Appropriate chemotherapy for palliating advanced cancer.
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
M S Hamilton
Publications and source records attributed to M S Hamilton.
Sustained engraftment of mice transplanted with IL-1-primed blood-derived stem cells.
IL-1 is considered the primary mediator of the acute phase response. One of the characteristic manifestations of this response is early neutrophilia that is probably caused by release of mature neutrophils from the bone marrow into the peripheral blood. In the present study, we assessed whether IL-1 had a similar releasing effect on the number of circulating progenitor cells and stem cells. Female BALB/c mice were injected i.p. with increasing (0.1-1.0 micrograms/mouse) concentrations of rhu-IL-1 alpha. IL-1 injection resulted in a marked dose-dependent increase in the number of polymorphonuclear neutrophils, granulocyte-macrophage colony-forming units (CFU-GM), and cells forming spleen colonies (CFU-S day 8 and day 12). The maximal increase was found at 4 to 8 h after injection of 1 micrograms IL-1 per mouse, yielding a mean fivefold elevation in neutrophil count, and a mean 30-fold and 10-fold increase in the number of circulating CFU-GM and CFU-S, respectively. In a subsequent series of experiments, lethally irradiated (8.5 Gy) female recipient animals were transplanted with 5 x 10(5) blood mononuclear cells derived from male IL-1-treated animals. Long-term survival was obtained in 68% of mice transplanted with peripheral blood cells derived from donor animals at 6 h after a single injection of 1 micrograms IL-1. The mean number of circulating CFU-GM in these donor animals was 557/ml blood. At 6 mo after transplantation, greater than 95% of the bone marrow cells were of male origin, as determined using in situ hybridization with a Y-chromosome specific probe. In contrast, long-term survival was reached in less than 10% of mice transplanted with an equal number of blood cells derived from saline-treated controls or donor animals treated with a dose of 0.1 micrograms IL-1. These results indicate that a single injection of IL-1 induces a shift of hematopoietic progenitor cells and marrow repopulating cells into peripheral blood and that these cells can be used to rescue and permanently repopulate the bone marrow of lethally irradiated recipients.
Animals↗
Expression of adhesion molecules LFA-3 and N-CAM on normal and malignant human plasma cells.
Normal and malignant plasma cells were investigated for the expression of seven cellular adhesion molecules by immunofluorescence microscopy. The antigens investigated were CD2 and its ligand, LFA-3 (CD58). LFA-1 alpha (CD11a) and LFA-1 beta (CD18) and their ligand ICAM-1 (CD54), H-CAM (lymphocyte homing receptor; CD44) and N-CAM (CD56). Marrow from 18 patients with myeloma, two with plasma cell leukaemia (PCL), four with monoclonal gammopathy of uncertain significance (MGUS) and 10 normal allogeneic bone marrow donors was studied. All plasma cells from normals and multiple myeloma patients were negative for CD2, CD11a and CD18. All normal and myeloma marrow plasma cells were positive for ICAM-1. 16/18 myeloma cases tested, and all other samples (normal, MGUS and PCL), contained plasma cells positive for H-CAM. Only one normal, but 12/16 myelomas tested were positive for N-CAM (P less than 0.02). One of four MGUS cases was moderately positive and one other weakly positive for N-CAM. Both PCLs were N-CAM negative. 12/18 myelomas were positive for LFA-3, but only two normals (P less than 0.05). All MGUS cases were negative for LFA-3, as was one PCL, the other being weakly positive. Three cases were negative for both adhesion molecules, three cases expressed only N-CAM or LFA-3 and 10 cases expressed both. LFA-3 and N-CAM are expressed significantly in myeloma rather than normal plasma cells. Cases of MGUS may express N-CAM but not, in this small series, LFA-3. Plasma cells in the peripheral blood (PCL) and plasma cell lines express little or no LFA-3 or N-CAM.
Antigens, CD↗
A comparison of differential white cell counting on the Coulter VCS and the Technicon H1 using simple and multiple regression analysis.
