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Biomedical subjects

Karoly Toth

Publications and source records attributed to Karoly Toth.

14 recordsLinked to original sources
PubMed2006

A Phase I study of weekly intravenous oxaliplatin in combination with oral daily capecitabine and radiation therapy in the neoadjuvant treatment of rectal adenocarcinoma.

PURPOSE: We conducted a Phase I study to determine the maximum tolerated dose (MTD) of neoadjuvant capecitabine, oxaliplatin, and radiation therapy (RT) in Stage II to III rectal adenocarcinoma. METHODS AND MATERIALS: Capecitabine was given orally twice daily Monday through Friday concurrently with RT. Oxaliplatin was given i.v. once weekly x 5 (for 5 weeks) starting the first day of RT. RT was given daily except on weekends and holidays at 1.8 Gy per fraction x 28. Escalation for capecitabine or oxaliplatin was to occur in cohorts of three patients until the maximum tolerated dose (MTD) was defined. Endorectal tumor biopsy samples were obtained before and on Day 3 of treatment to explore the effects of treatment on thymidine phosphorylase, thymidylate synthase, dihydropyrimidine dehydrogenase, DNA repair, and apoptosis. RESULTS: Twelve patients were enrolled on this study. Two of 6 patients at dose level (DL) 1 (capecitabine 825 mg/m2 orally (p.o.) given twice daily (b.i.d.); oxaliplatin 50 mg/m2/week) had a dose-limiting diarrhea. One of 6 patients at DL (-)1 (capecitabine 725 mg/m2 p.o., b.i.d.; oxaliplatin 50 mg/m2/week) experienced-dose-limiting diarrhea. Three of 11 patients who underwent resection had a complete pathologic response. No remarkable variations in rectal tumor biologic endpoints were noted on Day 3 of treatment in comparison to baseline. However, a higher apotosis index was observed at baseline and on Day 3 in complete pathologic responders (no statistical analysis performed). CONCLUSIONS: Capecitabine 725 mg/m2 p.o., twice daily in combination with oxaliplatin 50 mg/m2/week and RT 50.4 Gy in 28 fractions is the recommended dose for future studies.

Administration, Oral↗
PubMed2006

Syrian hamster as a permissive immunocompetent animal model for the study of oncolytic adenovirus vectors.

Oncolytic adenoviruses represent an innovative approach to cancer therapy. These vectors are typically evaluated in immunodeficient mice with human xenograft tumors. However, in addition to being immunodeficient, this model is limited because normal and cancerous mouse tissues are poorly permissive for human adenovirus replication. This prompted us to search for a model that more accurately reflects the use of oncolytic adenoviruses in cancer patients. To this end, we developed a novel Syrian hamster model that is both immunocompetent and replication-permissive. We found that human adenovirus replicates well in Syrian hamster cell lines and confirmed replication in the lungs. Oncolytic adenovirus injection showed efficacy in three different hamster tumor models. Furthermore, i.t. oncolytic adenovirus injection resulted in suppression of primary and metastatic lesions, i.t. replication and necrosis, vector entrance into the bloodstream, replication in the liver and lungs, and anti-adenovirus antibody induction. Our findings show that the Syrian hamster is a promising immunocompetent model that is permissive to human adenovirus replication in tumors as well as normal tissues. Therefore, the Syrian hamster model may become a valuable tool for the field of oncolytic adenovirus vectors in which vector safety and efficacy can be evaluated.

Adenoviruses, Human↗
PubMed2005

Adenovirus immunoregulatory E3 proteins prolong transplants of human cells in immunocompetent mice.

The majority of proteins encoded in the early 3 (E3) region of human subgroup C adenoviruses function to modulate the host immune response. For example, gp19K, one of these E3 proteins, prevents the major histocompatibility complex type I (MHC-I) from presenting viral antigens on the surface of the infected cell. Other E3 proteins, such as the RID and 14.7K proteins, counteract the effector phase of the cellular immune response. In order to study further the effects of these proteins, we constructed an E1-/E3- adenovirus vector, Ad/E3, that contains all the E3 genes with the exception of the cytolytic adp gene, inserted into the deleted E1 region. The transcription of the E3 genes in this vector is driven by a CMV promoter in place of the native E3 promoter. Ad/E3 expressed close to wild-type adenovirus levels of all E3 proteins, and these proteins appear to function normally in cell culture. For example, in Ad/E3-infected cells, surface expression of MHC-I was down-regulated, as was cell surface display of death receptors Fas and TRAIL Receptor 1. A human cell line of lung origin (A549), which was rapidly rejected after transplantation into C57BL/6 mice, was protected for an extended time from the host immune response after infection with an Ad/E3, and went through a number of divisions in immunocompetent mice. These latter results indicate that the E3 proteins protect cells from destruction by the immune system.

