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J Lindemans

Publications and source records attributed to J Lindemans.

At least 73 records · Page 4Linked to original sources
PubMed1991

Interleukin-6 and interleukin-1 enhancement of GM-CSF-dependent proliferation of haematopoietic progenitor cells in myelodysplastic syndromes.

Interleukin-1 (Il-1) and Interleukin-6 (Il-6) have been reported to enhance the growth factor dependent colony formation of normal primitive haematopoietic progenitor cells as well as of leukaemic blast-cell progenitors. We investigated the effects of Il-1 beta and Il-6 in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) on the in vitro colony formation of myeloid progenitors from 23 patients with a myelodysplastic syndrome (MDS). Neither Il-1 beta nor Il-6 were found to have colony stimulating activity on their own. In normal bone marrow cultures, either stimulated with optimal or suboptimal doses of GM-CSF, no enhancing or antagonistic effect of Il-6 or Il-1 beta was detected. In a majority of the MDS cases, however, an enhancing effect of Il-6 and Il-1 beta in combination with GM-CSF was observed (20/23 and 10/21 cases respectively). In three cases of the Il-6 and GM-CSF combination an antagonistic effect was observed as well as in four cases of the Il-1 beta and GM-CSF combination. A delayed addition of Il-6 to the cultures did not result in an abrogation of the effect, indicating that Il-6 is not required immediately at the initiation of the culture. These results indicate that costimulation with Il-6 or Il-1 beta is able to augment the GM-CSF activity on MDS myeloid progenitor cells.

Antigen-Presenting Cells↗
PubMed1990

Anti-leukemic potential of methyl-cobalamin inactivation by nitrous oxide.

Myelo-cytotoxicity of extended nitrous oxide (N2O) inhalation was described almost forty years ago and then incidentally applied already with temporary success for suppressing leukemia. In 1948 the accompanying megaloblastic maturation arrest was explained by inactivation of the methylcobalamin coenzyme and subsequent folate deficiency. We studied the anti-leukemic effect of N2O on a transplantable acute leukemia in B(rown) N(orway) rats. Progression of this B,N,M(yelocytic)L(eukemia) was measured as spleen and liver weights, and leukemic blood cell counts. The deoxyuridine (dU)-suppression test provided in vitro indication of the functional folate activity of leukemic cells. Breathing of N2O-oxygen considerably reduced but did not eradicate, BNML-proliferation. Addition of anti-metabolites, interfering with some enzyme in the folate metabolism beyond the methylcobalamin co-enzyme dependent methionine synthase step, acted at least synergistically. The anti-leukemic effect of cycloleucine, which reduces S-adenosyl-methionine synthesis by inactivation of methionine adenosyltransferase, was moderate but became much stronger with N2O inhalation. Methotrexate, a potent anti-leukemic agent by inhibiting tetrahydrofolate (THF) generation through inactivation of di-HF reductase, became highly anti-BNML, even in low dosage when combined with or preceded by N2O. 5-Fluorouracil, which inhibits methylene-THF dependent thymidilate synthase, itself was surprisingly anti-BNML, but also became much more potent with previous or concomitant N2O exposure. Preliminary dU-suppression test results with human acute leukemia cells, exposed to N2O and/or folate antagonists in vitro, correlated well with the in vivo BNML-experiments. Combining the anticobalamin activity of N2O with an anti-folate therefore seems to be a promising chemotherapeutic approach.

Animals↗
PubMed1990

The combined effects of Il-3, GM-CSF and G-CSF on the in vitro growth of myelodysplastic myeloid progenitor cells.

