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Biomedical subjects

D Hoelzer

Publications and source records attributed to D Hoelzer.

At least 289 records · Page 16Linked to original sources
PubMed1989

In vivo effects of recombinant human erythropoietin on circulating human hemopoietic progenitor cells.

Recombinant human erythropoietin (rhEpo), now available, has become increasingly more important for clinical use, e.g., in the treatment of anemia of chronic renal failure, and has been shown to reverse anemia in these patients. When patients with anemia of chronic renal failure were treated with rhEpo at dosages between 40 and 120 U/kg three times per week, the numbers of circulating erythroid burst-forming units (BFU-E) and granulocyte-erythrocyte-macrophage-megakaryocyte colony-forming units (CFU-GEMM) significantly increased during the first week of therapy. In contrast, the incidence of circulating granulocyte-monocyte CFU (CFU-GM) was not significantly altered.

Cell Separation↗
PubMed1988

Reduced methyl group acceptance of 1-beta-D-arabinofuranosylcytosine-containing DNA polymers.

Previous studies have shown that 1-beta-D-arabinofuranosylcytosine (ara-C) can induce differentiation of various malignant cells and that DNA methylation patterns become altered under ara-C treatment of those cells. The aim of this study was to investigate whether this influence on DNA methylation is caused by a direct effect of DNA-incorporated ara-C molecules on nuclear DNA methylase. For this reason, we constructed various ara-C-substituted DNA polymers and used them as substrates for highly purified eukaryotic DNA methylase isolated from murine P815 mastocytoma cells. The ara-C incorporation into DNA polymers was measured by either an ara-C-specific radioimmunoassay or by use of radioactive-labelled ara-C during the synthesis of those polymers. We found an inverse correlation between the level of ara-C substitution of the DNA polymers and their methyl group acceptance. Kinetic experiments performed with ara-C-modified DNA polymers pointed out that the mode of action of DNA methylase remains unaltered. DNA methylase is neither detached nor fixed at an ara-C site, but is somehow hindered in its enzymatic activity, probably by slowing down the walking mechanism. Hence, the previously observed hypermethylation of DNA of some eukaryotic cells, propagated in the presence of ara-C, is apparently not due to a direct effect of DNA-incorporated ara-C molecules on endogenous DNA methylase.

Animals↗
PubMed1988

Effect of human recombinant erythropoietin on human hemopoietic progenitor cells in vitro.

Recombinant human erythropoietin (rhEpo), now available, might become increasingly more important for clinical use, e.g., in the treatment of anemia of chronic renal failure. As a prerequisite of clinical trials, we analyzed the stimulatory and suppressive effects of rhEpo on human hemopoiesis by adding rhEpo to in vitro cultures of nonadherent low-density bone marrow cells obtained from normal persons and from patients undergoing hemodialysis for chronic renal failure. rhEpo was shown to be an effective stimulus for erythroid and multilineage colony formation. The dose-response curve was similar for erythroid progenitors BFU-E from normal controls and patients with chronic renal failure. rhEpo had no effect on megakaryocytic colony formation nor on the megakaryocytic differentiation of multilineage stem cells. Because of a good stimulatory activity on erythroid and multilineage stem cells and lack of toxic effects, rhEpo might be useful in the treatment of certain kinds of anemia.

Bone Marrow↗
PubMed1988

Induction of myeloperoxidase in five cases of acute unclassified leukaemia.

For further analysis of their lineage affinity the differentiation capacity of five cases of acute unclassified leukaemias were studied in vitro using 5 nM 12-O-tetradecanoyl-phorbol-13-acetate as an inducing agent. After 4 d in vitro a co-expression of both myeloid and early B-lymphoid or myeloid and early T-lymphoid antigens on the same population of cells was found. While ultrastructural analysis of the blasts prior to culture revealed the morphology of undifferentiated blasts without any specific endogenous peroxidase activity, the cultured blasts displayed monoblastic features and myeloperoxidase activity after 4 d in vitro. Since this type of peroxidase is highly specific for the myelomonocytic lineage the data indicate myelomonocytoid differentiation of all five cases studied. The co-expression of lymphoid as well as myeloid antigens and myeloperoxidase by the same blasts after culture could be indicative of bilineage differentiation capacity characterizing the original blasts as bipotential progenitor cells.

Acute Disease↗
PubMed1988

[Induction and intensive combined therapy of acute myeloid leukemia in adults].

In a prospective multicenter study the efficacy and toxicity of an induction therapy with daunorubicin, cytosine-arabinoside and VP 16-213, followed by an intensified consolidation with high-dose cytosine-arabinoside and daunorubicin, is evaluated in adult patients with acute myelogenous leukemia. The upper age limit for inclusion in the study was 50 years. Within the first two years of this study 91 patients were enrolled. In 84 patients who have finished the remission induction therapy the rate of complete remissions is 67%. The median survival time of all patients is 22 months and the probability of survival is 46% after 24 months. So far 34 patients in complete remission have been given one or two courses of the intensified consolidation therapy with high-dose cytosine-arabinoside and daunorubicin. The probability of relapse-free survival in these patients is 46% after 22 months and the median remission duration is 20 months.

