Update of alpha fetoprotein growth-inhibitory peptides as biotherapeutic agents for tumor growth and metastasis.

The present update describes the biological activities of an alpha fetoprotein (AFP)-derived peptide termed the growth-inhibitory peptide (GIP), which is a synthetic 34-amino acid segment produced from the native molecule. The GIP has been shown to be growth-suppressive in both fetal and tumor cells but not in adult cells. Even though its mechanism of action has not been completely elucidated, GIP has been shown to engage in cellular events such as endocytosis, cellular aggregation, hemagglution, and cytoskeleton-induced cell shape changes.

Review of Growth Inhibitory Peptide as a biotherapeutic agent for tumor growth, adhesion, and metastasis.

This review surveys the biological activities of an alpha-fetoprotein (AFP) derived peptide termed the Growth Inhibitory Peptide (GIP), which is a synthetic 34 amino acid segment produced from the full length 590 amino acid AFP molecule. The GIP has been shown to be growth-suppressive in both fetal and tumor cells but not in adult terminally-differentiated cells. The mechanism of action of this peptide has not been fully elucidated; however, GIP is highly interactive at the plasma membrane surface in cellular events such as endocytosis, cell contact inhibition and cytoskeleton-induced cell shape changes.

Anti-prostate cancer and anti-breast cancer activities of two peptides derived from alpha-fetoprotein.

A chemically synthesized 34-amino-acid peptide and a select analog have been studied to determine their activities against the growth of prostate and breast cancer tumors. It was of interest to determine if the peptide has anti-prostate cancer activity. Previously, the peptide was shown to inhibit the growth of breast cancer tumor cells.

Luminescence applications for chemotherapeutic drug development.

The application of in vitro and in vivo ATP bioluminescence systems as an integrated approach for preclinical research and development of new chemotherapeutic drugs is described. This approach includes both (a) the in vitro tumor response assay (TRA) system that utilizes new technologies for cell culture and ATP measurement of clinical specimens and (b) the use of human tumor cell lines transfected with Photinus pyralis luciferase (luc) gene for both in vitro and in vivo studies. Dried reagent microplates for TRA culture and counting procedures are described for a two-stage TRA method, which can be used to evaluate drug sensitivity and resistance of cells from clinical specimens after initial drug exposure in vitro.

Human alpha-fetoprotein contains potential heterodimerization motifs capable of interaction with nuclear receptors and transcription/growth factors.

Alpha-fetoprotein (AFP) serum levels in man have long been utilized as a tumor marker and as a birth defect screening agent in the clinical laboratory. Although the physiological role of AFP has remained obscure, the stereotypic carrier/transport function of a fetal counterpart to albumin has been attributed to this oncofetal protein. However, reports from a multitude of investigators in the last decade have provided a rationale to reconsider and extend the biological role of AFP to include cell growth modulation during development.

Five-chlorodeoxycytidine, a tumor-selective enzyme-driven radiosensitizer, effectively controls five advanced human tumors in nude mice.

Purpose: The study's goals were as follows: (1) to extend our past findings with rodent tumors to human tumors in nude mice, (2) to determine if the drug protocol could be simplified so that only CldC and one modulator, tetrahydrouridine (H4U), would be sufficient to obtain efficacy, (3) to determine the levels of deoxycytidine kinase and dCMP deaminase in human tumors, compared to adjacent normal tissue, and (4) to determine the effect of CldC on normal tissue radiation damage to the cervical spinal cord of nude mice.

Methods And Materials: The five human tumors used were as follows: prostate tumors, PC-3 and H-1579; glioblastoma, SF-295; breast tumor, GI-101; and lung tumor, H-165. The duration of treatment was 3-5 weeks, with drugs administered on Days 1-4 and radiation on Days 3-5 of each week.

IRIDIUM exposure increases c-fos expression in the mouse brain only at levels which likely result in tissue heating.

With the rapid development of wireless communication technology over the last 20 years, there has been some public concern over possible health effects of long-term, low-level radiofrequency exposure from cellular telephones. As an initial step in compiling a database for risk analysis by government agencies, the effects of 1-h exposure of mice to a 1.6-GHz radiofrequency signal, given as either a continuous wave or pulse modulated at 11 Hz with a duty cycle of 4:1 and a pulse duration of 9.

Delayed type hypersensitivity in patients with rheumatoid arthritis.