This study uses the statistical methods of simple and multiple regression to compare the differential white blood count on the Coulter VCS and Technicon H1 analysers. The results demonstrate that both are good at distinguishing lymphocytes, neutrophils and eosinophils. Monocyte differential counts show disappointing correlation, both by simple and multiple regression techniques. Basophils, though less frequently a clinical problem, also correlated poorly in this study.
Basophils↗
Granulocytic sarcomas of small intestine and brain are associated with acute myelomonocytic leukaemia with abnormal eosinophils and inversion of chromosome 16.
We report two cases of acute myelomonocytic leukaemia with abnormal eosinophils (M4Eo) in which the presenting feature was small bowel obstruction. We suggest there is a unique clinicopathological association between small intestine involvement with leukaemia and the M4Eo subtype. Central nervous system involvement by myeloblastoma occurred in one of the two cases which is a recognised feature of M4Eo and should necessitate prophylaxis with intrathecal therapy. Inversion of chromosome 16 which is a cytogenetic marker for M4Eo was demonstrable in one of the two cases.
Biomarkers, Tumor↗
The role of adhesion molecules in multiple myeloma.
Human myeloma plasma cells had been considered to express few surface antigens until recently. The past two International Workshops on Leucocyte Differentiation Antigens have shown that myeloma cells can express a range of surface molecules, and it has become clear that many of these have adhesive functions. The identification of ICAM-1 (CD54) and H-CAM (CD44) on human plasma cells was the initial observation, and other antigens such as N-CAM (CD56) and LFA-3 (CD58) have been confirmed as features of malignant plasma cells in particular. The degree of expression of LFA-1 (CD11a) remains to be characterised fully. It seems probable that the loss of some adhesion structures may be associated with increased malignancy and plasma cell leukaemia. At the present time there are few studies relating to the function of these molecules, although homotypic adhesion appears to occur, and it is likely that such studies will shed light on the pathogenesis of myeloma.
Antigens, CD↗
Akathisia, suicidality, and fluoxetine.
BACKGROUND: The propose link between fluoxetine and suicidal ideation is explained by fluoxetine-induced akathisia and other dysphoric extrapyramidal reactions. METHOD: The following literature is reviewed: (1) the subjective response of schizophrenics to akathisia, including evidence that akathisia gives rise to suicidal ideation; (2) the subjective reports of patients taking fluoxetine; and (3) preclinical studies describing the role of serotonin in the extrapyramidal system and suggesting a mechanism whereby fluoxetine can induce extrapyramidal side effects. RESULTS: The literature suggests that fluoxetine-induced extrapyramidal reactions may be a mediator of de novo suicidal ideation. CONCLUSION: We propose a syndrome which we name Extrapyramidal-Induced Dysphoric Reactions, one extreme manifestation of which is the emergence of suicidal ideation. We further propose a heuristic "Four Neuron Model of the Extrapyramidal Motor System" in which increased serotonin activity, by inhibiting the nigrostriatal dopamine tract, is capable of inducing extrapyramidal side effects.
Akathisia, Drug-Induced↗
Surface antigen expression of human neoplastic plasma cells includes molecules associated with lymphocyte recirculation and adhesion.
The surface phenotype of neoplastic plasma cells from peripheral blood of plasma cell leukaemia patients and bone marrow of patients with myelomatosis was investigated with two monoclonal antibody panels including 50 selected from the B cell panel of the IVth International Workshop on Leucocyte Differentiation Antigens. The majority of myelomas expressed CD24 (HB8 epitope only), CD38, CD44, CD54, and the antigen recognized by the monoclonal antibody 8A. A range of other antigens may also be expressed including CD10, CD32 (FcR II), CD19, CD20 and MHC Class II. Antigens expressed by myeloma plasma cells can be considered in three groups: (a) antigens associated with lymphocyte and plasma cell differentiation: (b) antigens which are not lineage specific: and (c) molecules concerned with lymphocyte recirculation and intercellular adhesion (CD44 and CD54). The significance of CD44 and CD54 expression by plasma cells and the potential interaction of plasma cells with T lymphocytes and monocytes is discussed.
