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R K Burt

Publications and source records attributed to R K Burt.

At least 55 records · Page 3Linked to original sources
PubMed1998

T cell-depleted autologous hematopoietic stem cell transplantation for multiple sclerosis: report on the first three patients.

Multiple sclerosis (MS) is a disease of the central nervous system characterized by immune-mediated destruction of myelin. In patients with progressive deterioration, we have intensified immunosuppression to the point of myeloablation. Subsequently, a new hematopoietic and immune system is generated by infusion of CD34-positive hematopoietic stem cells (HSC). Three patients with clinical MS and a decline of their Kurtzke extended disability status scale (EDSS) by 1.5 points over the 12 months preceding enrollment and a Kurtzke EDSS of 8.0 at the time of enrollment were treated with hematopoietic stem cell (HSC) transplantation using a myeloablative conditioning regimen of cyclophosphamide (120 mg/kg), methylprednisolone (4 g) and total body irradiation (1200 cGy). Reconstitution of hematopoiesis was achieved with CD34-enriched stem cells. The average time of follow-up is 8 months (range 6-10 months). Despite withdrawal of all immunosuppressive medications, functional improvements have occurred in all three patients. We conclude that T cell-depleted hematopoietic stem cell transplantation can be performed safely in patients with severe and debilitating multiple sclerosis. Stem cell transplantation has resulted in modest neurologic improvements for the first time since onset of progressive disease although no significant changes in EDSS or NRS scales are evident at this time.

Adult↗
PubMed1998

Adoptive immunotherapy after hematopoietic stem cell transplantation.

Adoptive immunotherapy may be performed with either autologous or allogeneic lymphocytes. Autologous cellular immunotherapy is hindered by the inability to break anergy or self-tolerance. Advances in this area have focused on the use of tumor-specific lymphocytes activated by antigen-pulsed or transgene modified dendritic cells. Allogeneic cellular immunotherapy is effective even with the use of non-specific and unactivated donor lymphocytes. Allogeneic cellular therapy is, however, complicated by graft-versus-host disease (GVHD). Advances in allogeneic immunotherapy will require better control of GVHD.

Hematopoietic Stem Cell Transplantation↗
PubMed1998

Hematopoietic stem cell therapy of autoimmune diseases.

Hematopoietic stem cell transplantation is a new therapy for severe autoimmune diseases. Patients who have failed standard therapies and are at high risk of subsequent morbidity and mortality are being considered as candidates. Early results are encouraging. However, the number of patients treated is limited, only short-term follow-up is available, the mechanism of improvement or stabilization is unknown, and the procedure has the potential for life-threatening toxicity.

Arthritis, Rheumatoid↗
PubMed1997

Immune ablation and hematopoietic stem cell rescue for severe autoimmune diseases (SADS).

In addition to our center (Northwestern University, Chicago), several institutions in the United States (Fred Hutchinson Cancer Center, University of California at Los Angeles, and Medical College of Wisconsin) and Europe are activating protocols to transplant patients with SADS. In this age of cost-effectiveness, it will be difficult to arrange third-party reimbursement for a hematopoietic stem cell transplant that may lead to medical charges of between $100,000 and $200,000. However, the cost of standard medical care for patients with SADS is not trivial. Dialysis for an SLE patient with renal failure costs $40,000 per year, while the medical resources required to care for a patient with progressive multiple sclerosis may exceed $35,000 per year. Unique BMT regimen-related toxicities may occur, including intracranial hemorrhage in the SLE or rheumatoid arthritis patient who has vasculitis; acute neurologic decompensation in patients with multiple sclerosis, especially if the conditioning regimen contains neurotoxic agents that cross a compromised blood-brain barrier; respiratory failure in patients with myasthenia gravis; and increased renal or pulmonary toxicity in patients with scleroderma and parenchymal fibrosis. Scleroderma-associated gastrointestinal dysmotility and bacterial overgrowth may also lead to greater fungal and bacterial infections [76]. BMT is currently considered appropriate therapy for patients with chronic-phase Chronic myelogenous leukemia (CML) and indolent lymphomas who otherwise have a relatively long life expectancy of 5 and 10 years, respectively. The roughly similar long survival but greater functional impairment of patients with SADS may justify consideration of immune ablation and hematopoietic stem cell rescue.

