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F Varricchio

Publications and source records attributed to F Varricchio.

At least 19 recordsLinked to original sources
PubMed2001

In situ expression of interleukin-4 (IL-4) receptors in human brain tumors and cytotoxicity of a recombinant IL-4 cytotoxin in primary glioblastoma cell cultures.

We have reported that human malignant glioma cell lines express high levels of plasma membrane interleukin-4 receptors (IL-4R). We have also reported that biopsy/surgical samples or primary explant cell cultures from brain tumors express mRNA and protein for the IL-4Ralpha chain, a primary IL-4-binding protein. However, whether IL-4R are expressed in brain tumors in situ has not been resolved. In addition, expression of IL-4R on the cell surface of various normal brain tissues is not known. We examined the expression of IL-4R by using a monoclonal antibody to the IL-4Ralpha chain (also known as IL-4R beta) in surgical/biopsy samples of brain tumor tissues by immunohistochemistry. Our data indicate that 15 of 18 glioblastoma multiforme (GBMs) tumors obtained from two different institutions and 12 other brain tumor samples are moderately to intensely positive for IL-4Ralpha. In contrast, although IL-4Ralpha mRNA was expressed, no IL-4R protein was detectable in two adult and one pediatric brain tissue specimens. In addition, a commercially available human neural tissue grid containing fixed tissues from various areas of brain showed no positive staining for the IL-4Ralpha chain. IL-4Ralpha expression was also demonstrated on astrocytoma grades I, II, and III. Because IL-4 cytotoxin comprised of a circularly permutated IL-4 and a mutated form of Pseudomonas exotoxin [IL4(38-37)-PE38KDEL] is cytotoxic to IL-4R-expressing cells, we tested whether primary GBM explant cell cultures are sensitive to IL-4 cytotoxin. Our data indicate that 13 of 15 GBM cell cultures were 25-74 times more sensitive to IL-4 cytotoxin compared with normal human astrocytes or the NT2 neuronal cell line. These observations indicate that human brain tumors in situ overexpress IL-4R compared with normal brain tissues, thus confirming our previous conclusions that IL-4R in brain tumors may serve as an attractive target for anticancer therapy.

Brain Neoplasms↗
PubMed2000

Intratumoral administration of recombinant circularly permuted interleukin-4-Pseudomonas exotoxin in patients with high-grade glioma.

Human glioblastoma but not normal brain cells express numerous receptors for the cytokine interleukin (IL)-4. To target these receptors, we have investigated the safety and activity of directly infusing IL-4(38-37)-PE38KDEL, a chimeric protein composed of circularly permuted IL-4 and a truncated form of Pseudomonas exotoxin (PE), into recurrent malignant high-grade gliomas. IL-4(38-37)-PE38KDEL (IL-4-toxin) was infused over a 4-8-day period into gliomas of nine patients by one to three stereotactically placed catheters. No apparent systemic toxicity occurred in any patient. The infusion of IL-4-toxin in six of nine patients showed glioma necrosis as evidenced by diminished gadolinium enhancement on magnetic resonance imaging. Seven of nine patients underwent craniotomy because of increased intracranial pressure at 16-101 days after the beginning of infusion. In six of these seven patients, partial-to-extensive tumor necrosis with edema was confirmed pathologically. No histological evidence of neurotoxicity to normal brain was identified in any patient. Two patients were not operated on; by magnetic resonance imaging, one showed mottled gadolinium enhancement, and the other showed extensive necrosis of tumor leading to complete remission; this patient remains disease-free > 18 months after the procedure. We conclude that direct glioma injection of IL-4(38-37)-PE38KDEL is safe without systemic toxicity. Local toxicity seemed attributable mainly to tumor necrosis or occasionally to the volume of infusion. Histological evidence of toxicity to normal brain was not observed and in many patients, could be pathologically excluded. Additional patients are being treated to determine the maximal tolerated concentration and volume of IL-4(38-37)-PE38KDEL.

Adult↗
PubMed1998

Interferon beta-1b injection site reactions and necroses.

We conducted a comprehensive review of selected adverse event reports that were submitted to the Food and Drug Administration (FDA) for interferon beta-1b during the first 30 months following licensure. The adverse events reviewed were injection site reactions, injection site necroses, and non-injection site necroses. These adverse events were selected because of the relative frequency of injection site reactions and because of the severity and sequelae of certain injection site and non-injection site necroses. Our review enabled us to characterize the clinical presentation and the treatment received, which were not described in the package insert or by the IFN beta (interferon beta-1b) Multiple Sclerosis Study Group publication. The time of onset of the adverse events ranged from 1-29 months after initiation of interferon beta-1b treatment, with a mean of 1 month. In general, the more clinically significant adverse events (i.e., injection site necrosis and non-injection site necrosis) developed more slowly than the injection site reactions. Greater than 85% of the adverse events presented with one or two signs/symptoms, although the number of signs/ symptoms ranged from 1-8. No predominance of treatments for the adverse events was observed. The most striking finding was that the overall sex ratio, which could be due to reporting artifacts, was 8.1:1 female:male.

