Biomedical subjects

A A Elshami

Publications and source records attributed to A A Elshami.

13 recordsLinked to original sources

PubMed1997

Use of a "replication-restricted" herpes virus to treat experimental human malignant mesothelioma.

Modified, nonneurovirulent herpes simplex viruses (HSVs) have shown promise in the treatment of brain tumors. However, HSV-1 can infect and lyse a wide range of cell types. In this report, we show that HSV-1716, a mutant lacking both copies of the gene coding ICP-34.5, can effectively treat a localized i.p. malignancy. Human malignant mesothelioma cells supported the growth of HSV-1716 and were efficiently lysed in vitro. i.p. injection of HSV-1716 into animals with established tumor nodules reduced tumor burden and significantly prolonged survival in an animal model of non-central nervous system-localized human malignancy without dissemination or persistence after i.p. injection into SCID mice bearing human tumors. These findings suggest that this virus may be efficacious and safe for use in localized human malignancies of nonneuronal origin such as malignant mesothelioma.

Animals↗

PubMed1997

Retinoids augment the bystander effect in vitro and in vivo in herpes simplex virus thymidine kinase/ganciclovir-mediated gene therapy.

Metabolic cooperation via gap junctional intercellular communication (GJIC) is an important mechanism of the bystander effect in gene therapy using the herpes simplex virus thymidine kinase/ganciclovir (HSVtk/GCV) 'prodrug' system. Since retinoids have been reported to increase GJIC by induction of connexin expression, we hypothesized that these compounds could be used to augment the HSVtk/GCV bystander effect. Addition of all-trans retinoic acid increased GJIC in tumor cell lines, augmented expression of connexin 43, and was associated with more efficient GCV-induced in vitro bystander killing in cells transduced with HSVtk via either retrovirus or adenovirus vectors. This augmentation of bystander effect could also be seen in vivo. HSVtk-transduced tumors in mice treated with the combination of GCV and retinoids were significantly smaller than those treated with GCV or retinoids alone. These results provide evidence that retinoids can augment the efficiency of cell killing with the HSVtk/GCV system by enhancing bystander effects and may thus be a promising new approach to improve responses in gene therapy utilizing the HSVtk/GCV system to treat tumors or vascular restenosis.

Animals↗

PubMed1996

Safety of intrapleurally administered recombinant adenovirus carrying herpes simplex thymidine kinase DNA followed by ganciclovir therapy in nonhuman primates.

Preclinical safety and toxicity studies of intrapleural administration of recombinant adenovirus carrying the herpes simplex thymidine kinase gene (H5.010RSVtk) were performed. Previously reported experimental evidence has demonstrated the efficacy of this approach in animal models of a localized thoracic cancer, malignant mesothelioma. H5.010RSVtk was delivered at high dose (10(12) pfu) into the pleural cavity of three non-human primates followed by systemic administration of ganciclovir. No clinical toxicity was noted. Although an inflammatory reaction observable by microscopy was noted in the serosal spaces of the chest cavity, these changes were reversible and were not associated with radiographic sequelae. Extrathoracic viral dissemination was minimal and detectable only by sensitive polymerase chain reaction techniques. This low level of viral dissemination was not associated with detectable clinical, biochemical, or pathologic abnormalities.

Adenoviridae↗

PubMed1996

Treatment of pleural mesothelioma in an immunocompetent rat model utilizing adenoviral transfer of the herpes simplex virus thymidine kinase gene.

Previously, we have treated malignant mesothelioma (MM) growing in the peritoneal cavity of immunodeficient mice utilizing a recombinant adenovirus vector carrying the herpes simplex virus-thymidine kinase gene (Ad.RSVtk) followed by administration of the anti-viral drug ganciclovir (GCV). To mimic more closely the clinical situation in human MM, a syngeneic model of pleural MM was developed in immunocompetent Fischer rats. Administration of Ad.RSVtk into the pleural space of animals with established multifocal tumor followed by systemic GCV therapy resulted in significant tumor regression at 20 days in HSVtk/GCV-treated animals (average tumor weight 0.6 +/- 0.2 gram; n = 12) versus control animals (average weight 5.4 +/- 0.2 grams; n = 21; p < 0.001). In additional studies, Ad.RSVtk/GCV-treated animals had a mean survival of 34 days (average tumor weight 1.0 +/- 0.3 gram at death) versus 26 days in control animals (average tumor weight 6.2 +/- 0.6 grams at death). A significant reduction in tumor burden was also seen when more advanced, bulkier disease was treated. These studies demonstrate the Ad.RSVtk/GCV system is effective in the treatment of pleural-based tumors in an immunocompetent host. However, there are limitations to this treatment approach that result in only small increments in survival.