Our study examines the relationship between in vivo delayed type hypersensitivity (DTH) and clinical and laboratory variables associated with rheumatoid arthritis (RA). Eleven patients with RA were examined. They were receiving no disease modifying drugs, immunosuppressive agents or corticosteroids.

Signal transduction in Sjögren's syndrome T cells. Abnormalities associated with a newly described human A-type retrovirus.

Objective: To study the effects of a novel A-type retrovirus, detected in cocultures of lip biopsy specimens from Sjögren's syndrome (SS) patients and a human T cell line, on the infected T cells.

Methods: Interleukin-2 (IL-2) and IL-6 secretion were measured by bioassay and enzyme-linked immunosorbent assay, respectively, in the infected and noninfected cell lines. Surface antigen expression was determined by flow cytometry, using monoclonal antibodies.

Detection of serum antibodies to retroviral proteins in patients with primary Sjögren's syndrome (autoimmune exocrinopathy).

Primary Sjögren's syndrome (SS) is considered a benign autoimmune disease; it is characterized by lymphoid infiltration of salivary and lacrimal glands, often accompanied by the presence of serum autoantibodies, particularly anti-Ro (SS-A) and anti-La (SS-B). There are important immunologic similarities between primary SS and acquired immunodeficiency syndrome. To investigate for a possible immune response to retroviral proteins in primary SS, we performed immunoblotting against human immunodeficiency virus-1 (HIV-1) proteins using sera from 47 patients with primary SS.

A conserved idiotype and antibodies to retroviral proteins in systemic lupus erythematosus.

22 of 61 systemic lupus erythematosus (SLE) patients produced antibodies to the p24 gag protein of HIV-1 demonstrated by Western blotting. 20 of these 22 patients (91%) also express the 4B4 idiotype (Id 4B4) previously identified on a human anti-Sm monoclonal antibody called 4B4. This represents an enrichment for this Id (seen in only 52% of SLE patients generally).

Anti-peptide antibodies detect a lupus-related interspecies idiotype that maps to H chain CDR2.

Antibodies to the small nucleoprotein Sm occur spontaneously in human and murine systemic lupus erythematosus. Human and mouse monoclonal anti-Sm autoantibodies designated 4B4 and Y2 share an idiotype (Id) determinant located on the Ig H chain. To understand the molecular basis of this cross-reactivity, the VH regions of both antibodies were sequenced and analyzed for homology.

Characterization of the IL-2-receptor on rheumatoid arthritis synovial fluid T cells.

We studied the hypoproliferative response of synovial fluid (SF) T cells in rheumatoid arthritis (RA) using a mitogenic monoclonal antibody (MoAb) specific for the T-cell antigen receptor-associated CD3 complex. RASF T cells are defective in their proliferative response and in the induction of the Tac (p55) component of the IL-2-receptor (IL-2-R) when stimulated with anti-CD3 monoclonal antibody (MoAb). However, fresh RASF T cells bear demonstrable IL-2-R in cross-linking experiments which are not seen in unstimulated peripheral blood (PB).

Autostimulatory growth factors produced by Sjögren's syndrome B cell lines.

Sjögren's syndrome (SS) is a systemic autoimmune disorder characterized by polyclonal hypergammaglobulinemia, autoantibody formation, and intense tissue infiltration by lymphoid and plasma cells. These patients have a predisposition to the development of monoclonal immunoglobulins and B cell lymphomas. To study the role of B cells in this disease, we established B cell lines from three patients with benign primary SS.

Autostimulatory factor produced by B-cell lines from patients with Sjögren's syndrome.

Sjögren's syndrome (SS) is an autoimmune disease with a predisposition to transform into a B-cell lymphoma. Stable B-cell lines were established (without exogenous stimulation other than fetal bovine serum) from the peripheral blood of three SS patients. These cell lines secreted immunoglobulin (either IgG, IgM or both) and expressed cytoplasmic immunoglobulin.

Estrogen induces normal murine CD5+ B cells to produce autoantibodies.

Females have better humoral immune responses and are more susceptible to autoimmune diseases than males. Normal female mice (C57BL/6J, C3H/HeJ, and NZW) have significantly increased spontaneous autoimmune plaque-forming cells (APFC) to mouse erythrocytes pretreated with bromelain (Br-ME) in spleen, peritoneal exudate cell, and bone marrow compared to their male counterparts. A minor subpopulation of B cells, CD5+ B, is thought to produce this autoantibody.