Adjuvants, Immunologic↗
PubMed1997

Interleukin-4 receptor expression in vivo on human AIDS-related Kaposi's sarcoma.

We have investigated the expression of interleukin-4 receptors (IL-4R) in acquired immunodeficiency syndrome (AIDS)-related Kaposi's Sarcoma (KS) in situ by immunohistochemistry. Frozen and fixed sections from five patch stage and two nodular stage KS lesions were stained with anti-IL-4R monoclonal antibody with similar results. Skin biopsies from the clinically apparent lesions and adjacent clinically uninvolved skin were also examined. We observed that individual KS cells lining the irregular vascular spaces were stained with anti-IL-4R antibody, although the degree of staining was variable. The epithelioid and oval cells appear to stain more than the spindle cells in plaque stages or nodular lesions. The sections from nonclinically involved skin also contained a few cells with features of KS, singly or in clusters that also stained for IL-4R. Skin sections from four normal donors did not stain with IL-4R antibody except for hair follicles, sweat glands, and faint staining of blood vessels. KS sections were also stained with antibodies to basic fibroblast growth factor (FGF), S100, fibronectin, and von Willebrand factor. KS lesions from clinically involved and uninvolved skin sections were positive for all four antibodies. Thus, the differences between KS lesion and clinically uninvolved skin adjacent to a KS lesion may be more quantitative than qualitative. The IL-4 receptors on KS cells were functional as IL-4 modulated intercellular adhesion molecule 1 (ICAM-1) on these cells. Taken together, our results suggest that AIDS-KS cells express elevated levels of IL-4R compared to normal endothelial and skin cells and, thus, the receptors for IL-4 on KS may serve as an attractive target for anticancer therapy.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Detection of human herpesvirus 6 sequences in lymphoma tissues by immunohistochemistry and polymerase chain reactions.

We have analyzed one Hodgkin's and six non-Hodgkin's lymphomas for the presence of human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) DNA by polymerase chain reaction (PCR) and antigens by immunohistochemistry. A large cell B-cell lymphoma and a T-cell lymphoma were positive for HHV-6 antigens by immunohistochemistry. Using PCR primers from the HHV-6 ZVH14 transforming DNA segment, all seven tumors were positive. EBV DNA was not detected by PCR using sequences from EBV internal repeat-3 region as primers. The data suggest an etiologic involvement of HHV-6 in some human lymphomas. Although all seven of the lymphoma tissues examined contained HHV-6 DNA, expression of HHV-6 antigens was observed in only two cases, suggesting that expression of proteins was not required for transformation.

Adult↗
PubMed1994

Human herpesvirus-6-associated malignant lymphoma in a bone marrow transplant recipient.

BACKGROUND: Human herpesvirus-6 (HHV-6), the sixth member of the herpesvirus family, can infect and replicate in human hematopoetic cell lines and can cause various illnesses in humans. HHV-6 has been suggested to be linked to various lymhoproliferative disorders. In vitro studies have demonstrated the oncogenic potential of HHV-6. The role of HHV-6 in human lymphomas needs to be examined. OBJECTIVE: To determine the involvement of HHV-6 in an immunoblastic lymphoma which developed in a bone marrow transplant patient, who had HHV-6 viremia. STUDY DESIGN: Paraffin-embedded lymphoma tissues were examined for the presence of HHV-6 by immunohistochemistry, PCR and in-situ hybridization. This is a case report investigation. RESULTS: An acute myelogenous leukemia patient received an allogeneic bone marrow transplant. He developed human herpesvirus-6 (HHV-6) viremia approximately 6 weeks after transplantation and HHV-6 was concurrently isolated from his bone marrow. Soon afterward, a large cell immunoblastic lymphoma was diagnosed. Complications of this tumor subsequently resulted in the patient's death. Periaortic lymph nodes and tumor cells infiltrating the liver and kidneys showed the presence of HHV-6 by immunohistochemistry and polymerase chain reaction (PCR). Southern blot analysis of the PCR amplified DNAs confirmed the presence of transforming pZVH14 DNA sequences of HHV-6 in the tumor tissues. Lymph nodes of 6 immunologically intact individuals were negative for HHV-6 by immunohistochemistry and PCR analysis. Tumor tissues were negative for EBV DNA by in situ hybridization with DNA probes specific for the EBV EBER RNAs. CONCLUSION: Our data suggest that HHV-6 may be involved in the pathogenesis of some immunoblastic lymphomas.