Animals↗
PubMed1997

BMT for severe autoimmune diseases: an idea whose time has come.

Most patients with autoimmune diseases are thought to have a a normal life expectancy, and thus are treated conservatively. However, these diseases have a diverse clinical course. A small subset of patients have "severe autoimmune diseases," or SADS, which are rapidly progressive and are associated with early mortality. If patients with SADS can be identified before they develop irreversible organ damage, aggressive intervention would be indicated. Consequently, patients with SADS are now being enrolled in experimental protocols of immune ablation and hematopoietic stem-cell rescue (ie, bone marrow transplantation [BMT] at several US institutions. For various reasons, including the high cost of BMT, it will probably be years before the benefits, if any, of this procedure are known.

Adult↗
PubMed1995

Syngeneic bone marrow transplantation eliminates V beta 8.2 T lymphocytes from the spinal cord of Lewis rats with experimental allergic encephalomyelitis.

Experimental allergic encephalomyelitis (EAE), an animal model for multiple sclerosis (MS), is a paralytic disease of the central nervous system (CNS) mediated by T-lymphocytes reactive to myelin basic protein (MBP). Lewis rats actively immunized with fragment 68 to 82 of guinea pig MBP develop a monophasic disease with spontaneous recovery. Lymphocyte recognition of the primary encephalitogenic sequence of MBP (fragment 68 to 82) is V beta 8.2 T cell receptor (TCR) skewed [1-3]. Lewis rats in clinical remission at 1 month and 3 months after spontaneous resolution of EAE retain V beta 8.2 T-lymphocytes in the CNS when analyzed by reverse transcriptase polymerase chain reaction or in situ hybridization. In contrast, 1 and 3 months after clinical remission from syngeneic bone marrow transplantation, V beta 8.2 T lymphocytes are absent from the CNS. During clinically active EAE and inflammatory breakdown of the blood-brain barrier, immune ablation and reconstitution with syngeneic bone marrow results in clinical tolerance of the new immune system to myelin.

Animals↗
PubMed1995

Bone marrow transplantation for multiple sclerosis.

Multiple sclerosis is the most common demyelinating neurologic disease. Animal studies from three separate institutions suggest that BMT may be beneficial. Of paramount concern is the risk to benefit ratio. However, for patients with progressive disease at onset, survival is similar to patients with indolent lymphomas; while for patients with malignant MS, survival is roughly equivalent to chronic phase CML. In addition, for these patients, life may become intolerable due to progressive pain and disability. The fate of such individuals may justify, in carefully selected patients and in a controlled investigational protocol, the risk of early mortality from BMT.

Animals↗
PubMed1992

Mental neuropathy (numb chin syndrome). A harbinger of tumor progression or relapse.

The authors report four patients whose initial symptom of tumor recurrence or progression was unilateral numbness of the chin. Two patients had Hodgkin lymphoma, one had malignant melanoma, and one had prostate cancer. Physical examination was notable only for unilateral anesthesia of the chin and lower lip. Diagnostic evaluation, including computed tomography (CT) scan and magnetic resonance imaging (MRI) of the brain, plain radiographs of the mandible, and cerebrospinal fluid analysis for protein, glucose, and cytology were normal. Bone scans revealed osseous lesions in the axial skeleton of all patients, whereas only two patients had abnormal uptake in the mandible. The authors conclude that in the setting of a negative evaluation for central nervous system (CNS) or local mandibular disease, mental neuropathy is associated with recurrent or progressive skeletal disease. In addition, to document relapsed or progressive cancer, the skeletal system may have to be examined at sites distant from the mandible.