Adenoviruses, Human↗

PubMed1996

Plastic bronchitis.

Plastic bronchitis is generally associated with some type of pulmonary disease and improves either spontaneously or with medical therapy. We present a case of plastic bronchitis with no known cause. The patients' symptoms were not responsive to medical therapy but were relieved after right middle lobectomy.

Adolescent↗

PubMed1996

Coexistent asthma and functional upper airway obstruction. Case reports and review of the literature.

Three asthmatic patients with dyspnea and episodes of apparent bronchospasm unresponsive to conventional therapy are described. During these episodes variable extrathoracic upper airway obstruction and airflow limitation typical of bronchial asthma were demonstrated by spirometry test results. In one patient, paradoxical vocal cord motion was identified by fiberoptic laryngoscopy. We believe these patients represent an unusual subgroup of asthmatic subjects who manifest laryngeal dysfunction. Recognition of this upper airway component to airflow limitation in some asthmatic patients may help physicians avoid potentially unnecessary therapy with systemic steroids and endotracheal intubation.

Adult↗

PubMed1996

Gap junctions play a role in the 'bystander effect' of the herpes simplex virus thymidine kinase/ganciclovir system in vitro.

Tumor cells transduced with the herpes simplex virus thymidine kinase (HSVtk) gene are sensitive to the anti-viral drug ganciclovir (GCV). However, nearby untransduced tumor cells are also efficiently killed. The mechanism of this 'bystander effect' was studied by comparing pairs of tumor cell lines transfected with connexin genes that differed only in their degree of gap junctional communication. More efficient cell killing was uniformly seen in connexin transfectants compared with the less coupled cell lines. These results provide direct evidence that gap junctional communication plays an important role in mediating the bystander effect of the HSVtk/GCV system in vitro and have important prognostic and therapeutic implications for future gene therapy trials.

Adenoviruses, Human↗

PubMed1995

Pleural-based mesothelioma in immune competent rats: a model to study adenoviral gene transfer.

BACKGROUND: Despite multimodality approaches, pleural-based malignant mesothelioma remains a disease with a very poor prognosis. Novel therapeutic strategies such as gene therapy clearly are needed to improve the survival of patients with this neoplasm. To aid in the evaluation of new treatment strategies, animal models that closely mimic human disease are required. This article describes the establishment of a pleural-based model of malignant mesothelioma in immune-competent Fischer rats. METHODS: Via a modified left anterior lateral thorocotomy, a syngeneic malignant mesothelioma cell line, called II-45, was placed into the pleural cavity of Fischer rats. RESULTS: Placement of II-45 cells into the pleural cavity of Fischer rats results in a model of pleural mesothelioma that closely resembles the disease seen in patients and is highly reproducible, with animals dying within 1 month. We also demonstrate the feasibility of adenoviral-mediated gene transfer to normal mesothelial cells lining the pleural cavity, as well as to malignant cells deep within the substance of pleural-based malignant mesothelioma. CONCLUSIONS: The model described here offers the opportunity to study a variety of new treatment modalities, especially somatic gene transfer, against pleural-based malignant mesothelioma in an immune competent setting.

Adenoviridae↗

PubMed1995

Differential sensitivity of thoracic malignant tumors to adenovirus-mediated drug sensitization gene therapy.

Malignant mesothelioma may prove to be an attractive candidate for somatic gene therapy with replication-deficient recombinant adenovirus transfer of a toxic, or drug sensitization gene. Transfer of the herpes simplex thymidine kinase type I gene (HSVtk), followed by exposure to the acyclic nucleoside drug ganciclovir, has been shown to be an effective tumor cell killing system. To study generalized applicability, we tested a number of thoracic malignant cell lines for their sensitivity to gancyclovir after infection with an adenoviral vector containing the HSVtk gene (Ad.RSVtk). Using the concentration of gancyclovir required to kill 50% of the cells (IC50) as a measure of sensitivity, we detected variable sensitivity among cell lines, with mesothelioma most sensitive (IC50 = 0.075 to 2.8 mumol/L gancyclovir), and non-small-cell carcinoma lines having an intermediate sensitivity (IC50 = 1.5 to 100 mumol/L). In contrast, an ovarian carcinoma line was extremely resistant (IC50 > 2000 mumol/L). To study the possible mechanisms for these differences, we studied cell lines with regard to their ability to be infected with an adenoviral vector containing a marker gene (Ad.CMVlacZ) and expression of the vitronectin receptor alpha v (an integrin cell adhesion molecule shown to be required for adenovirus internalization after initial binding). We found that the degree of lacZ transduction correlated with HSVtk sensitivity, whereas vitronectin receptor expression did not, suggesting that differences in initial viral binding ability, rather than internalization, may explain the sensitivity differences seen in vitro.