Adenovirus E3 Proteins↗
PubMed2005

Cotton rat tumor model for the evaluation of oncolytic adenoviruses.

Oncolytic human adenovirus (Ad) vectors exert their antitumor effect by replicating in and lysing tumor cells. These vectors are commonly evaluated in immunodeficient mice bearing human tumor xenografts. However, this model suffers because the mice are immunodeficient and are not permissive for human Ads. We have developed a cotton rat model to test the selectivity, immunogenicity, and efficacy of oncolytic Ad vectors. The cotton rat is a rodent species that is semipermissive for human Ads. We show that the cotton cancer rat cell line LCRT supports the replication of human Ad in tissue culture and that the cells are destroyed on virus replication. When injected subcutaneously, LCRT cells formed tumors in immunocompetent cotton rats, and the growth of these tumors was delayed by the injection of an oncolytic Ad vector. Replication of the Ad vector in the tumor was demonstrated by sampling tumor tissue and isolating infectious virus particles at various times after intratumoral injection of the virus. We propose that the cotton rat can be used as an animal model to evaluate oncolytic Ad vectors.

Adenovirus Infections, Human↗
PubMed2004

An oncolytic adenovirus vector combining enhanced cell-to-cell spreading, mediated by the ADP cytolytic protein, with selective replication in cancer cells with deregulated wnt signaling.

We have constructed a novel oncolytic adenovirus (Ad) vector named VRX-009 that combines enhanced cell spread with tumor-specific replication. Enhanced spread, which could significantly increase antitumor efficacy, is mediated by overexpression of the Ad cytolytic protein named ADP (also known as E3-11.6K). Replication of VRX-009 is restricted to cells with a deregulated wnt signal transduction pathway by replacement of the wild-type Ad E4 promoter with a synthetic promoter consisting of five consensus binding sites for the T-cell factor transcription factor. Tumor-selective replication is indicated by several lines of evidence. VRX-009 expresses E4ORF3, a representative Ad E4 protein, only in colon cancer cell lines. Furthermore, VRX-009 replicates preferentially in colon cancer cell lines as evidenced by virus productivity 2 orders of magnitude higher in SW480 colon cancer cells than in A549 lung cancer cells. Replication in primary human bronchial epithelial cells and human umbilical vein endothelial cells was also significantly lower than in SW480 cells. When tested in human tumor xenografts in nude mice, VRX-009 effectively suppressed the growth of SW480 colon tumors but not of A549 lung tumors. VRX-009 may provide greater level of antitumor efficacy than standard oncolytic Ad vectors in tumors in which a defect in wnt signaling increases the level of nuclear beta-catenin.

Adenoviridae↗
PubMed2004

Adenovirus E3-6.7K protein is required in conjunction with the E3-RID protein complex for the internalization and degradation of TRAIL receptor 2.

Adenoviruses (Ads) encode several proteins within the early region 3 (E3) transcription unit that help protect infected cells from elimination by the immune system. Among these immunomodulatory proteins, the receptor internalization and degradation (RID) protein complex, which is composed of the RIDalpha (formerly E3-10.4K) and RIDbeta (formerly E3-14.5K) subunits, stimulates the internalization and degradation of certain members of the tumor necrosis factor (TNF) receptor superfamily, thus blocking apoptosis initiated by Fas and TNF-related apoptosis-inducing ligand (TRAIL). The experiments reported here show that TRAIL receptor 2 (TR2) is cleared from the cell surface in Ad-infected cells. Virus mutants containing deletions that span E3 were used to show that the RID and E3-6.7K proteins are both necessary for the internalization and degradation of TR2, whereas only the RID protein is required for TRAIL receptor 1 downregulation. In addition, replication-defective Ad vectors that express individual E3 proteins were used to establish that the RID and E3-6.7K proteins are sufficient to clear TR2. These data demonstrate that E3-6.7K is an important component of the antiapoptosis arsenal encoded by the E3 transcription unit of subgroup C Ads.