The expression and function of CD3 and CD5 in patients with primary Sjögren's syndrome.

We studied the expression and function of 2 cell surface markers that induce T cell activation, CD3 and CD5, in 19 patients with primary Sjögren's syndrome (SS). The expression of CD3+ lymphocytes was normal, but CD3 function was moderately reduced, as measured by anti-CD3-induced T cell proliferation. Anti-CD3-induced stimulation of T cell help for Ig production and non-major histocompatibility complex-restricted (natural) killing were normal.

Synergistic interaction between anti-CD3 and IL-2 demonstrated by proliferative response, interferon production, and non-MHC-restricted killing.

Anti-CD3 monoclonal antibody acts on normal peripheral blood mononuclear cells to induce T cell proliferation, interferon-gamma production, and non-MHC-restricted cytotoxicity against both NK (CD16+)-sensitive and -resistant target cells. Moreover, anti-CD3 and interleukin 2 (IL-2) act synergistically to give greater proliferative, interferon-gamma (IFN-gamma), and natural cytotoxicity responses than those expected by the simple addition of the individual responses to each stimulus acting alone. This synergistic response is macrophage independent, greatest at low concentrations of anti-CD3, inhibited by anti-IL2 receptor, and depends upon the induction of IL-2 receptors by CD3 activation which are then available to respond to exogenously added IL-2.

Defective induction of T-cell help and natural killing following anti-CD3 stimulation of autoimmune lymphocytes.

Anti-CD3 monoclonal antibody (MoAb) stimulates T cells in normal peripheral blood to proliferate and develop cytotoxic activity against NK-sensitive tumor cell lines. We now find that anti-CD3 MoAb also generates cytotoxic activity against a cell line (MEL-21) resistant to classical NK cell killing. After activation in vitro with anti-CD3 MoAb for 18 h, normal peripheral blood mononuclear cells (PBMNC) develop more HLA-DR-positive helper than suppressor T cells, manifest a functional helper effect as measured by increased IgG synthesis (P less than 0.

B cells expressing CD5 are increased in Sjögren's syndrome.

In this investigation of B cells expressing the CD5 (Leu-1) cell surface marker, we found increased numbers of these cells in 13 of 19 patients with primary Sjögren's syndrome (SS) (68%), as well as in the rheumatoid arthritis patients. The percentage of B cells that demonstrated increased expression of CD5 was 46% in SS patients, 47% in rheumatoid arthritis patients, 24% in systemic lupus erythematosus patients, and 26% in normal subjects. Over a 2-year period, CD5 expression on B cells was a stable finding in several patients, except for 2 who required either steroid therapy or combined chemotherapy and irradiation for malignant lymphoma.

Abnormalities of T cell activation in the rheumatoid synovium detected with monoclonal antibodies to CD3.

The chronic inflammation of rheumatoid arthritis (RA) is associated with hypofunction of synovial fluid (SF) T cells. We studied the mechanisms leading to this abnormality using a mitogenic monoclonal antibody specific for the T cell receptor-associated CD3 complex. We found that SF cells are defective in their response to anti-CD3 antibodies as measured by proliferation, generation of natural cytotoxicity, and induction of the Tac (p55) component of the IL2 receptor.

A shared B-T cell phenotype in autoimmune mice bearing the lpr gene.

MRL-lpr mice and MRL-+/+ mice are identical except for the presence of an autosomal recessive lymphoproliferation gene (designated lpr) in the former. Mice bearing the lpr gene develop autoimmune and lymphoproliferative abnormalities. An antigenic marker designated 14D10, characteristically expressed on the surface of Lyt-2+ T cells and B cells of normal mice, is expressed in unusually high levels on Thy-1+ cells of lpr mice which are Lyt-2-.

Altered natural killer and natural cytotoxic cellular activities in lpr mice.

Three strains of mice bearing the autosomal recessive lpr gene (MRL, C57BL/6, and C3H) that had spontaneously developed a lupus-like disease were studied sequentially for functional natural killer (NK) and natural cytotoxic (NC) cell activity. Natural killing was impaired in spleen and bone marrow cells from all the lpr strains, as well as from the congenic strain MRL--+/+, which develops a late onset lupus-like disease. The NK cell activity was found to be depleted as early as 2 months of age in all lpr strains, and decreased further with age.