Adolescent↗
PubMed1988

[Intensive combined therapy for high-risk ALL patients].

In the risk-adapted multicenter trial (02/84) for adult ALL the effectiveness of a consolidation therapy consisting of VM26 and Ara-C for high-risk patients was tested. Out of a total of 442 patients in the study, 79.2% achieved a complete remission. For the 182 high-risk patients the median remission duration is 17 months and the probability of being in continuous complete remission (CCR) is 34%. Improved results were found for elderly ALL patients between 35 and 65 years of age, whose median remission duration and CCR rate are 19 months and 40% respectively, compared to 15 months and 26% in the former study 01/81. The consolidation therapy has apparently also benefited patients with the immunological subtype c-ALL, for whom the CCR rate at 3 years is 53% in comparison to the previous value of 34%.

Adolescent↗
PubMed1988

Recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes--a phase-I/II trial.

A phase-I/II trial was initiated to study the effect of rhGM-CSF in patients with myelodysplastic syndromes who were not eligible for other kinds of therapy, rhGM-CSF was given to 9 patients in doses of 15 micrograms/m2-150 micrograms/m2 as an intravenous 8-h infusion for a cycle of 7 days followed by an interval of 14 days and a second 7-day treatment course. A dose-dependent increase in the leukocyte count was observed in 7 out of 9 patients. No change in reticulocyte numbers was seen and only 1 patient experienced an increase in platelet count. Toxicity mainly consisted of mild local phlebitis at the site of infusion and sternal pain after bolus injection.

Aged↗
PubMed1988

Reproductive and endocrine gonadal functions in adults following multidrug chemotherapy for acute lymphoblastic or undifferentiated leukemia.

The impact of aggressive chemotherapy on reproductive and endocrine gonadal function was studied in ten women and ten men with acute lymphoblastic leukemia (ALL) or acute undifferentiated leukemia (AUL) in complete remission. Hormone determinations, sperm analyses, measurements of basal body temperature, and interviews with a standardized questionnaire were used for diagnostic evaluation. Elevated serum follicle-stimulating hormone (FSH) levels and azoospermia were seen in all male patients after completion of induction and consolidation therapy as a result of germ cell and stem cell loss. Recovery of spermatogenesis, as indicated by normalization of serum FSH values and sperm density, occurred in the second year of maintenance therapy in all men. Serum testosterone and luteinizing hormone (LH) values remained within normal limits indicating resistance of Leydig cells to chemotherapy. All female patients showed normal serum levels of gonadal steroids and gonadotropins, as well as an adequate increase in basal body temperature after intensified chemotherapy, indicating intact follicle function and ovulation. Most patients reported normal sexual functions after induction and consolidation therapy. These results demonstrate that multidrug chemotherapy induced significant impairment of reproductive function in all male patients with early and complete recovery. In contrast, endocrine gonadal function was unaffected in men treated with ALL/AUL. In female patients, neither reproductive nor endocrine functions were influenced by aggressive chemotherapy.

Acute Disease↗
PubMed1988

In vitro and in vivo action of recombinant human GM-CSF (rhGM-CSF) in patients with myelodysplastic syndromes.

The availability of rhGM-CSF has allowed the in vivo treatment of patients with cytopenia. Therefore, a phase I-II trial was initiated to study the effect of rhGM-CSF in patients with myelodysplastic syndromes who were not eligible for other kinds of therapy. rhGM-CSF has been tested in 10 patients in doses from 15 micrograms/m2 to 150 micrograms/m2 given intravenously over 8 hours for a cycle of 7 days followed by an interval of 14 days and a second 7-day treatment course. A dose-dependent increase in leukocyte count was observed in 9 of 10 patients. No change in reticulocyte numbers was seen and only one patient experienced an increase in platelet count. Toxicity mainly consisted of mild phlebitis at the site of infusion and sternal pain after bolus injection. An increase in blast cell counts in some patients necessitated the start of low-dose Ara-C therapy.

Colony-Stimulating Factors↗
PubMed1988

Phase I/II study with GM-CSF in patients with myelodysplastic syndromes.

The availability of rh GM-CSF has allowed the in vivo treatment of patients with cytopenia. Therefore a phase I/II trial was initiated to study the effect of rh GM-CSF in patients with myelodysplastic syndromes who were not eligible for other kinds of therapy. rh GM-CSF has been tested in 10 patients in doses from 15 micrograms/m2 to 150 micrograms/m2 given intravenously over 8 hours for a cycle of 7 days followed by an interval of 14 days and a second 7-day treatment course. A dose dependent increase in leukocyte count was observed in 9 out of 10 patients. No change in reticulocyte numbers was seen and only one patient experienced an increase in platelet count. Toxicity mainly consisted of mild local phlebitis at the site of infusion and sternal pain after bolus injection. An increase in blast cell counts in some patients necessitated the start of low dose Ara-C therapy.

