOX-1-positive and LOX-1-negative cells after adenovirus-mediated gene transfer. This strategy confirmed selectivity to LOX-1 for many peptides and highlighted the peptides LSIPPKA, FQTPPQL, and LTPATAI as principal candidates. These peptides will be useful for the selective targeting of viral and nonviral gene transfer vectors to endothelial cells expressing the LOX-1 receptor in vitro and in vivo and in particular dysfunctional endothelial cells associated with hypertension and atherosclerosis.

Adenoviridae↗
PubMed2001

Analysis of cell-specific promoters for viral gene therapy targeted at the vascular endothelium.

The use of viral vectors for vascular gene therapy targeted at the endothelium is limited by the promiscuous tropism of vectors and nonspecificity of viral promoters, resulting in high-level transgene expression in multiple tissues. To evaluate suitable endothelial cell (EC)-specific promoters for vascular gene therapy, we directly compared the ability of the fms-like tyrosine kinase-1 (FLT-1), intercellular adhesion molecule-2 (ICAM-2), and von Willebrand factor (vWF) promoters to drive EC-restricted transcription after cloning into adenoviral vectors upstream of lacZ. Vastly different expression profiles were observed. Whereas both FLT-1 and ICAM-2 promoters generated transgene expression levels similar to cytomegalovirus in ECs in vitro, vWF expression levels were extremely low. Analysis of non-EC types revealed that ICAM-2 but not FLT-1 evoked leaky transgene expression, thus identifying FLT-1 as the most selective promoter. With an ex vivo human gene therapy model, the FLT-1 promoter demonstrated EC-specific transgene expression in intact human vein but no detectable expression from infected exposed smooth muscle cells in EC-denuded vein. Furthermore, when adenoviruses were systemically administered to mice, the FLT-1 promoter demonstrated extremely low-level gene expression in the liver, the major target organ for adenoviral transduction in vivo. This study highlights the potential of using the FLT-1 promoter for local and systemic human gene therapy in hypertension and its complications.

Adenoviridae↗
PubMed2001

Local gene transfer of tissue inhibitor of metalloproteinase-2 influences vein graft remodeling in a mouse model.

Recently, we established a new mouse model of vein graft arteriosclerosis by grafting vena cava to carotid arteries. In many respects, the morphological features of this murine vascular graft model resemble those of human venous bypass graft disease. Using this model, we studied the effects of local gene transfer of tissue inhibitor of metalloproteinase-2 (TIMP-2) on vein graft remodeling. Mouse isogeneic vessels of the vena caval veins were grafted end to end into carotid arteries, then enveloped with the replication-defective recombinant adenoviruses overexpressing human TIMP-2 (RAdTIMP-2) or beta-galactosidase (RAdLacZ) at 1x10(10) plaque-forming units/mL in a total volume of 50 microL, and incubated at room temperature for 20 minutes. In the untreated group, vessel wall thickening was observed as early as 1 week after surgery and progressed to 4- to 10-fold the original thickness in grafted veins at 4 and 8 weeks, respectively. RAdLacZ vector treatment significantly enhanced neointimal lesions at 8 weeks, which was completely blocked by RAdTIMP-2 gene overexpression. Interestingly, RAdTIMP-2 gene transfer resulted in a reduction in vessel diameter of grafted veins compared with ungrafted veins (819+/-96 versus 624+/-67 microm, respectively; P<0.05). Maximal beta-galactosidase activity was found at 2 weeks and was detectable until 4 weeks after gene transfer. Double immunofluorescence studies demonstrated that cells overexpressing TIMP-2 were mostly localized in the adventitia and were MAC-1-positive monocytes/macrophages but not smooth muscle cells. Furthermore, the activity of matrix metalloproteinases was markedly decreased in the vessel walls treated with RAdTIMP-2 compared with that in the untreated control group and the RAdLacZ-treated group. Thus, this mouse model has been proven to be useful in gene transfer studies. Our findings demonstrate that local TIMP-2 gene transfer significantly reduces vein graft diameter, ie, remodeling to an artery-like vessel via inhibition of matrix metalloproteinase activity.

Adenoviridae↗
PubMed2000

Localization of the death domain of tissue inhibitor of metalloproteinase-3 to the N terminus. Metalloproteinase inhibition is associated with proapoptotic activity.

