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Biomedical subjects

L A Smets

Publications and source records attributed to L A Smets.

At least 73 records · Page 4Linked to original sources
PubMed1985

S1-phase cells of the leukemic cell cycle sensitive to 1-beta-D-arabinofuranosylcytosine at a high-dose level.

To investigate the effects of 1-beta-D-arabinofuranosylcytosine (ara-C) at high doses as applied in human acute leukemia, the cytotoxic effect of high-dose ara-C was studied in L1210 leukemia cells grown in tissue culture or as tumors in syngeneic mice. Exponentially growing cells displayed the expected S-phase specificity and dose saturation properties of drug action. In contrast, in stationary cultures, progressively more cells were killed by increasing the concentration of the drug. Moreover, the fraction of cells killed at high doses exceeded by 2- to 3-fold the number of cells in drug-sensitive S phase detectable by flow cytometry or [3H]thymidine radioautography. To identify these apparent non-S targets of ara-C at high doses, L1210 cells were separated according to cell cycle position by velocity sedimentation at unit gravity. Large fractions of cells, accumulating at the G1-S boundary by nutrient starvation, were detected in stationary tissue culture cells as well as in ascites or solid tumor cells. The cells located in this cell cycle compartment (termed S1 cells) were sensitive to the cytotoxic effect of high-dose ara-C. The putative presence of similar S1 fractions in advanced human acute nonlymphocytic leukemia may explain in part the clinical efficacy of a high-dose application of the drug.

Animals↗
PubMed1983

Cytotoxic effects of dexamethasone restricted to noncycling, early G1-phase cells of L1210 leukemia.

The cytostatic and cytolytic effects of dexamethasone were studied as functions of cell cycle position in mouse L1210 leukemia cells. To this end, the cells were separated according to size by sedimentation at unit gravity in a specially designed sedimentation chamber. The fractions were analyzed by radioautography and flow cytophotometry. The size-distributions obtained by 1g sedimentation coincided with cell-cycle age distribution. With increasing fraction number, samples highly enriched in G1, S, and G2/M cells, respectively were obtained: the smallest cells being in early G1 and the largest in mitosis. In the presence of dexamethasone (10(-6)-10(-5) M), growth slowed down after a few cell cycles and the cells accumulated in early G1 phase. Lytic cell kill by continued exposure to the drug was confined to the fractions containing the small, early G1-phase cells. These fractions were also enriched in noncycling cells that were not labeled by prolonged exposure to 3H-thymidine. After removal of dexamethasone, the cells in S and G2/M phase completed cell cycle traverse but were retarded again in the G1 and early S phase of the next division cycle. The data suggest a memory effect for previous drug exposure. It is concluded that the cytostatic and cytolytic effects of dexamethasone are separate, though not unrelated events. Cytolysis is confined to the noncycling cells that in untreated populations can exit from the dividing compartment during a transitional phase of about 60 minutes subsequent to mitotic division. The cytostatic effects potentiate cytolysis by accumulating the cells in the early G1 phase and thus increasing the probability of their transit to the G0 compartment, sensitive for drug-mediated cytolysis.

Animals↗
PubMed1983

Cell kinetic responses in childhood acute nonlymphocytic leukemia during high-dose therapy with cytosine arabinoside.

Sequential bone marrow aspirates obtained from 10 children with relapsed acute nonlymphocytic leukemia (ANLL) after a high dose of cytosine arabinoside (Ara-C; 1000 mg/sq m) were analyzed by flow cytophotometry. The drug causing elimination of proliferating cells followed by a synchronous wave of cell recruitment. Among individual patients, considerable variation was observed in the degree of recruitment as well as in the time of appearance of the recruitment maximum (range 17-36 hr). However, both parameters appeared inversely correlated with the proliferative status in the bone marrow before treatment. In 6 other patients, cell kinetic responses were studied during treatment with repeated Ara-C injections scheduled individually according to the expected optima of recruitment. Waves of recruitment could be observed during 4-5 consecutive injections. The results suggest that in childhood ANLL, characteristic and individual cytokinetic responses to treatment with high-dose Ara-C can be monitored during therapy. These observations may allow the development of individual treatment schedules.

Acute Disease↗
PubMed1983

Isolation and characterization of subclones of L1210 murine leukemia with different sensitivities to various cytotoxic agents.