Adenoviridae↗

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

The role of immunosuppression in the efficacy of cancer gene therapy using adenovirus transfer of the herpes simplex thymidine kinase gene.

OBJECTIVE: To determine whether the immune system limits or improves the therapeutic efficacy of an adenovirus vector expressing the herpes simplex thymidine kinase (HSVtk) gene in a subcutaneous tumor model. BACKGROUND DATA: Enhanced immune reactions against tumors may be therapeutically useful. However, recent studies with adenoviral vectors show that immune responses limit the efficacy and persistence of gene expression. The effect of the immune response on cancer gene therapy with HSVtk gene delivery by an adenovirus vector followed by treatment with ganciclovir is unclear. METHODS: After adenoviral transduction of a Fischer rat syngeneic mesothelioma cell line with the HSVtk gene in vitro, subcutaneous flank tumors were established. The ability of the HSVtk/ganciclovir system to inhibit tumor growth was compared among normal Fischer rats, immunodeficient nude rats, and Fischer rats immunosuppressed with cyclosporin. RESULTS: HSVtk/ganciclovir therapy was more effective in nude rats and immunosuppressed Fischer rats than in immunocompetent Fischer rats. CONCLUSION: These results indicate that the immune response against adenovirally transduced cells limits the efficacy of the HSVtk/ganciclovir system and that immunosuppression appears to be a useful adjunct. These findings have important implications for clinical trials using currently available adenovirus vectors as well as for future vector design.

Adenoviridae↗

PubMed1995

Gene therapy using adenovirus carrying the herpes simplex-thymidine kinase gene to treat in vivo models of human malignant mesothelioma and lung cancer.

Previous studies have shown adenoviral transfer of the herpes simplex virus thymidine kinase (HSVtk) gene followed by the anti-viral drug ganciclovir (GCV) can be used to successfully treat established human mesothelioma tumors growing within the peritoneal cavities of severe combined immune deficient (SCID) mice. These findings raised a number of questions important to the applicability, efficiency, and safety of this treatment strategy. In this report, we have further characterized the use of recombinant adenovirus carrying the HSVtk gene to treat mesothelioma and other localized malignancies. Our results indicate that the Ad.RSVtk/GCV system is effective in causing tumor regression in animals inoculated with another mesothelioma cell line and a lung cancer cell line and that animals with bulky disease can be successfully treated. Effects are seen at a wide range of virus doses and significant anti-tumor activity is present at doses of ganciclovir that are clinically achievable. Finally, this treatment approach appears safe, with limited dissemination of virus using a sensitive RT-PCR detection system. These studies further characterize the use of adenoviral transfer of the HSVtk gene to treat experimental mesothelioma and suggest that clinical trials using this approach may be feasible.

Adenocarcinoma↗

PubMedDate not supplied

The effect of promoter strength in adenoviral vectors containing herpes simplex virus thymidine kinase on cancer gene therapy in vitro and in vivo.

The use of adenoviral vectors to deliver the herpes simplex virus thymidine kinase (HSVtk) gene followed by treatment with the prodrug ganciclovir (GCV) has promise for a variety of applications where excess cell proliferation is detrimental such as treatment of tumors and vascular restenosis. Optimizing this system is thus an important goal. The purpose of this study was to determine if the induction of higher levels of HSVtk expression would augment the sensitivity to GCV. This was accomplished by generating adenoviral vectors that expressed HSVtk from promoters of different efficiencies (the CMV versus RSV promoters). Despite higher levels of HSVtk expression per cell with the CMV promoter, there was no significant enhancement of antitumor effects between RSV- and CMV-driven adenovirus vectors in in vitro and in vivo studies indicating that simply increasing HSVtk enzyme levels per cell above a minimal threshold level will not be effective in augmenting the HSVtk/GCV system. These results suggest that other strategies, e.g., the use of higher doses of GCV, augmentation of the "bystander effect," the generation of mutant HSVtk genes with higher substrate affinities, the discovery of improved vectors with increased transduction efficiencies, or the development of new prodrugs with higher affinities for HSVtk will therefore be needed to enhance therapeutic responses.

Adenoviridae↗