Adenovirus E3 Proteins↗
PubMed2003

Overexpression of the ADP (E3-11.6K) protein increases cell lysis and spread of adenovirus.

Adenoviruses replicate in the nucleus and induce lytic cell death. We have shown previously that efficient cell lysis and release of adenovirus from infected cells requires an 11.6-kDa protein named Adenovirus Death Protein (ADP). The adp gene is located in the early E3 transcription unit, but the gene is expressed primarily at very late stages of infection. The putative function of ADP was discerned previously from the use of virus mutants that lack functional ADP. Here we describe two adenovirus mutants, named VRX-006 and VRX-007, that overexpress ADP. VRX-006 lacks all other genes in the E3 region, and VRX-007 lacks all other E3 genes except 12.5K. VRX-006 and VRX-007 display the phenotype predicted by the proposed function for ADP: they produce early cytopathic effect, early cell lysis, large plaques, and increased cell-to-cell spread. They grow as well in cultured cells as does adenovirus type 5. These results are consistent with the conclusion that ADP functions in adenovirus infections to promote virus release from cells at the culmination of infection.

Adenoviridae↗
PubMed2003

Radiation increases the activity of oncolytic adenovirus cancer gene therapy vectors that overexpress the ADP (E3-11.6K) protein.

We have described three potential adenovirus type 5 (Ad5)-based replication-competent cancer gene therapy vectors named KD1, KD3, and VRX-007. All three vectors overexpress an Ad5 protein named Adenovirus Death Protein (ADP, also named E3-11.6 K protein). ADP is required for efficient lysis of Ad5-infected cells and spread of virus from cell to cell, and thus its overexpression increases the oncolytic activity of the vectors. KD1 and KD3 contain mutations in the Ad5 E1A gene that knock out binding of the E1A proteins to cellular p300/CBP and pRB; these mutations allow KD1 and KD3 to grow well in cancer cells but not in normal cells. VRX-007 has wild-type E1A. Here we report that radiation increases the oncolytic activity of KD1, KD3, and VRX-007. This increased activity was observed in cultured cells, and it was not because of radiation-induced replication of the vectors. The combination of radiation plus KD3 suppressed the growth of A549 lung adenocarcinoma xenografts in nude mice more efficiently than radiation alone or KD3 alone. The combination of ADP-overexpressing vectors and radiation may have potential in treating cancer.

Adenoviridae↗
PubMed2002

Construction and characterization of E1-minus replication-defective adenovirus vectors that express E3 proteins from the E1 region.

Previous research has indicated that the adenovirus protein complex named RID, derived from the E3 transcription unit, functions to remove the receptors named Fas/Apo1/CD95 (Fas) and epidermal growth factor receptor (EGFR) from the surface of cells. (The RID complex is composed of the RIDalpha and RIDbeta polypeptides, previously named 10.4K and 14.5K, respectively.) In response to RID, Fas and EGFR appear to be internalized into endosomes and degraded in lysosomes. Fas is a death receptor in the tumor necrosis factor (TNF) receptor superfamily. RID inhibits apoptosis via the Fas pathway, presumably because RID gets rid of Fas. Earlier work further showed that another adenovirus E3-coded protein, E3-14.7K, inhibits apoptosis induced by TNF. Most of the above studies have been conducted using viable virus mutants that lack one or more of the genes for RID, E3-14.7K, or E1B-19K (this protein, coded by the E1B transcription unit, also inhibits apoptosis via the TNF and Fas pathways). Some studies have also been conducted with the genes for RID or E3-14.7K transiently or stably transfected into cells. We now report a new approach to studying the E3 genes. We have constructed four E1-minus replication-defective vectors that have all the E3 genes deleted from their natural position and then reinserted, in different permutations, into the deleted E1 region under control of the cytomegalovirus immediate early promoter. Vector Ad/RID only has the genes for RIDalpha and RIDbeta. Vector Ad/14.7K only has the gene for E3-14.7K. Vector Ad/RID/14.7K only has the genes for RIDalpha, RIDbeta, and E3-14.7K. Vector Ad/E3 has all E3 genes, but there are two missense mutations in the gene for Adenovirus Death Protein. These vectors expressed RID and/or E3-14.7K, as expected. The RID-expressing vectors forced the internalization and degradation of Fas and EGFR, and they inhibited apoptosis induced through the Fas pathway. These vectors should be useful reagents to study the E3 proteins.