The decreased or absent in vitro colony formation in response to single recombinant haematopoietic growth factors has been reported previously. Here we report on the effects of the combination of interleukin 3 (Il-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte-CSF (G-CSF) and the effect of the conditioned medium of the giant tumour cell line (GCT-CM) on the proliferation of myelodysplastic (MDS) marrow myeloid progenitor cells and normal bone marrow (NBM) controls. Colony growth was most effectively sustained by GCT-CM and G-CSF in normal bone marrow (NBM) cultures. GM-CSF and Il-3 were less effective in inducing myeloid granulocytic colony growth, whereas the effects of Il-3 and GM-CSF were found to be approximately additive. The number of NBM granulocytic colonies induced by G-CSF and GCT-CM stimulation were comparable, whereas this granulocyte colony stimulating activity could be neutralized by anti-G-CSF antibodies. In addition GCT-CM was found to contain burst promoting activity, which could be neutralized by anti-Il-3 antibodies. Il-3 did not enhance the G-CSF activity in NBM cultures. No additive effect of stimulation with the combination of Il-3 and GM-CSF was observed in MDS marrow cultures, suggesting that these growth factors act on an identical progenitor cell population in MDS. G-CSF stimulated the growth of significantly lower colony numbers than GCT-CM, in contrast to NBM cultures. The decreased granulocytic colony formation of MDS marrow cells could clearly be enhanced by co-stimulation with Il-3. These results suggest that MDS myeloid progenitor cells require the exposure to both a pluripotent colony stimulating factor, like Il-3, and a lineage specific factor, like G-CSF, for optimal proliferation.

Bone Marrow↗
PubMed1990

Transfusion of red cells after autologous bone marrow harvest in patients with acute leukemia and malignant lymphoma.

Bone marrow was harvested for the purpose of autologous bone marrow transplantation (ABMT) in 21 patients previously treated with chemotherapy and in complete remission from acute leukemia or non-Hodgkin's lymphoma. The volume required to obtain 2 x 10(8) nucleated cells per kg was less than 15 mL per kg in 13 patients and more than 15 mL per kg in 8 patients. The blood admixture was proportional to the aspirated volume (p less than 0.0001). The number of granulocyte-macrophage colony-forming units (CFU-GM) harvested in the groups was 8.4 +/- 2.2 and 3.4 +/- 1.4 x 10(4) per kg, respectively (p less than 0.0001). Autologous red cells were transfused into 16 of 21 patients, who did not require further homologous transfusions. The mean drop in hemoglobin from the preoperative level was 1.0 +/- 0.2 g per dL. No adverse effects were noted. It is concluded that large single-volume bone marrow harvests are possible and may reduce the need for a second harvest, and that, through the transfusion of autologous red cells obtained during marrow harvest, homologous blood transfusion can be avoided in most patients.

Acute Disease↗
PubMed1990

The effects of interleukin-3, GM-CSF, and G-CSF on the growth kinetics of colony-forming cells in myelodysplastic syndromes.

In order to obtain more insight into the nature of the abnormal in vitro colony formation in myelodysplastic syndromes (MDS), we investigated the kinetics of the colony formation of 23 MDS cases in response to recombinant human interleukin-3 (IL-3), Granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating Factor (G-CSF), and giant cell tumor cell line conditioned medium (GCT-CM). The kinetics of GCT-CM-induced colony formation were comparable to that of G-CSF-induced colony growth, both in MDS and in normal bone marrow cultures. Colony formation was found to be delayed in MDS. The delay in colony formation was most apparent in the GCT-CM (G-CSF) responsive progenitor cell compartment. In MDS cases with clinical features of high risk disease, this delay was more pronounced as compared with low risk cases (7 and 3 days, respectively, in response to GCT-CM). The delay in colony formation was found to be caused by an increase in the time interval before progenitor cells had begun to divide. These results suggest that a prolongation of the time spent in G0 of myeloid progenitor cells in MDS may be the cause of the indolent in vitro colony formation observed in this disease.

Bone Marrow↗
PubMed1989

Toxicity of methotrexate in rats preexposed to nitrous oxide.