Adult↗
PubMed1992

Cellular pattern of multidrug-resistance gene expression during chemical hepatocarcinogenesis in the rat.

Increased expression of multidrug-resistance (mdr) gene transcripts and of the encoded protein, P-glycoprotein, is found in many types of tumors. The biological significance of mdr overexpression during the stepwise process of neoplastic development, however, is not well understood. To assess the possible significance of mdr overexpression in carcinogenesis, we examined the cellular distributions of both mdr gene transcripts and P-glycoprotein during hepatocarcinogenesis induced in rats by the Solt-Farber protocol and then compared them to the distributions of the placental form of glutathione S-transferase (GST-P), a known marker of preneoplastic and neoplastic lesions in the liver. In situ hybridization and immunohistochemical techniques were employed. Neither mdr transcripts nor P-glycoprotein was expressed in oval cells that appeared early in the carcinogenic process. GST-P was strongly expressed in the early focal lesions, whereas the levels of mdr transcripts and P-glycoprotein expressed were low and heterogeneous. Expression of mdr transcripts and P-glycoprotein was increased and became more uniform in hyperplastic nodules and carcinomas, although considerable heterogeneity of expression was still found, particularly at the nodular stage. These data suggest that increased expression of mdr is associated with later stages of neoplastic development in the liver. Furthermore, that no chemical treatment of the animals was employed when the expression of mdr was increasing in the preneoplastic and neoplastic lesions suggests that the enhanced mdr expression is intrinsic to the carcinogenic process.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Regulation of 2-acetylaminofluorene-and 3-methylcholanthrene--mediated induction of multidrug resistance and cytochrome P450IA gene family expression in primary hepatocyte cultures and rat liver.

Previous studies by this laboratory have indicated that expression of the multidrug resistance (mdr) gene can be increased in vivo by exposure to a variety of xenobiotics. Because of the nature of these compounds, it was proposed that mdr gene expression might, at least in part, be regulated by the arylhydrocarbon (Ah) receptor. In the present study, we used a primary hepatocyte culture model to examine the relationship between induction of cytochrome P450IA and mdr expression in vitro. Both 3-methylcholanthrene (MC) and 2-acetylaminofluorene (AAF) were efficient inducers of mdr expression in this model. Induction of mdr gene expression by both MC and AAF obeyed a log10 concentration/response relationship. In contrast, 2,3,7,8-tetrachlorodibenzo-P-dioxin did not induce mdr expression at concentrations that yielded maximum induction of cytochrome P450IA expression. These data suggest that mdr induction was not mediated via the Ah receptor. Nuclear run-off analysis indicated that both AAF and MC induced mdr expression by increasing transcription. Primer extension analysis indicated that mdr gene transcription was initiated at one major site 151 bp upstream of the ATG site in both the uninduced and induced state in vivo and in vitro. The sequence of the primer and the site of initiation of gene transcription indicate that the main gene induced was the mdr 1b gene.

2-Acetylaminofluorene↗
PubMed1991

Antineoplastic drug resistance and DNA repair.

Important aspects of the DNA repair mechanisms in mammalian, and especially human, cells are reviewed. The DNA repair processes are essential in the maintenance of the integrity of the DNA and in the defense against cancer. It has recently been discovered that the DNA repair efficiency differs in different regions of the genome and that active genes are preferentially repaired. There is mounting evidence that DNA repair processes play a role in the development of drug resistance by tumor cells. We will discuss such data as well as further approaches to clarify the relationship between DNA repair and antineoplastic drug resistance. Specifically, there is an increasing need to investigate the intragenomic heterogeneity of DNA repair and correlate the repair efficiency in specific genes to aspects of drug resistance. We also discuss the therapeutic potential of inhibiting the DNA repair processes and thereby possibly overcoming drug resistance.

Antineoplastic Agents↗
PubMed1991

Gene-specific repair of DNA damage induced by UV irradiation and cancer chemotherapeutics.