Adenoviridae↗
PubMed2002

HEK? No!

Explore the source record for details and available documents.

Adenoviridae↗
PubMed2002

Adenovirus replication-competent vectors (KD1, KD3) complement the cytotoxicity and transgene expression from replication-defective vectors (Ad-GFP, Ad-Luc).

The successful clinical application of adenovirus (Ad) in cancer control has been of limited success because of the current inability to infect the majority of cancer cells with a large amount of vector. In this study, we show that when human lung tumors growing in immunodeficient nude mice were coinfected with a replication-defective (RD) Ad vector expressing green fluorescent protein and a replication-competent (RC) Ad vector named KD3, KD3 enhanced the expression of green fluorescent protein throughout the tumor. Also, KD3 and another RC vector named KD1 complemented the expression of luciferase from a RD vector in a human liver tumor xenotransplant in nude mice. Altogether, these results suggest that the combination of a RD vector with a RC vector might be a more effective treatment for cancer than either vector alone due to more widespread dissemination of the virus.

Adenoviridae↗
PubMed2002

[Morning glory syndrome -- a clinical study of two cases].

BACKGROUND: Handmann was the first to describe the morning glory syndrome in 6 cases in 1929. In 1970 Kindler published some cases with an "unusual congenital anomaly of the optic disc". Since then, several authors have come to the conclusion that both authors described the same disease. PATIENTS AND METHODS: In January 2000, morning glory syndrome was diagnosed in two patients, mother and daughter. Ophthalmological and electrophysiological examinations, further brain scan and magnetic resonance imaging (MRI) of the orbit were performed. RESULTS: Malformation of the optic disc was bilateral in both cases. Optic disc abnormality was accompanied by no other anomalies or malformations. Ultrasound examination and MRI of the orbit did not detect posterior staphyloma in our cases. Thus, our two patients are the first to be described in the literature, where the anomaly of the optic disc occurred in isolation. DISCUSSION: Our cases are different from those described in the literature as far as the characteristic anomaly of the optic disc was bilateral and the occurrence was genetical. It is also noteworthy that no other ophthalmological or general malformations could be detected in our patients besides the anomaly of the optic disc. Morning glory syndrome occurred in isolation, which makes our cases unique.

Adolescent↗
PubMedDate not supplied

Functions and mechanisms of action of the adenovirus E3 proteins.

In the evolutionary battle between viruses and their hosts, viruses have armed themselves with weapons to defeat the host's attacks on infected cells. Various proteins encoded in the adenovirus (Ad) E3 transcription unit protect cells from killing mediated by cytotoxic T cells and death-inducing cytokines such as tumor necrosis factor (TNF), Fas ligand, and TNF-related apoptosis-inducing ligand (TRAIL). The viral protein E3-gp19 K blocks MHC class-I-restricted antigen presentation, which diminishes killing by cytotoxic T cells. The receptor internalization and degradation (RID) complex (formerly E3-10.4 K/14.5 K) stimulates the clearance from the cell surface and subsequent degradation of the receptors for Fas ligand and TRAIL, thereby preventing the action of these important immune mediators. RID also downmodulates the epidermal growth factor receptor (EGFR), although what role, if any, this function has in immune regulation is uncertain. In addition, RID antagonizes TNF-mediated apoptosis and inflammation through a mechanism that does not primarily involve receptor downregulation. E3-6.7 K functions together with RID in downregulating some TRAIL receptors and may block apoptosis independently of other E3 proteins. Furthermore, E3-14.7 K functions as a general inhibitor of TNF-mediated apoptosis and blocks TRAIL-induced apoptosis. Finally, after expending great effort to maintain cell viability during the early part of the virus replication cycle, Ads lyse the cell to allow efficient virus release and dissemination. To perform this task subgroup C Ads synthesize a protein late in infection named ADP (formerly E3-11.6 K) that is required for efficient virus release. This review focuses on recent experiments aimed at discovering the mechanism of action of these critically important viral proteins.

Adenoviridae↗