The tissue inhibitors of metalloproteinases (TIMPs) are a family of four secreted inhibitors of matrix metalloproteinases (MMPs). Recently, additional functions have been attributed to the TIMPs, including cell growth and inhibition of angiogenesis. In particular, we demonstrated that TIMP-3 overexpression using gene transfer induces apoptosis in a variety of cell types and can inhibit vascular neointima formation in vivo. However, little is know about the mechanisms underlying TIMP-3-mediated apoptosis. Here, using both purified recombinant proteins and novel adenoviral vectors we demonstrate that the prodeath domain of TIMP-3 is located within the N-terminal three loops of TIMP-3. Although both wild type and N-terminal TIMP-3 proteins promoted apoptosis, a T-2/T-3 chimera, in which the N-terminal three loops of TIMP-3 are replaced by those of TIMP-2, failed to induce cell death. Furthermore, a point mutation at residue 1 of TIMP-3 totally abolished MMP-inhibitory activity of TIMP-3 and also failed to promote apoptosis. This study demonstrates, using multiple apoptosis assays, that the prodeath function of TIMP-3 is located within the N-terminal three loops and the presence of functional metalloproteinase-inhibitory activity is associated with the induction of apoptosis.

Animals↗
PubMed2000

Treatment of colorectal liver metastases by adenoviral transfer of tissue inhibitor of metalloproteinases-2 into the liver tissue.

Metastatic disease is the leading cause of death in cancer patients. Here, we describe a novel gene therapeutic strategy for prevention of metastatic spread by providing a suitable defense mechanism for the target organ. The production of metalloproteinase (MMP) enzymes by cancer cells is critical for local invasion and for infiltration of metastatic cells into distant sites. Using a nude mouse model of colorectal liver metastasis, we have overexpressed the MMP inhibitor, tissue inhibitor of MMP-2 (TIMP-2) in the liver prior to, or following, tumor challenge by metastatic LS174T cells in vivo. Transduction of approximately 50% of hepatocytes resulted in 95% reduction in metastasis after tumor challenge compared with controls. Furthermore, TIMP-2 gene transfer into livers with preexisting metastatic spread resulted in a 77% reduction in tumor cell growth. Our data imply that MMP activity of metastatic cancer cells is required for spread and subsequent tumor growth and that enhancing antiproteolytic defense mechanisms in target organs represents a novel form of cancer gene therapy.

Adenoviridae↗
PubMed2000

Inhibition of matrix metalloproteinases by lung TIMP-1 gene transfer or doxycycline aggravates pulmonary hypertension in rats.

Chronic hypoxic pulmonary hypertension (PH) results from persistent vasoconstriction, excess muscularization, and extracellular matrix remodeling of pulmonary arteries. The matrix metalloproteinases (MMPs) are a family of proteinases implicated in extracellular matrix turnover and hence in smooth muscle and endothelial cell migration and proliferation. Because MMP expression and activity are increased in PH, we designed the present study to investigate whether inhibition of lung MMPs in rats subjected to chronic hypoxia (CH) contributes to or protects against vascular remodeling and PH. To achieve lung MMP inhibition, rats exposed to 10% O(2) for 15 days were treated with either doxycycline (20 mg/kg per day by gavage starting 2 days before and continuing throughout the CH period) or a single dose of recombinant adenovirus (Ad) for the human tissue inhibitors of metalloproteinases-1 (hTIMP-1) gene (Ad.hTIMP-1, 10(8) plaque-forming units given intratracheally 2 days before CH initiation). Control groups either received no treatment or were treated with an adenovirus containing no gene in the expression cassette (Ad.Null). Efficacy of hTIMP-1 gene transfer was assessed both by ELISA on bronchoalveolar lavages and by hTIMP-1 immunofluorescence on lung sections. MMP inhibition in lungs was evaluated by in situ zymography and gelatinolytic activity assessment using [(3)H]gelatin. Rats treated with either doxycycline or Ad.hTIMP-1 had higher pulmonary artery pressure and right heart ventricular hypertrophy more severe than their respective controls. Worsening of PH was associated with increased muscularization and periadventitial collagen accumulation in distal arteries. In conclusion, our study provides compelling evidence that MMPs play a pivotal role in protecting against pulmonary artery remodeling.

Animals↗
PubMed2000

Selective targeting of gene transfer to vascular endothelial cells by use of peptides isolated by phage display.

BACKGROUND: Gene transfer to vascular cells is a highly inefficient and nonselective process, defined by the lack of specific cell-surface receptors for both nonviral and viral gene delivery vectors. METHODS AND RESULTS: We used filamentous phage display to isolate a panel of peptides that have the ability to bind selectively and efficiently to quiescent human umbilical vein endothelial cells (HUVECs) with reduced or negligible binding to nonendothelial cells, including vascular smooth muscle cells and hepatocytes. By direct biopanning on HUVECs and a second approach involving preclearing steps before panning on HUVECs, we isolated and sequenced 140 individual phages and identified 59 peptides. We selected 7 candidates for further investigation by secondary screening of homogeneous phages on a panel of cell types. Using adenovirus-mediated gene transfer as a model gene delivery system, we cloned the peptide SIGYPLP and the positive control peptide KKKKKKK upstream of the S11e single-chain Fv ("adenobody") directed against the knob domain of the adenovirus to create fusion proteins. Adenovirus-mediated gene transfer via fiber-dependent infection was blocked with S11e, whereas inclusion of the KKKKKKK peptide retargeted gene transfer. The peptide SIGYPLP, however, retargeted gene delivery specifically to endothelial cells with a significantly enhanced efficiency over nontargeted adenovirus and without transduction of nontarget cells. CONCLUSIONS: Our study demonstrates the feasibility of using small, novel peptides isolated via phage display to target gene delivery specifically and efficiently to HUVECs and highlights their use for retargeting both viral and nonviral gene transfer to vascular endothelial cells for future clinical applications.