Several chemotherapeutic protocols for the treatment of malignancies include administration of methotrexate (MTX) during or shortly after total anesthesia. Clinical observations in patients treated for breast carcinoma or childhood cancer have shown unexpected myelosuppression and mucosal damage. This phenomenon may be attributed to the synergistic effects of nitrous oxide, which inactivates the cobalamin coenzyme of methionine synthase, and MTX, which inhibits dihydrofolate reductase, on folate metabolism. However, no quantitative data on dose-effect relationships are available regarding the combined toxicity of MTX and N2O. We investigated the effect of exposure to N2O on the toxicity of MTX. Groups of male Wistar rats were exposed to either 50% N2O/50% O2 or air for 12-48 h. Subsequently, a single i.p. injection of 10, 20, 40, or 80 mg MTX/kg body weight was given. Gastrointestinal toxicity resulted in diarrhea and weight loss in all groups for 5 days after MTX administration. Concomitantly, bone marrow depression with leukocytopenia and thrombocytopenia occurred. Exposure to N2O did not alter the plasma clearance of MTX. No substantial liver or kidney toxicity could be detected, but the 50% lethal dose for MTX was reduced from 60 mg/kg to 10 mg/kg if rats had been exposed to N2O for 48 h; the main causes of death were dehydration and bleeding. The administration of 5-formyl-tetrahydrofolate (4 x 10 mg i.p.) but not 5-methyltetrahydrofolate protected completely against the lethal effect of the drug combination. Altogether, cytotoxic effects of MTX on proliferating cells are potentiated by N2O. Therefore, the use of this anesthetic shortly before or during MTX administration should be avoided.

Animals↗
PubMed1989

Uptake of transcobalamin II-bound cobalamin by HL-60 cells: effects of differentiation induction.

Binding and uptake of transcobalamin II-bound cobalamin by HL-60 promyelocytic leukemia cells proceed through receptor-mediated endocytosis. The affinity constant of the receptor for transcobalamin II-cobalamin was found to be 6.1 liter/nmol and the maximal rate of uptake 12 pmol/10(9) cells/h. This uptake is mediated by about 3000 receptor sites per cell. Evidence is presented that the receptor recirculates from the cell surface to the lysosomes and vice versa. Upon differentiation induction of the cells by either DMSO in granulocytic direction or by 1,25-dihydroxy-vitamin D3 in monocytic direction a rapid decline in cellular uptake and cell surface binding of the protein-bound vitamin ensues. In particular the internalization of the complex decreases faster than all other observed signs of the ongoing differentiation process, such as reduction in the OKT9-reactive transferrin receptor, increase in lineage-specific surface markers, and decrease in [3H]thymidine incorporation and actual cell proliferation. The transcobalamin II receptor on the cell surface appears to be a proliferation-associated membrane component in human leukemic cells.

Calcitriol↗
PubMed1989

Nitrous oxide selectively reduces the proliferation of the malignant cells in experimental rat leukemia.

A considerable reduction of hepatosplenomegaly and leucocytosis in leukemic rats of the Brown Norway Myeloid Leukemia (BNML) can be achieved by exposure to 50% nitrous oxide/50% oxygen. In this study the differential antiproliferative effect of nitrous oxide, inactivating vitamin B12, on normal and leukemic hemopoiesis was investigated in this rat model. Rats injected with leukemic cells and exposed to nitrous oxide for 10 days showed 30% reduction of hepatosplenomegaly and 50% reduction of leukocytosis. Similarly treated healthy rats showed no signs of impaired hemopoiesis as measured by peripheral blood parameters. Clonogenic assays of erythroid and myeloid progenitors from both healthy and leukemic rats revealed that exposure to nitrous oxide did not suppress normal bone marrow functioning. On the contrary, the reduction of leukemic proliferation by nitrous oxide retarded the leukemic infiltration of the bone marrow compartment.

Animals↗
PubMed1988

Separation of transcobalamin II isoproteins by means of chromatofocusing.

Transcobalamin II, the principal cobalamin-binding protein in human plasma, expresses a genetic polymorphism. Four more or less common alleles, denoted by X, S, M and F, have been defined earlier by means of gel electrophoretic techniques followed by autoradiography. This technique is less suitable for the analysis of individual samples and requires long exposure times. This paper describes the analysis of transcobalamin II phenotypes by means of fast protein liquid chromatofocusing. This technique has the advantage that the results of the analysis of several samples can be obtained within a day, and it also seems applicable to the preparative separation of transcobalamin II isoproteins. The sequence of elution of the isoproteins was in complete accordance with the banding pattern obtained by electrophoretic separation. The characteristic doublet bands found with polyacrylamide gel electrophoresis were less obvious in the chromatofocusing elution pattern.

