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Biomedical subjects

G Morstyn

Publications and source records attributed to G Morstyn.

103 records · Page 6Linked to original sources
PubMed1984

Heterogeneity in the radiation survival curves and biochemical properties of human lung cancer cell lines.

Human lung cancers of distinct histology exhibit different responses to radiation therapy in vivo. For examination of the basis of this phenomenon, the radiation survival curves and levels of relevant enzymes were determined in 16 lung cancer cell lines derived from tumors of different histology. These included lines from 5 adenocarcinomas, 7 small cell tumors, 3 variant small cell tumors, and 1 large cell tumor. These findings were compared to those obtained with the use of a normal skin fibroblast cell line. Whether cloned in liquid culture or soft agarose, cell lines had similar radiation survival curves. These curves were consistent with the apparent in vivo radiation responsiveness of the tumors. Although considerable heterogeneity in radiation survival curves was observed among the cell lines, cells from large cell lines and small variant lines had pronounced shoulders and extrapolation numbers (n) from 5.6 to 14. In contrast, cells from small cell lines and adenocarcinoma cell lines were more "sensitive" (-n values of 1-3.3). In these cell lines, levels of DNA polymerase beta, glutathione (GSH), GSH transferase, GSH reductase (NAD(P)H), gamma-glutamyltransferase did not correlate with radiation parameters of sensitivity. DNA polymerase beta and GSH levels were, however, higher than those in a line of normal skin fibroblasts. These cell lines may be useful in identifying the basis of the variable responsiveness of human lung cancer cells to ionizing radiation.

Cell Line↗
PubMed1984

Therapy for multiple myeloma with alternating non-cross-resistant chemotherapy combinations: heterogeneity of tumor responsiveness.

Thirty-five previously untreated patients with multiple myeloma were treated with a 60-week course of alternating, potentially non-cross-resistant chemotherapy combinations (melphalan and prednisone; vincristine, cyclophosphamide, doxorubicin, and prednisone; and carmustine, melphalan, and prednisone), alternating every 15 weeks in an attempt to prevent the development of drug resistance. The overall objective response rate (greater than 50% decrease in M protein) was 60% and six patients (17%) had a complete disappearance of the M protein. After 60 weeks, chemotherapy was discontinued in 17 responding or stable patients until relapse occurred from 4 to 39 months later (median, 12 months). Patients relapsing late (greater than 12 months after discontinuation of therapy) responded more frequently than those relapsing earlier to the reinstitution of the same chemotherapy program. The overall response rate and the actuarial median survival of 26 months in the 35 patients do not differ from the results reported recently with nonalternating combinations given until clinical tumor progression. The failure of this study to prolong survival by using alternating regimens may be due to (a) the likely possibility that the initial two regimens are not actually non-cross-resistant in most myeloma patients, and (b) the long interval between the alternating regimens, particularly in the face of the low response rate to the initial regimen of melphalan and prednisone.

Adult↗
PubMed1983

Bromodeoxyuridine in tumors and chromosomes detected with a monoclonal antibody.

Using a monoclonal antibody to bromodeoxyuridine (BUdR) and immunohistochemistry, we measured the incorporation of this thymidine analogue into the DNA of human normal and malignant cells exposed in vivo. BUdR given as a constant intravenous infusion for 12 or 24 h daily for up to 13 d resulted in a steady-state plasma level of 10(-6) M during the infusion. We demonstrated extensive incorporation of BUdR into both normal skin, normal bone marrow, and malignant melanoma cells. In addition, this infusion of BUdR was adequate to identify sister chromatid exchanges from human marrow chromosomes exposed in vivo. Using this constant infusion, significant but reversible (acute) toxicity was observed with myelosuppression and skin photosensitivity. These techniques, which are considerably less cumbersome and time-consuming than the use of radioactive isotopes of thymidine, can be used for further human studies of cell kinetics and chromosomal replication in both normal and malignant cells.

Animals↗
PubMed1983

Combination chemotherapy of hepatocellular carcinoma with doxorubicin and streptozotocin.