Adenoviridae↗
PubMed2000

Inhibition of late vein graft neointima formation in human and porcine models by adenovirus-mediated overexpression of tissue inhibitor of metalloproteinase-3.

BACKGROUND: Autologous saphenous vein coronary artery bypass graft surgery is complicated by late graft failure due to neointima formation and subsequent atherosclerosis. Growth factors and metalloproteinases (MMPs) act in concert to promote neointima formation. Tissue inhibitor of metalloproteinase-3 (TIMP-3), an extracellular matrix-associated MMP inhibitor, uniquely promotes apoptosis of isolated vascular smooth muscle cells. Here, we overexpressed TIMP-3 at the luminal surface of human saphenous veins before organ culture and in pig saphenous veins before interposition grafting into carotid arteries in vivo to assess neointima formation. METHODS AND RESULTS: In both models, high TIMP-3 immunoreactivity occurred in the luminal and upper medial extracellular matrix after adenovirus delivery. MMP activity measured by in situ zymography was reduced throughout the veins, confirming a bystander effect. By use of 3 independent techniques, apoptosis levels in the neointima and medial layer were significantly elevated by TIMP-3 overexpression. Neointima formation was reduced by 84% in 14-day human organ cultures and by 58% in 28-day pig vein grafts (both P<0.05). In contrast, TIMP-2 overexpression had no effect on neointima formation in vivo. CONCLUSIONS: Our results highlight the potential therapeutic benefit for TIMP-3 overexpression to reduce neointima formation associated with late vein graft failure.

Adenoviridae↗
PubMed1999

Nuclear factor kappaB activity is essential for matrix metalloproteinase-1 and -3 upregulation in rabbit dermal fibroblasts.

Expression of matrix metalloproteinases (MMPs)-1 and -3 in fibroblasts is upregulated by pro-inflammatory cytokines and growth factors during proliferative inflammatory processes, including wound healing and rheumatoid arthritis. The Activator Protein-1 (AP-1) transcription factor is essential but, we show here, not sufficient for upregulation because platelet derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), which strongly activate AP-1, poorly induce MMP-1 and -3. Interleukin-1alpha, which activates nuclear factor-kappaB (NF-kappaB), synergistically upregulates MMP-1 and -3 expression in the presence of bFGF or PDGF. Adenovirus mediated overexpression of IkappaBalpha, the inhibitor of NF-kappaB, completely suppresses MMP-1 and -3 protein and mRNA expression. Hence, we show for the first time that (NF-kappaB) activity is also essential for MMP-1 and -3 upregulation.

Adenoviridae↗
PubMed1999

Inhibition of invasion and induction of apoptotic cell death of cancer cell lines by overexpression of TIMP-3.

Dysregulation of matrix degrading metalloproteinase enzymes (MMPs) leads to increased extracellular matrix turnover, a key event in the local invasion and metastasis of many tumours. The tissue inhibitors of metalloproteinases (TIMPs) limit the activity of MMPs, which suggests their use in gene therapy. We have previously shown that overexpression of TIMP-1, -2 or -3 inhibits vascular smooth muscle and melanoma cell invasion, while TIMP-3 uniquely promotes apoptosis. We have therefore sought to determine whether TIMP-3 can inhibit invasion and promote apoptosis in other cancer cell types. Adenoviral-mediated overexpression of TIMP-3 inhibited invasion of HeLa and HT1080 cells through artificial basement membrane to similar levels as that achieved by TIMP-1 and -2. However, TIMP-3 uniquely promoted cell cycle entry and subsequent death by apoptosis. Apoptosis was confirmed by morphological analysis, terminal dUTP nick end labelling (TUNEL) and flow cytometry. The apoptotic phenotype was mimicked by addition of exogenous recombinant TIMP-3 to uninfected cultures demonstrating that the death signal is initiated extracellularly and that a bystander effect exists. These results show that TIMP-3 inhibits invasion in vitro and promotes apoptosis in cancer cell type of differing origin. This clearly identifies the potential of TIMP-3 for gene therapy of multiple cancer types.

Adenoviridae↗