Chromatography, Liquid↗
PubMed1988

The reduction of intracellular polyamines by sequential inhibition of the synthesis of decarboxylated S-adenosylmethionine: effects on rat leukemia.

Decarboxylated S-adenosylmethionine (SAM) is an aminopropyl donor in the synthesis of the polyamines, spermidine and spermine. The decarboxylation of SAM is inhibited by the toxic cytostatic drug methylglyoxalbis-(guanylhydrazone) (MGBG). To achieve more specific and less toxic effects of MGBG, this drug was combined with cycloleucine, which inhibits SAM synthesis, and with nitrous oxide, which inhibits methionine synthetase. This treatment thus aimed at sequential inhibition of the synthesis of decarboxylated SAM, and was studied in a rat leukemia model (BNML). Combined treatment further decreased the level of spermine, but not of spermidine, in leukemic cells, compared to the effects of MGBG alone. The therapeutic effects of this combination were additive or less than additive, however. MGBG was not very effective in reducing leukemic growth and severely toxic, although less with combined treatment. Another inhibitor of SAM decarboxylase, berenil, was also used, and although this drug was about equally active in inhibition of leukemic growth, alterations in intracellular polyamines were not observed. The combination of nitrous oxide and cycloleucine, which effectively reduced leukemic growth at non-toxic dosages, selectively inhibited spermine synthesis, and therefore may be used to interfere with polyamine metabolism. The relevance of this polyamine deprivation to the treatment of leukemia could not be demonstrated.

Adenosylmethionine Decarboxylase↗
PubMed1988

Application of heparin-conjugated Sepharose for the measurement of cobalamin-saturated and unsaturated transcobalamin II.

The cobalamin-binding plasma protein transcobalamin II has a high affinity for the anticoagulant heparin. This phenomenon has been exploited in a new method for the quantification of cobalamin-saturated (holo-) and unsaturated (apo-) transcobalamin II in human plasma. Transcobalamin II is adsorbed from human plasma to heparin-conjugated Sepharose under suitable conditions and either cobalamin from adsorbed holo-transcobalamin II is measured by a radioisotope dilution assay or apo-transcobalamin II is determined by measuring the adsorbed unsaturated cobalamin-binding capacity with radioactive cobalamin. The assay results for apo- and holo-transcobalamin II are similar (r = 0.99 and 1.0, respectively) to those obtained with the established radioimmunosorbent assay using specific rabbit anti-human transcobalamin II-conjugated Sepharose. The assay cannot be carried out in heparin-anticoagulated plasma, because the free heparin competes with the immobilized heparin for the binding of transcobalamin II. The amount of heparin in plasma from patients being treated with subcutaneous or intravenous heparin is too low to interfere significantly with the measurement of transcobalamin II. Also the presence of circulating anti-transcobalamin II antibodies, as occur in some rare patients after frequent intramuscular injections of cobalamin, does not influence the assay.

Heparin↗
PubMed1988

Effect of cobalamin inactivation on folate metabolism of leukemic cells.

Exposure to nitrous oxide inactivates the cobalamin coenzyme of methionine synthetase, an essential enzyme in folate metabolism. Hemopoietic cells are especially dependent on the function of cobalamin for the folate-dependent synthesis of thymidylate (dTMP). Inhibition of methionine synthetase may therefore be of potential value in the treatment of hematological malignancies. In the present study we investigated the effect of nitrous oxide induced cobalamin inactivation on folate metabolism of fresh leukemic cells and the human myelomonocytic cell line U937. Cells were exposed to nitrous oxide for 20 h. Subsequently they were subjected to the deoxyuridine suppression test (dU test), which measures the disturbance of folate-dependent dTMP synthesis. In all bone marrow samples, cobalamin inactivation resulted in a 200% increase of the dU test value, implicating a decreased de-novo synthesis of dTMP. Incubation of leukemic cells with methotrexate, 5-fluorouracil or cycloleucine induced similar increases of the dU test values which could be further raised to 400% with the addition of N2O exposure. Prolonged experiments with U937 cells revealed that the disturbance of folate metabolism aggravated up to 48 h of nitrous oxide exposure. It can be concluded that cobalamin inactivation in human leukemic cells results in disturbed folate-dependent dTMP synthesis. Moreover, effects of several drugs interfering with folate metabolism can be enhanced.