Two subclones of L1210 murine leukemia (L1210-46.1 and L1210-56.3) were isolated in the absence of selective agents. Subclone 56.3 appeared to be more sensitive than was subclone 46.1 to treatment with dexamethasone, 1-beta-D-arabinofuranosyl cytosine, vincristine, and X-irradiation. No differences between the parent cells and the two subclones could be observed in population-doubling time, cloning efficiency, number of chromosomes, and tumorigenic potential in DBA/2 mice. The subclones did not differ in the per cell number of glucocorticoid receptor sites. Animal experiments revealed an increase in life span of 65% in mice inoculated with cells from subclone 46.1 and of 130% of mice with subclone 56.3 after treatment with 1-beta-D-arabinofuranosylcytosine. The present results indicate that the L1210 wild-type murine leukemia cells contained stable subpopulations with a different but collateral sensitivity to various cytotoxic treatments. It is postulated that differences in drug sensitivity between cells are partly determined by cellular properties which are independent of the mechanism of action of any specific treatment.

Animals↗
PubMed1981

Expression of chronic myeloid leukaemia-associated changes in membrane glycopeptides in somatic cell hybrids.

Hybrid cell lines, derived from fusion of rodent cells with peripheral leukocytes from patients with chronic myeloid leukaemia (CML) and from normal donors, were assayed for the present of CML-associated changes in the carbohydrate moieties of membrane glycoproteins. Expression of this characteristic phenotype did occur in several hybrid clones derived from fusions both with leukaemic and normal human leukocytes. But, expression was only observed when tumourigenic rodent cells were used as fusion partners, and was not observed after fusion with non-tumourigenic rodent cells. Chromosome analysis of the hybrid cells did not reveal a single human chromosome- or chromosomal aberration (e.g. the Philadelphia chromosome)-bearing factor(s) responsible for this expression. The phenotypic expression observed could be due to dissociation of certain human genes from their regulator(s), as a result of chromosome loss in interspecific cell hybrids.

Animals↗
PubMed1979

Selective effects of trypsinization on established and tumour-derived mouse 3T3 cells.

Explanted tumour cells are much more sensitive to the deleterious effects of routine trypsinization than are the parent 3T3 or SV40 transformed established cell lines. This differential sensitivity causes the disappearance of tumour-derived cells when grown in co-culture with untransformed 3T3 cells and accounts in some tumor explants for the emergence of trypsin-resistant varient cells which have lost tumour-specific properties.

Animals↗
PubMed1977

Membrane glycoprotein changes in primary mammary tumors associated with autonomous growth.

Primary and transplanted mammary tumors of the GR mouse were explanted in tissue culture and grown in the presence of radioactive fucose. Labelled membrane glycopeptides were isolated and compared by cochromatography with differentially labelled glycopeptides from normal mammary gland tissue. Differences with controls in the glycopeptide elution profiles were observed in autonomous, hormone-independent tumors but were absent in histologically similar tumors which required a continuous hormonal stimulus for growth. The results suggest that alterations in membrane glycopeptides are associated with the capacity of autonomous, hormone-independent growth of murine adenocarcinoma cells.

Adenocarcinoma↗
PubMed1976

Surface glycoproteins and concanavalin-A-mediated agglutinability of clonal variants and tumour cells derived from SV40-virus-transformed mouse 3T3 cells.

Cell strains isolated from an established line of SV40-transformed mouse 3T3 cells (SV3T3) showed large variations in the various parameters of transformation, viz. saturation density, serum requirement, contact inhibition of movement and of growth and Concanavalin-A-mediated agglutinability. These cell strains were studied for changes in elution profiles of fucose-labelled surface glycoproteins, using actively growing, untransformed 3T3 cells as controls. A cell strain established from a tumour arising after injection of wild-type SV3T3 cells and SV3T3 cells grown in vivo in diffusion chambers, was similarly studied. Changes in surface glycoproteins were observed only in the tumour-derived cell strain. The results suggest that alterations in surface glycoproteins are associated with the tumorigenic potential of the cells rather than with the transformed phenotype per se.

Agglutination↗
PubMed1976

Early responses to chemotherapy detected by pulse cytophotometry.

DNA/cell distributions were recorded by automated cytofluorometry (=pulse cytophotometry) in bone-marrow aspirates of leukaemia and lymphosarcoma patients subjected to chemotherapy. In most cases, early perturbations in DNA/cell histographs were observed, characteristically reflecting the known mode of action of the drugs. These changes in general preceded the clinical observation of drug response. In a series of 23 measurements in 19 patients, a positive correlation between early cytophotometric changes and clinical effects of chemotherapy was observed in 17 patients. Five patients were negative for both cytophotometric and clinical reactions and one patient was probably false-positive. The validity of the assay for early detection of drug resistance in acute leukaemia and related diseases is discussed.

Adult↗