Antigens, Differentiation, B-Lymphocyte↗
Normal and neoplastic human plasma cells express bcl-2 antigen.
The bcl-2 (B-cell leukaemia/lymphoma 2) proto-oncogene is associated with the 14;18 translocation in follicular lymphoma juxtaposing bcl-2 with the immunoglobulin heavy chain region. bcl-2 has been cloned and sequenced and a monoclonal antibody to amino acids 41 to 54 of the bcl-2 protein has been raised. The expression of bcl-2 in follicular lymphoma has been demonstrated by immunohistological staining and also in normal lymphocytes. The presence of the bcl-2 onco-protein has been demonstrated by immunofluorescence using conventional and confocal microscopy in normal and malignant plasma cells from myeloma patients and myeloma cell lines. Plasma cells from 8/8 normal donors were positive, although the proportion of positive cells and the intensity of staining varied. Eight of 10 patients with myeloma or plasma cell leukaemia had positive plasma cells, and 6/11 plasma cell lines and one lymphoma cell line also expressed the onco-protein. bcl-2 expression is a feature of normal plasma cells and data from the cell lines confirm that expression is not dependent on the presence of the 14;18 translocation.
Chromosomes, Human, Pair 14↗
A monoclonal antibody, 4H12, recognizes a surface antigen found on granulated metrial gland cells in the murine decidua.
A monoclonal antibody (MAb), designated 4H12, was selected for reactivity to a surface antigen on PYS-2 teratocarcinoma cells. 4H12 was the product of a fusion of lymphoid cells of a non-immunized pregnant C57BL/6 mouse to NS-1 myeloma cells. Initial studies utilizing immunohistochemistry revealed that MAb 4H12 bound to an antigen found on cells in the decidua basalis of 7-, 8- and 10-day pregnant mice. Antigen-positive cells of 11--19-day pregnant mice were also found predominantly in the decidua. A few antigen-positive cells were found in the labyrinth of the placenta and up against Reichert's membrane. Antigen-positive cells were morphologically and spatially distinct, oval to round with large periodic acid Schiff positive granules. Indirect immunofluorescent (IIF) labeling of decidual cultures showed antigen on the surface of cells that were small, oval to round and adherent. The antigen recognized by MAb 4H12 was removed from tissue sections with trypsin and protease and therefore is suggested to be a protein. We conclude that MAb 4H12 recognizes a surface antigen found on cells historically described as granulated metrial gland (GMG) cells. This MAb should greatly facilitate the further analysis of the life history and function of GMG cells during pregnancy.
Animals↗
Characterization of new IgG lambda myeloma plasma cell line (EJM): a further tool in the investigation of the biology of multiple myeloma.
A new IgG lambda myeloma plasma cell line known as EJM was established from a peritoneal effusion from a patient with extramedullary myeloma. The EJM cells have a plasmablastic morphology with abundant rough endoplasmic reticulum and grow in liquid culture with a doubling time of 72 h and a labelling index of 36%. In addition to cytoplasmic IgG lambda, the cells are positive for CD9, 20, 32, 38, 44, 54, 71, 78, MHC Class II DR, DP and DQ. Studies on the control of the cell line proliferation by cytokines have demonstrated stimulation with interleukin 6. In contrast interferon alpha produces marked inhibition of proliferation in doses of greater than 100 units/ml. The culture conditions and the importance of accessory cells and cytokines in supporting myeloma plasma cell growth in vitro are discussed.
Ascitic Fluid↗
Chlordiazepoxide and valproate enhancement of saline drinking by nondeprived rats: effects of bicuculline, picrotoxin and Ro15-1788.