Colony-Stimulating Factors↗
PubMed1988

Effect of recombinant human granulocyte-macrophage colony-stimulating factor on the hemopoietic progenitor cells from patients with AIDS.

Derangement of the hemopoietic progenitor cells has been observed in the majority of patients with the acquired immunodeficiency syndrome (AIDS). In this study the effect of recombinant human GM-CSF was evaluated for the in vitro growth of hemopoietic progenitor cells from the bone marrow of patients with AIDS. A significant reduction of growth (mean +/- SEM) of CFU-GEMM (2.5 +/- 1.2), BFU-E (23 +/- 9), and CFU-GM (55 +/- 21) was found in AIDS patients in comparison to normal controls. There was a linear correlation between the number of CFU-GM growing in vitro after stimulation with rh GM-CSF as compared to medium conditioned by phytohemagglutinin-stimulated leukocytes (PHA-LCM). However, CFU-GM from patients with AIDS appear to need higher concentrations of rh GM-CSF for maximal growth.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Recombinant gamma-interferon induces in vitro monocytic differentiation of blast cells from patients with acute nonlymphocytic leukemia and myelodysplastic syndromes.

gamma-Interferon (IFN-gamma) has previously been found to induce monocytic differentiation in established leukemic cell lines, such as HL-60 and U937. The aim of the present study was to evaluate the differentiative effect of highly purified recombinant (r)IFN-gamma on fresh bone marrow cells from patients with acute nonlymphocytic leukemia (n = 11) or myelodysplastic syndromes (n = 3). Blast cells were cultured in suspension in the presence or absence of rIFN-gamma (10-10(3) U/ml). While 6 out of 14 cases were unresponsive to rIFN-gamma in vitro, the remaining 8 patients showed a significant increase (0.05 greater than p greater than 0.001) in the percentage of cells expressing C3bi receptors, detected by OKM1 (median value in control cell, 9.5; median value in rIFN-gamma-treated cells, 31) and Mo1 (8.5 vs. 36), and in the percentage of cells expressing the monocytic antigens detected by Mo2 (8 vs. 28) and MY4 (6.5 vs. 32.5). In the responsive patients morphologic changes consistent with monocytic maturation, as well as a strong increase of alpha-naphthyl acetate esterase activity and of nitroblue tetrazolium reducing capability were observed upon culture with rIFN-gamma. We conclude that (a) rIFN-gamma may induce in vitro monocytic differentiation of blasts from acute nonlymphocytic leukemia and myelodysplastic syndrome patients, and that (b) this agent should be investigated for its capacity to be active in vivo.

Acute Disease↗
PubMed1988

Synergistic antiproliferative effect of recombinant interferon-gamma with recombinant interferon-alpha on chronic myelogenous leukemia hematopoietic progenitor cells (CFU-GEMM, CFU-Mk, BFU-E, and CFU-GM).

Recombinant interferons, alpha (rIFN-alpha) and gamma (rIFN-gamma), have been demonstrated to have significant antitumor activity as single agents in the treatment of chronic myelogenous leukemia (CML). Due to their possible synergistic efficacy, a combination rIFN therapy in CML has been proposed. To establish a biologic basis for this, we have studied the suppressive effects of rIFN-alpha and rIFN-gamma on the in vitro growth of CML-derived progenitor cells (CFU-GEMM, CFU-Mk, BFU-E, CFU-GM), the optimal conditions for rIFN synergism, and the possible role of hematopoietic accessory cells (T-lymphocytes and monocytes-macrophages) in mediating rIFN-induced growth inhibition. When added to unseparated bone marrow cells, rIFN-alpha and rIFN-gamma significantly reduced colony formation, with 50% inhibition occurring at 71 and 186 U/mL for CFU-GEMM, 40 and 152 U/mL for CFU-Mk, 222 and 1,458 U/mL for BFU-E, and 119 and 442 U/mL for CFU-GM, respectively. A small amount of rIFN-gamma (5 U/mL) acted synergistically with increasing doses of rIFN-alpha, and the values of 50% inhibitory concentrations fell outside the lower limit (10 U/mL) used in our experiments. This synergy was evident even when rIFN-gamma was added 72 hours after the initiation of cultures; however, it was completely lost when the target cells were depleted of accessory cells. When a low dose of rIFN-alpha (5 U/mL) was added to rIFN-gamma, the 50% inhibitory concentration values were decreased up to tenfold. These studies (1) confirm that CML-derived hematopoietic progenitors are responsive to the suppressive activity of both rIFN-alpha and rIFN-gamma in vitro, (2) demonstrate that different mechanisms are responsible for the suppressive activity of the two rIFNs, and (3) characterize their synergistic interaction, providing a basis for future clinical trials aimed at investigating combination rIFN therapy in CML.

Bone Marrow↗