Twenty-three patients with unresectable hepatocellular carcinoma were given doxorubicin 60 mg/m2 I.V. day 1 and streptozotocin 0.5 g/m2 I.V. days 1-5 every 3 weeks. This regimen was chosen because of the activity of doxorubicin and nitrosoureas in hepatocellular carcinoma and the ability to administer both drugs in full doses. Twelve patients were fully ambulatory, 14 had normal serum bilirubin, 11 had pathologic proof of cirrhosis, and 11 had no known extrahepatic tumor dissemination. Partial responses lasting 10 and 14 months occurred in two patients (9%), one had stable disease for 15 months, 12 had documented tumor progression within 4 months, and eight died within 6 weeks of the start of chemotherapy. Median survival of all patients was only 3 months (range 0.3-27), but eight (35%) lived more than 1 year. Of these eight, two responded to doxorubicin and streptozotocin, another two to subsequent chemotherapy, and four had no tumor response whatever. More than 90% of the intended doses of doxorubicin and streptozotocin was administered, with severe leukopenia in three patients, moderate thrombocytopenia in one, and moderate proteinuria in nine. There were no drug-related deaths. Various physical, radiologic, and biochemical parameters were employed in detecting tumor response and progression. Initially abnormal physical examination of the liver, hepatic radionuclide and computed tomographic (CT) scans, and serum alpha-fetoprotein levels improved in both responding patients. Tumor progression was detected by physical examination (7/12), radionuclide (10/12) and CT liver scan (3/7), rising alpha-fetoprotein (5/12), and rising carcinoembryonic antigen (3/8). Physical examination and radionuclide liver scan together documented all tumor response and progression. The combination of doxorubicin and streptozotocin has only modest activity in hepatocellular carcinoma and appears no more active than doxorubicin alone.

Adolescent↗
PubMed1982

Bullous pemphigoid blister fluid stimulates eosinophil colony formation and activates eosinophils.

An eosinophil stimulating material (ESM) is described in the blister fluids (BF) of six patients with bullous pemphigoid (BP). This ESM is similar in function to a subspecies of human colony stimulating factor (CSF), CSF-alpha, since (i) it stimulated the production from bone marrow cells of day 14 colonies (31 +/- 15, arithmetic mean +/- 1 s.e.m. colonies, n = 5) in semi-solid agar, (ii) a large proportion (47 +/- 12%, n = 5) of these colonies were eosinophilic and (iii) it activated purified peripheral eosinophils as judged by increased autofluorescence (a mean increase of 23.6 +/- 6.6 units measured by flow cytometry, n = 10). BF from patients with four other blistering diseases, burn blisters, suction blisters from normal, eosinophilic or BP patients, various sera, histamine and eosinophil chemotactic factor (ECF-A) lacked activities in these assays. This description of a tissue accumulation of a CSF like substance suggests that there exists a physiological role for CSF in the periphery. In addition it supports the concept that local activation of eosinophils contributes to the pathogenesis of BP.

Aged↗
PubMed1981

Separate actions of different colony stimulating factors from human placental conditioned medium on human hemopoietic progenitor cell survival and proliferation.

More than 20% of human granulocyte-macrophage and eosinophil colony-forming cells survived in agar culture for up to 4 days without the addition of exogenous colony stimulating factors (human placental-conditioned medium, HPCM). Survival was reduced slightly but not significantly, by the removal of adherent cell populations. Significant survival occurred even when only 100 cells enriched for colony-forming cells (CFCs) were cultured per dish. When individual colonies, initiated by stimulation with HPCM for 5 days, were transferred to dishes without HPCM, subsequent proliferation was significantly reduced compared with control cultures containing HPCM. Using the fluorescence-activated cell sorter and the fluoresceinated lectin from Lotus tetragonolobus, two populations of marrow cells were obtained, one enriched for day 7 and the other for day 14 colony-forming cells. Two colony-stimulating factors fractionated from HPLCM (CSF beta and CSF alpha) have been shown previously to stimulate the day 7 and day 14 colony-forming cell populations, respectively. Developing clones from cultures initiated with CSF beta died between the fifth and tenth day of culture after transfer to dishes with CSF alpha or CSF beta or to dishes with no stimulus. Cells in clusters initiated with CSF alpha proliferated significantly between the fifth and tenth day of culture when transferred to CSF alpha or CSF beta but not when transferred to dishes with not stimulus. These studies provide further evidence for the existence of two subtypes of human granulocyte-macrophage progenitor cells each under the primary control of a specific regulator and indicate that these two regulators can both act on some developing clones of cells.