Drinking of 0.85% saline by nondeprived rats was significantly enhanced by chlordiazepoxide (5 or 10 mg/kg) and by valproate (100 or 300 mg/kg), drug effects being strongest in the earlier parts of a 30-minute test. When given alone, both bicuculline and picrotoxin significantly reduced saline drinking at 2.5 mg/kg, but not 1.5 mg/kg. Administration of valproate at either dose or of chlordiazepoxide (10 mg/kg) completely prevented bicuculline action and 5 mg/kg chlordiazepoxide reduced it. Picrotoxin, however, largely prevented the actions of both chlordiazepoxide and valproate. The increase in saline drinking induced by valproate (300 mg/kg) was also blocked by RO15-1788 (10 or 25 mg/kg). These findings are discussed in the context of the three-site model of the GABA/benzodiazepine receptor complex. It is concluded that drugs acting at the benzodiazepine site or the chloride ion channel affect saline drinking, but that there is little evidence of an important functional role for the GABAa site at present.
Animals↗
A monoclonal antibody, MA21, recognizes a surface component that is present on F9 teratocarcinoma cells and that appears vectorially on the trophectoderm of peri-implantation-stage mouse blastocysts.
A monoclonal antibody (MAb) "MA21", derived from lymphoid tissue of a multiparous mouse and selected for binding to mouse teratocarcinoma cell line F9, recognizes a surface antigen that appears on peri-implantation-stage mouse blastocysts. In indirect immunofluorescence assays, MAb MA21 does not bind to 1-cell-through morula-stage embryos, nor to early, 3.5-day post-coitum (p.c.) blastocysts. When 3.5-day p.c. blastocysts are maintained 17 h in vitro and then assayed, MAb MA21 binds to a limited number of trophectoderm cells that are centered at the embryonic pole. As culture time lengthens, the number of antigen-expressing trophectoderm cells increases, forming a cap that spreads from the embryonic pole into the abembryonic region. Embryos maintained 48 h in vitro bind MAb MA21 over as much as 100% of the trophectoderm surface. MAb MA21 does not bind to the inner cell mass. When mouse pregnancy uteri are assayed by the immunoperoxidase method, MAb MA21 binds to extra-embryonic ectoderm and trophectoderm of 5-day p.c. implanted blastocysts, but does not bind to 6-day p.c. blastocysts. MAb MA21 recognizes a component with an estimated mol. wt of 44,000 from NP-40 detergent extracts of F9 cells and peri-implantation-stage mouse blastocysts. The component appears to be firmly associated with the plasma membrane; it is resistant to removal by high salt or moderate concentrations of non-ionic detergent.
Animals↗
The detection in human sera of antisperm antibodies reactive with FA-1, an evolutionarily conserved antigen, and with murine spermatozoa.
Evolutionarily conserved antigens are present on spermatozoa of several mammalian species. We tested sera from infertile men and women containing antisperm antibodies (ASAs) for their reactivity with FA-1, an antigen known to be present on murine and human spermatozoa. Fifty percent of male sera and 63% of female sera contained anti-FA-1 antibodies, as judged by enzyme linked immunosorbent assay (ELISA). Fourteen percent of male sera and 50% of female sera were also shown to possess ASAs reactive with living mouse spermatozoa, and murine in vitro fertilization was inhibited by human antibodies. These results suggest that the transfer of immunoglobulins from human sera to spermatozoa of other species may provide a model to study how ASAs effect sperm function.
Absorption↗
A single low dose of human recombinant interleukin 1 accelerates the recovery of neutrophils in mice with cyclophosphamide-induced neutropenia.