DNA repair processes are critically important in the prevention of carcinogenesis, and currently much research is directed toward elucidation of the biochemical mechanisms by which DNA repair occurs. Techniques have been developed for examining individual genes to quantitate the lesions induced by various chemotherapeutic agents and to measure the rate of gene-specific DNA repair. In mammalian cells, the DNA repair response exhibits intragenomic heterogeneity-active genes are preferentially repaired and the transcribed strand of DNA is repaired more rapidly than the nontranscribed strand. These studies have provided new insight into the molecular biology of DNA repair and a new perspective on the role of repair processes in cellular resistance to DNA damage and malignancy. Elucidation of the mechanisms by which gene-specific lesions are formed and repaired will be important if we are to understand the fundamental processes of malignancy.

Animals↗
PubMed1990

Multidrug resistance due to P-glycoprotein.

P-glycoprotein is a cell membrane transport protein in various human tissues that acts as an efflux pump, apparently to protect normal cells from environmental toxins. It is also a mechanism used by some cancer cells to resist chemotherapy. The gene responsible for P-glycoprotein is partially defined. Agents that inhibit the protein in tumors may make chemotherapy more effective and less toxic.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Reversal of left ventricular dysfunction after renal transplantation.

We report the cases of four patients with end-stage renal disease and New York Heart Association class III or IV heart failure of nonischemic origin as documented by coronary angiography. Because of left ventricular dysfunction (left ventricular end-diastolic pressure, 23 to 30 mm Hg; ejection fraction, 20% to 35%), all four patients were initially considered poor surgical candidates for renal transplantation. These same four patients became asymptomatic, however, with markedly improved cardiac function (ejection fraction, 43% to 69%) detected as early as 6 and 14 days after renal engraftment. Therefore, there exists a subset of patients with end-stage renal disease in whom congestive heart failure should not be considered a contraindication to renal transplantation. We conclude that some dialysis-dependent patients who manifest symptomatic heart failure of nonischemic origin have a reversible cardiomyopathy and should not be denied renal transplantation.

Adult↗
PubMed1988

Coinduction of MDR-1 multidrug-resistance and cytochrome P-450 genes in rat liver by xenobiotics.

The levels of mRNA for multidrug-resistance (MDR-1) and selective cytochrome P-450 genes were determined in adult rat liver following administration of various natural and synthetic xenobiotics. MDR-1 (also known as PGY1) was induced following administration of aflatoxin B1, 2-(acetylamino)fluorene (AAF), N-hydroxy-2-(acetylamino)fluorene, isosafrole, phenothiazine, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), but not after phenobarbital or 7-hydroxy-2-(acetylamino)fluorene treatment. Cytochrome P-450 isoform d was induced by TCDD, isosafrole, phenothiazine, and AAF, while cytochrome P-450 isoform b was induced by phenobarbital, and to a lesser extent by isosafrole. These observations suggest that both MDR and cytochrome P-450 gene families are evolutionarily selected by the capacity of various xenobiotics to induce their own detoxification either through metabolism to hydrophilic derivatives by the cytochrome P-450 system or direct excretion from the cell by the MDR gene family. Furthermore, the data indicate that induction of selective members of the MDR and the cytochrome P-450 gene families may depend on overlapping regulatory elements.

2-Acetylaminofluorene↗
PubMed1988

Transformation of rat liver epithelial cells with v-H-ras or v-raf causes expression of MDR-1, glutathione-S-transferase-P and increased resistance to cytotoxic chemicals.

We have examined the relationship between transformation and multidrug resistance by employing the v-H-ras or v-raf oncogenes to transform rat liver epithelial (RLE) cells in vitro. The data indicate that transformation of RLE cells with v-H-ras or v-raf results in increased resistance to the cytotoxins adriamycin, vinblastine and 2-acetylaminofluorene. This multidrug resistance is accompanied by increasing expression of P-glycoprotein (MDR-1) and glutathione-S-transferase P (GST-P). Thus, neoplastic transformation of RLE cells with v-raf or v-H-ras, independently of chemical exposure, results in multidrug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