Bone Marrow Cells↗
PubMed1981

Effects of high dose busulphan on leukaemic progenitor cells in chronic myeloid leukaemia.

Six patients with Philadelphia positive chronic myeloid leukaemia (CML) were treated with single high doses of busulphan. The action of busulphan on the in vivo kinetics of circulating progenitor cells (colony forming cells) was measured using an agar culture system which involved scoring of total colonies and clusters at 7 days and of granulocyte, monocyte and eosinophil colonies at 14 days. High dose busulphan was found to be effective in suppressing circulating granulocyte, monocyte and eosinophil progenitor cells. The effect of busulphan on progenitor cells was rapid and their levels fell by at least 85% within five days. By contrast, the white blood cells fell by only 9% and the platelets fell by 10% over this time. Subsequently, the white cell count and platelet count fell to near normal levels. The progenitor cell levels began to rise again at a mean of 35 days following busulphan treatment and the white blood cells at a mean of 39 days in four patients. One patient remained in haematological remission for six months following 100 mg of busulphan with less than 1 progenitor per 5 x 10(5) peripheral blood nucleated cells. One patient in myeloblastic transformation had a previously not described culture pattern consisting of a high cluster to colony ratio at 7 days and of an increased number of predominantly eosinophilic colonies at 14 days. There was no significant fall in progenitor cell levels following busulphan and this patient died.

Administration, Oral↗
PubMed1981

Surface antigens on normal and leukaemic human cells detected by monoclonal antibodies.

Surface antigens were analyzed on normal human marrow and chronic myeloid leukaemic cells using 4 monoclonal mouse anti-human antibodies. The fluorescence-activated cell sorter was used to quantify the binding of each antibody to different subpopulations of cells, and sorted fractions were cultured in agar-medium to assay for granulocyte-macrophage and eosinophil precursors. All cells in the granulocyte series including colony-forming cells bound a similar quantity of an antibody to the human leucocyte common antigen. This antibody did not bind to cells in the erythroid series. A monoclonal antibody to antigen present on brain, lymphocytes and granulocytes (and almost certainly homologous to the W3/13 antigen of the rat) bound to the cells in the order: blast greater than promyelocytes and myelocytes greater than granulocytes. The third monoclonal antibody was directed against a determinant of the leucocyte common antigen present predominantly on B lymphocytes and absent from the myeloid series. The fourth antibody, directed against the human homologue of Thy-1, reacted with less than 1% of marrow cells, none of which appeared to be granulocyte or eosinophil progenitors. The leucocoyte common antigen and the brain-lymphocyte-granulocyte-antigen were also present on colony- and cluster-forming cells from a patient with chronic myeloid leukemia. Using the low angle and wide angle light scatter properties of CML blood cells, 7-fold enrichment was obtained for progenitor cells from chronic myeloid leukaemia. With the monoclonal antibodies up to 4-fold enrichment was obtained.

Animals↗
PubMed1981

An autoantibody reactive with nuclei of polymorphonuclear neutrophils: a cell differentiation marker.