Journal Article↗
PubMed1994

Expression of high-affinity IL-4 receptors on human melanoma, ovarian and breast carcinoma cells.

It has previously been shown that murine sarcoma cells express high-affinity IL-4 receptors (IL-4R) which are internalized after binding to the ligand (Puri et al., Cancer Res 1991; 51:3011-7). We have also reported that human renal cell carcinoma cells express high-affinity IL-4R, and IL-4 inhibits tumour growth in vitro (Obiri et al., J Clin Invest 1993; 91:88). In this study we investigated the expression and function of IL-4R on other human solid tumours. Human melanoma, ovarian carcinoma and breast carcinoma cell lines were assessed for the cell surface expression of IL-4R by radio-ligand receptor binding and for IL-4R gene expression by Northern blot analysis. Primary cultures of mesothelioma and neurofibrosarcoma cells were similarly investigated. Human melanoma, ovarian carcinoma and breast carcinoma cell lines expressed IL-4R on their cell surface with a dissociation constant (Kd) of 140-549 pM. These tumour lines expressed a single 4 kb species of mRNA for IL-4R. Similarly, primary cultures of mesothelioma and neurofibrosarcoma cells were positive for the IL-4R mRNA by Northern blot analysis. Fresh, non-cultured mesothelioma and neurofibrosarcoma tumour sections were also positive for the presence of IL-4R as determined by immunohistochemistry of frozen sections using anti-IL-4R antibody. In order to study possible functions of IL-4R, we evaluated the effects of IL-4 on cell growth and its effect on MHC antigen expression in the presence or absence of interferon-gamma (IFN-gamma). In tissue culture, IL-4 reduced the growth of tumour cell lines and primary cell cultures studied. IL-4 had very little effect on MHC class I antigen expression on ovarian, breast and melanoma cell lines; however, MHC class II (HLA-DR) expression was enhanced on melanoma and breast carcinoma cells. IL-4 also enhanced the IFN-gamma-induced class II expression on melanoma and breast carcinoma cells. Taken together, our observations indicate that IL-4R are expressed on a variety of human solid tumours and these receptors may be functional. IL-4 alone and in combination with IFN-gamma may play a role in host immune response against cancers.

Breast Neoplasms↗
PubMed1993

Immunostaining of interleukin-4 receptor on human renal cell carcinoma.

Immunocytochemistry on three primary cultures of RCC tumor cells and immunohistochemistry on five frozen sections of RCC were performed by utilizing a monoclonal antibody (M-57) to human IL-4R. We found that all three RCC tumor cell cytospin preparations stained with anti-IL-4R monoclonal antibody. Tumor cells stained with IgG control did not show any staining. Similarly, five histologically proven RCC frozen sections prepared from nephrectomy specimens had moderate to intense immunoreactivity to IL-4 receptor antibody. RCC sections stained with normal mouse IgG2b showed only background type staining. Frozen section prepared from uninvolved kidney showed only nonspecific staining. A flow cytometric analysis of primary cultures of RCC tumor cells confirmed the immunohistochemical data and showed that almost all of the cells were positive for IL-4 receptor expression. These results demonstrate that human RCC express immunoreactive IL-4 receptors, which may be a target for diagnosis and therapy by an anti-IL-4 receptor antibody fused to toxins or radionuclides or alternatively by IL-4 toxins.

Animals↗
PubMed1992

Comparison of supernatant-and ribosome-bound rat liver tRNA.

Transfer RNAs were separated into a ribosome bound fraction and a supernatant (cytoplasmic) fraction. The nucleoside composition, 2-dimensional PAGE pattern and in vivo labeling were compared. 12 minor nucleosides were identified by HPLC. In general, the minor nucleosides, especially N2-methyl-guanidine and ribothymidine, were higher in the ribosome-bound fraction. The PAGE patterns were similar but there were quantitative and qualitative differences among the smaller spots. In vivo labeling by 32P showed that new tRNA goes preferentially to the ribosome but mixing does occur. The results suggest the existence of two compartments of tRNA.

Animals↗
PubMed1982

The aminoacyl-tRNA population of human reticulocytes.

The aminoacyl-tRNA population of human reticulocytes has been examined. These studies include: 1) determination of the levels of amino acid acceptance for 20 aminoacyl-tRNAs; 2) comparison of 20 aminoacyl-tRNAs from human reticulocytes to those of rabbit reticulocytes by reverse phase chromatography; 3) comparison of the levels of Ile- and Leu-tRNAs in fetal and adult reticulocytes; and 4) determination of the codon recognition properties of human Ala-, Asn-, His-, Leu-, Thr-, and Val-tRNAs. These studies provide evidence that the aminoacyl-tRNA population of human reticulocytes is adapted to the requirements of protein synthesis.

Adult↗