The actions of the cytokine interleukin 1 (IL-1) in hematopoiesis involve induction of colony-stimulating factor (CSF) production on accessory cells in the hematopoietic microenvironment and synergy with CSF on early hematopoietic progenitor cells. We have used these properties to accelerate hematologic reconstitution in granulocytopenic mice. Mice with cyclophosphamide-induced granulocytopenia were injected i.p. at day 0 with a single dose (8-800 ng) of human recombinant IL-1 alpha. At daily intervals thereafter during a period of 7 days mice were sacrificed and blood granulocytes and bone marrow cellularity were assessed. Mice receiving a single dose of 80 or 800 ng IL-1 had significantly (p less than 0.05) higher blood granulocyte counts at days 4 and 5 than control animals receiving heat-activated IL-1. This activity of IL-1 was not affected by injection of the cyclooxygenase inhibitor ibuprofen. Bone marrow cellularity, as assessed in histological sections of femurs, was significantly greater (p less than 0.05) at day 2 in mice treated with 80 or 800 ng IL-1. These results show that a single low dose of IL-1 may be used to accelerate the reconstitution of granulocytes following granulocytopenia induced with chemotherapy.
Agranulocytosis↗
Vasectomy-induced autoimmunity: monoclonal antibodies affect sperm function and in vitro fertilization.
A panel of sperm-reacted monoclonal auto-antibodies developed from spleen cells of vasectomized mice (BDF1) were characterized. Immunogenic antigens were mainly located on the acrosome, midpiece and principal piece. All of the monoclonals were IgM; three demonstrated a multispecific reaction with testis and/or epididymis antigen extracts by immunoblotting. Immunobead studies indicated that most of the antibodies were to surface molecules, a finding supported by the observation that five of the seven antibodies caused complement-mediated immobilization (although not sperm agglutination) of mouse sperm. In vitro fertilization was significantly impaired when antibodies (Vx5, 8 and 10) were added to the sperm prior to exposure to the eggs. Furthermore, passive immunization with Vx5 antibody reduced in vivo fertilization. Our findings indicate that vasectomy-generated antibodies can reduce sperm function in vitro and in vivo.
Animals↗
Mechanism of immune dysfunction associated with minor antigen graft-vs-host disease in mice.
A well-characterized murine model of graft-vs-host disease (GVHD) that develops in response to minor histocompatibility antigens was used to study the mechanism of an immunodeficiency syndrome that is associated with GVHD. Lethally irradiated mice were transplanted with a combination of bone marrow and spleen cells from H-2 compatible donors that differed at multiple minor histocompatibility antigens, or from syngeneic donors. Four to 12 weeks later, the humoral responses of transplanted and control mice to the T dependent antigens bacteriophage phiX174 and TNP-sheep red blood cells (TNP-SRBC), and to the T independent antigen TNP-Brucella abortus (TNP-BA) were determined. The results demonstrate that mice with GVHD have relatively intact B Cell function and a profound defect in T helper cell function. The immune response to T dependent antigens normalized with repeated immunization. We conclude that immune dysfunction in mice with GVHD is due to a reversible defect in T helper cell function.
Animals↗
Maternally induced graft-vs-host disease to minor antigens as a possible etiology of an acquired immunodeficiency syndrome in mice.
It has been postulated that an acquired immunodeficiency syndrome develops in neonates as the result of a maternally induced graft-vs-host disease (GVHD) that develops when sufficient numbers of maternal lymphocytes are transferred to the fetus across the placental barrier. The present study was done to determine whether major histocompatibility complex (MHC) antigens or non-MHC minor histocompatibility antigens (MiHA) were involved. Female C57BL/6 mice were bred to males of eight selected strains such that maternal-fetal disparity existed at MHC antigens and/or minor histocompatibility antigens. Offspring were tested for immune function at 6-7 weeks of age using a Jerne plaque assay to measure the humoral response to that T dependent antigen sheep red blood cells (SRBC). None of the offspring developed clinical signs of GVHD, but 3 of 124 mice tested made no immune response to SRBC. Immunodeficiency was associated with maternal-fetal disparity only at a small number of MiHA and not at the MHC. We postulate that immunodeficiency in this model is mediated by a subclinical maternally induced GVHD to paternally derived MiHA of the fetus.
Acquired Immunodeficiency Syndrome↗