An autoantibody that reacted with nuclei of polymorphonuclear neutrophils (PMN) was detected at titers of greater than 10 in sera of 25 of 50 patients with rheumatoid arthritis and 36 of 50 with autoimmune chronic active hepatitis but in none of 160 controls comprising 24 patients with alcoholic cirrhosis, 36 with multiple myeloma, and 100 healthy subjects. Through the use of enriched populations of hemopoietic cells, this antibody was shown to be cell-specific, reacting only with the nucleus of the mature neutrophil. It was unreactive with nuclei of progenitor cells in the myeloid series and with nuclei of eosinophils, monocytes, lymphocytes, and thymocytes. It reacted with a determinant that appeared to be a differentiation antigen. This cell-specific autoantibody may prove to be of value in analytical studies of granulocyte maturation.

Antibodies, Antinuclear↗
PubMed1980

Purification of hemopoietic progenitor cells from human marrow using a fucose-binding lectin and cell sorting.

Human peripheral blood granulocytes, but not lymphocytes, erythrocytes, or monocytes, bound the fucose-binding lectin from Lotus tetragonolobus (FBP), and this binding was competitively inhibited by the sugar alpha-L-fucose. The fluorescence-activated cell sorter was used to study the appearance of this receptor on human marrow cells during granulocyte differentiation and to prepare fractions enriched for granulocyte-macrophage progenitor cells (granulocyte-macrophage colony-forming cells--GM-CFC). Cell binding of fluoresceinated FBP increased for bone marrow cells in the sequence--lymphocytes, blast cells, promyelocytes and myelocytes, monocytes, and polymorphonuclear cells. Selection of cells with appropriate low-angle or high-angle light scatter characteristics achieved a 10-fold or 2-3-fold enrichment of progenitor cells, respectively. By selecting cells with intermediate fluorescence intensity, a further 2-3-fold enrichment for GM-CFC was obtained. Cell sorting using the optimal selection of these three parameters produced up to 36-fold enrichment of the progenitor cells from human bone marrow. The most enriched fraction was composed of 23% progenitor cells (colony- and cluster-forming cells) with a yield of 36%. In populations most highly enriched by GM-CFC, immature cells (blast cells, promyelocytes, and myelocytes) made up 95% of the cells present.

Binding Sites↗
PubMed1980

Lectin receptors on human blood and bone marrow cells and their use in cell separation.

A series of fluorescein-conjugated lectins (Sophora japonica agglutinin, Helix pomatia agglutinin, peanut agglutinin, the erythroagglutinin from Phaseolus vulgaris, pokeweed mitogen, wheat germ agglutinin and the fucose-binding lectin from Lotus tetragonolobus) were analyzed for their binding to human peripheral blood cells with a fluorescence-activated cell sorter. Most of the lectins showed increasing cell binding in the order erythrocytes less than lymphocytes less than monocytes less than neutrophils and the degree of fluorescence was not related to the major blood groups. The fucose-binding lectin (FBP) was the main exception in that it appeared to bind only to blood neutrophils. From an analysis of the binding of this lectin to human bone marrow cells it was found that the degree of binding within the granulocytic series increased with progressive differentiation. Marrow monocytes and nucleated erythroid cells bound to FBP in contrast to monocytes and non-nucleated red cells in the peripheral blood which showed negligible binding. Lymphocytes both in the marrow and blood displayed negligible binding of FBP. These properties allowed an enrichment of haemopoietic progenitor (colony-forming) cells from human marrow cell suspensions and a depletion of colony-inhibiting cells, when these were present, by selection of cells with the appropriate fluorescence intensity.

Blood Cells↗
PubMedDate not supplied

Stem cell factor is a potent synergistic factor in hematopoiesis.

Stem cell factor (SCF), a ligand for c-kit, has a broad range of activities including effects on cells at or near the level of the multipotential stem cell as well as on committed cells. Preclinical studies show that SCF can protect against lethal irradiation, elicit multilineage responses in peripheral blood and bone marrow cellularity, and increase circulating peripheral blood progenitor cells (PBPC) in a dose-dependent manner. Recombinant human SCF has major clinical potential through its synergy with other factors, especially recombinant human granulocyte colony-stimulating factor, to enhance mobilization of PBPC.

Animals↗