Bone Marrow↗
PubMed1988

In myelodysplastic syndromes progression to leukemia is directly related to PHA dependency for colony formation and independent of in vitro maturation capacity.

In an agar-liquid double-layer colony assay in which myeloid leukemia colony-forming cells require the presence of both the lectin PHA and CSF for in vitro proliferation, colony formation of bone marrow cells derived from patients with a myelodysplastic syndrome (MDS) was studied. In five of 14 MDS and all five leukemic transformed MDS cases, colony formation was found to require both PHA and CSF. Three of these five PHA-dependent MDS cases progressed to overt leukemia within 1 year, one progressed from RA to RAEB, and one patient received AML chemotherapy. PHA-dependent colony formation was associated with higher bone marrow blast counts, but not directly to FAB type or cytogenetic abnormalities. In nine other MDS cases only CSF was required for colony formation. In these PHA-independent cases the course of the disease was stable during the observation time (5-17 months). Two types of colonies were observed in this in vitro system: colonies adherent and colonies nonadherent to the agar underlayer. The former consisted of terminally differentiated myeloid cells, and the latter comprised immature cells. This suggests that the percentage of adherent colonies formed in vitro may be used as a measure for the maturation defect in MDS. However, no correlation was found between the percentage of adherent colonies and progression to leukemia of the MDS cases. Our findings suggest that the dependency on PHA for in vitro colony formation of colony-forming cells in MDS is predictive for the progression to leukemia. However, the in vitro differentiation capacity has no apparent prognostic significance.

Adolescent↗
PubMed1986

Enhanced therapeutic effect of methotrexate in experimental rat leukemia after inactivation of cobalamin (vitamin B12) by nitrous oxide.

Exposure to nitrous oxide interferes selectively with the coenzyme function of vitamin B12 and causes inactivation of methionine synthetase, with subsequent impairment of folate metabolism and reduction of cellular proliferation. In a rat leukemia model (BNML) we investigated the combined administration of nitrous oxide, inactivating vitamin B12, and methotrexate (MTX), a folate antagonist inhibiting the enzyme dihydrofolate reductase. Through different mechanisms, both agents decrease the availability of tetrahydrofolate, and subsequently of other reduced folates, with increased impairment of folate-dependent synthesis of thymidylate. Effects on leukemic growth and on hematological values in rats demonstrated enhancement of the therapeutic effect of MTX by exposure to nitrous oxide. With several treatment schedules, the results of combined treatment were seen to be better than additive when compared with the effects of single agents. In particular, pretreatment of leukemic rats with nitrous oxide for 3 days before administration of MTX appeared effective. With higher doses of MTX, concomitant exposure to nitrous oxide even resulted in toxic effects. These findings were in accordance with the results of some metabolic studies performed in leukemic rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Variant-specific differences in human unsaturated transcobalamin II.

Electrophoresis and subsequent autoradiography of 57Co-cobalamin (57 Co-Cbl)-labeled serum show intensity differences between the genetic variants of human transcobalamin II (TC2), suggesting differences in the unsaturated (apo-) TC2 concentration. In order to distinguish between variant-specific differences in the Cbl binding affinity and those in the total-TC2 concentration, techniques were developed to determine total, apo-, and holo-TC2. Prolonged incubation at 37 degrees C with a 20-fold excess of 57Co-Cbl resulted in an almost complete exchange of endogenously bound Cbl, which allowed determination of the total TC2. The holo-TC2 concentration of both gene products in TC2 heterozygotes could be estimated by comparison of the labeling levels of apo- and total TC2, using densitometric quantification of the autoradiographs. By means of ion-exchange chromatography, TC2 could be separated from other Cbl-binding proteins, permitting a simple quantitative assay of apo- and total TC2, the results of which correlate fairly well with those measured by an immunoadsorption assay. The results obtained in the present investigation indicate that the variant-specific variation in the apo-TC2 concentration is caused by differences in the total-TC2 concentration rather than in the Cbl binding affinity.

Apoproteins↗