Biomedical subjects

S L Eck

Publications and source records attributed to S L Eck.

27 records · Page 2Linked to original sources

PubMed1996

Adenovirus-mediated gene therapy of ovarian cancer in a mouse model.

OBJECTIVE: Our purpose was to test the feasibility of adenovirus-mediated gene therapy of ovarian cancer. STUDY DESIGN: Ovarian cancer cell lines were exposed to an adenovirus vector expressing a reporter gene (lacZ) and to the same vector bearing the herpes simplex virus thymidine kinase gene (Ad.RSVtk) followed by ganciclovir. lacZ expression and growth inhibition were quantitated. Immunodeficient mice were injected intraperitoneally and subcutaneously with human ovarian cancer cells and treated with Ad.RSVtk and ganciclovir. Statistical analyses included one-way analysis of variance and t tests. RESULTS: Staining for lacZ demonstrated viral transduction in vitro. After exposure to Ad.RSVtk all cell lines showed significant (p < 0.0001, analysis of variance) cytotoxicity to ganciclovir. Human ovarian tumor cells established subcutaneously or intraperitoneally in immunodeficient mice responded to therapy with Ad.RSVtk followed by ganciclovir. Treated mice had a 10- to 20-fold lower subcutaneous tumor burden than did control mice. Additionally, no intraperitoneal tumors were observed in treated mice. CONCLUSIONS: Ovarian cancer cells are readily transduced with recombinant adenovirus and become sensitive to ganciclovir after transduction with Ad.RSVtk. These data support the development of this method for human clinical trials.

Adenoviridae↗

PubMed1995

B7-1 and interleukin 12 synergistically induce effective antitumor immunity.

Enhanced host rejection of tumor cells is the primary goal of cancer immunotherapy and, in many murine tumor models, has been accomplished by engineering cells to express B7 costimulatory molecules or creating an environment rich in certain cytokines. We examined the effect of tumor cell B7-1 expression and administered recombinant interleukin 12 (IL-12) on the syngeneic host response to rapidly growing, poorly immunogenic SCK mammary carcinoma cells and to more slowly growing, immunogenic K1735 melanoma cells. Whereas B7-1 expression induced rejection of K1735 cells in 78% of mice, and IL-12 induced rejection in 38%, B7-1 expression induced rejection of SCK cells in only 28% of mice, and IL-12 induced rejection in none. The relative ineffectiveness of either B7-1 or IL-12 alone to induce rejection of SCK cells led us to combine the two manipulations. This resulted in rejection of SCK cells in 74% of mice and dramatically delayed tumor development in the remainder. Tumor rechallenge studies indicated that the surviving mice developed specific immunity to wild-type SCK cells. Lymphocyte subset ablation and IFN-gamma depletion studies indicated that rejection of SCK tumor cells brought about by the synergistic effects of B7-1 and IL-12 is mediated by a rapidly developing, systemic antitumor immune response that is dependent on the presence of both CD8+ and CD4+ T cells and involves IFN-gamma. Additionally, the synergistic effect of B7-1 expression and IL-12 administration is capable of inducing rejection of control SCK tumors simultaneously established in the opposite flank. The efficacy of B7-1 and IL-12 in inducing protective immunity against a poorly immunogenic, aggressive murine tumor indicates that this combination is particularly effective at producing a potent antitumor immune response that may be of therapeutic benefit.

Animals↗

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↗

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↗

PubMed1993

Inhibition of phorbol ester-induced cellular adhesion by competitive binding of NF-kappa B in vivo.

Adhesive interactions between cells are essential for the organization and function of differentiated tissues and organs and are mediated by inducible cell surface glycoproteins. In normal tissues, cell adhesion molecules contribute to immune regulation, inflammation, and embryogenesis. Additionally, they play an important role in a variety of pathogenic processes. Cell adhesion molecule expression can be induced by stimuli known to activate NF-kappa B, a ubiquitous transcription factor found in a variety of cell types. To investigate the role of NF-kappa B in cell adhesion molecule expression, we treated HL-60 cells with a double-stranded oligonucleotide which specifically inhibits NF-kappa B-mediated transcription. This treatment resulted in the inhibition of phorbol 12-myristate 13-acetate (PMA)-induced cellular adhesion, morphological changes, and the expression of leukocyte integrin CD11b. In a similar fashion, expression of intercellular adhesion molecule 1 on human endothelial cells induced by PMA was specifically inhibited by the NF-kappa B antagonist. We suggest that NF-kappa B activation is a necessary event for the PMA-induced differentiation of HL-60 cells and the expression of certain activation is a necessary event for the PMA-induced differentiation of HL-60 cells and the expression of certain adhesion molecules. Furthermore, the inhibition of transcription factor functions by this generally applicable mechanism can be used to define their role in cellular differentiation and function.

Base Sequence↗

PubMed1993

Angioedema presenting as chronic gastrointestinal symptoms.

Gastrointestinal complaints may be the presenting feature of patients with acquired or hereditary angioedema. We describe two patients with episodic nausea, abdominal pain, and cramping secondary to C1 inhibitor deficiency. In one patient, an acquired deficiency arose as a paraneoplastic syndrome with abdominal complaints preceding the diagnosis of an occult lymphoma. The second patient presented at age 61 with abdominal complaints secondary to a hereditary deficiency of C1 inhibitor. The patients' symptoms were due to gastrointestinal angioedema, resulting from episodic unregulated complement activation. The biochemical mechanism of this unusual syndrome and its diagnostic importance are discussed. A C1 inhibitor deficiency should be considered in patients with unexplained abdominal symptoms suggestive of intestinal pseudo-obstruction.

Abdominal Pain↗

PubMed1992

Evaluation and treatment of acute myocardial infarction complicating systemic lupus erythematosus.

Coronary artery disease has emerged as an important cause of death in young patients with SLE. We report three cases of acute myocardial infarction in young lupus patients who underwent emergent coronary angiography. One patient had a large coronary aneurysm and died five months later from myocarditis. The other two patients underwent coronary angioplasty. The difficulty in distinguishing coronary arteritis from premature atherosclerosis and its relevance to methods of treatment is discussed.

Adult↗

PubMed1991

Antisense oligonucleotides for therapeutic intervention.

Advances have been made in defining the best target sequences for use in antisense oligonucleotide technology, and new chemical derivatives of oligonucleotides are being investigated. Although the potential use of antisense oligonucleotide agents in the treatment of neoplastic, viral and parasitic diseases continues to be explored, they are not yet suitable for administration to humans for reasons that are discussed.

Animals↗

PubMedDate not supplied

Molecular characterization of an adenoviral vector resulting from both homologous and nonhomologous recombination.

Recombinant adenoviral vectors are being used extensively for gene transfer. During the construction of an E1-deleted virus expressing the human B7-1 gene, an aberrant recombinant (Ad.ihB7-1) arose with an unusual 5' sequence. Characterization and sequencing of Ad.ihB7-1 showed that its structure was the result of both homologous and nonhomologous events. The most striking features of the construct were the incorporation of bacterial genomic DNA, an additional inverted terminal repeat, and portions of E1a. The appearance of this construct has implications for vector design and indicates the need for careful analysis and characterization of recombinant adenoviral vectors for clinical use.

Adenoviridae↗