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Biomedical subjects

A Zander

Publications and source records attributed to A Zander.

At least 55 records · Page 3Linked to original sources
PubMed1996

Stem cell factor as a survival and growth factor in human normal and malignant hematopoiesis.

Stem cell factor (SCF) is an essential hematopoietic cytokine that interacts with other cytokines to preserve the viability of hematopoietic stem and progenitor cells, to influence their entry into the cell cycle and to facilitate their proliferation and differentiation. SCF on its own cannot drive noncycling hematopoietic progenitor cells into the cell cycle but does prevent their apoptotic death. SCF when combined with other cytokines increases the cloning efficacy of hematopoietic progenitor cells from all lineages. SCF also stimulates the growth of CD34+ leukemic progenitor cells from most patients with acute myeloid leukemia (AML). The mRNA expression of the SCF receptor c-kit has been shown to be significantly increased in all fresh AML blast cells compared with normal controls (healthy volunteers), in particular CD34+ cells. Two inhibitory cytokines, transforming growth factor-beta and interleukin-4, decreased c-kit expression, whereas tumor necrosis factor-alpha increased c-kit expression, but chemotherapeutic drugs showed no effect on c-kit expression, but chemotherapeutic drugs showed no effect on c-kit expression in AML cells. Apoptosis has been shown to be directly related to a high complete remission rate in AML patients following induction therapy. Since SCF has been shown to stimulate the proliferation of mainly CD34+ AML cells, we have investigated whether the poor response of patients with CD34+ myeloid leukemia cells to chemotherapy could be due to SCF-induced resistance to apoptosis. The effect of SCF on the apoptosis induced by chemotherapeutic drugs commonly used in the treatment of AML - cytarabine, daunorubicin and carboplatin - was examined in human CD34+ myeloid leukemia cells in serum-free cultures. SCF significantly reduced the induced apoptosis by more than 50% in all CD34+ human leukemia cells treated by any of the three chemotherapeutic drugs. Antibodies blocking c-kit reversed the significant inhibitory effect of SCF on chemotherapy-induced apoptosis, confirming the role of SCF in the resistance to chemotherapy-induced apoptosis in CD34+ human leukemia. These results suggest that the poor response of patients with CD34+ leukemia cells could be at least partially due to less chemotherapy-induced apoptosis resulting from protection by SCF as an adjuvant mechanism for drug resistance in myeloid leukemia. We conclude that an antisense strategy to block c-kit expression in AML blast cells may prove valuable for decreasing the chemoresistance of AML patients. The abrogation of leukemic resistance to apoptotic death through anti-SCF/c-pit expression combined with chemotherapy offers potential for designing novel therapeutic approaches for refractory AML patients.

Acute Disease↗
PubMed1996

Fatal outcome of disseminated candidosis after allogeneic bone marrow transplantation under treatment with liposomal and conventional amphotericin-B. A report of 4 cases with determination of the Mic values.

Four patients undergoing allogeneic bone marrow transplantation were treated with liposomal (3 patients) and conventional (one patient) amphotericin-B for disseminated candidosis. Candida krusei was isolated from 3, and C. glabrata from 1 patient. The patients were treated with liposomal amphotericin-B in doses from 3 to 5 mg/kg. The fourth patient received conventional amphotericin-B in a reduced dose due to renal impairment. The patients died from multiorgan failure due to disseminated fungal infection. In 1 case, the switch to the conventional drug resulted in clearance before death. The 3 fungus isolates, together with the fourth strain obtained from patient no. 4 without any exposition to liposomal amphotericin-B were tested for their susceptibility to conventional, liposomal and discoidal amphotericin-B. All strains showed good sensitivity to the conventional and discoidal drug. The minimal inhibitory concentrations (MIC) of liposomal amphotericin-B were 1 to 3 titre steps higher indicating a reduced sensitivity of the tested strains to this preparation. We conclude that the use of liposomal amphotericin-B is recommended mainly on the base of the low incidence of side-effects. Intensive microbial resistance tests, pharmacokinetic investigations and randomized studies are necessary before the conventional drug is replaced as the gold standard for systemic antimycotic therapy.

Adult↗
PubMed1996

Use of cryopreserved bone marrow in unrelated allogeneic transplantation.

Cryopreservation of donor bone marrow can facilitate scheduling allogeneic bone marrow transplantation (BMT) by affording independence of a preset time for donation. Previously, we and others have shown the feasibility of using cryopreserved related allogeneic bone marrow. Here, we report the results of the first 10 patients receiving cryopreserved unrelated bone marrow between 1992 and 1995. All evaluable patients (n = 9) engrafted. Time to reach an absolute neutrophil count (ANC) >0.2 x 10(9)/1 and ANC >0.5 x 10(9)/l was 21.4 +/- 9.1 days and 22.6 +/- 9.2 days, respectively. The incidence of acute GVHD > or = grade II and chronic GVHD was 75 and 20%, respectively. Five of nine evaluable patients were alive 100 days post-transplantation. We conclude that cryopreserved unrelated donor bone marrow may be used for allogeneic transplantation.

Adolescent↗
PubMed1996

Effect of cytokine treatment (granulocyte colony-stimulating factor and stem cell factor) on hematopoiesis and the circulating pool of hematopoietic stem cells in mice.

The mobilization of hematopoietic stem cells (HSCs) into the peripheral blood of mice was induced by recombinant human granulocyte colony-stimulating factor (rhG-CSF) (250 microgram/kg/d) alone or combined with recombinant rat stem cell factor (rrSCF) (34 microgram/kg/d), injected subcutaneously (s.c.) once a day for 10 and 17 days. After administering G-CSF plus SCF or G-CSF alone for 10 days, the level of day-11 spleen colony-forming units (CFU-S-11) in the peripheral blood increased 169- and 93-fold, respectively. The effect was lower--30- and 17-fold--after 17 days of treatment. A 1.5- to three-fold decrease in CFU-S-11 content in the bone marrow of treated mice was observed. In normal mice, the content of long-term culture initiating cells (LTC-IC) in blood was below the threshold level. Cytokine treatment mobilized LTC-IC in the circulation. Following a 10- and 17-day course of G-CSF plus SCF, the proliferation of CFU-S-11 in the peripheral blood but not in the bone marrow increased from <10% in the controls to 44 and 72%, respectively, as measured by hydroxyurea (HU) suicide. Spleen-repopulating ability (SRA) of CFU-S (daughter CFU-S-8 content in an 11-day-old spleen colony) increased two-fold in the peripheral blood after a 10-day course and seven-fold after a 17-day course of combined cytokines. One month after the final cytokine injection, all hematopoietic indexes (including the number of different precursors, their proliferative rate, and their SRA) were near normal. The results suggest that the age structure of the mobilized progenitor population depends on both the cytokines used and the duration of the treatment: more immature CFU-S with higher proliferative activity and an increased SRA were mobilized preferentially after a 17-day course of combined cytokines.

Animals↗
PubMed1996

Serum interleukin-6 levels during bone marrow transplantation: impact on transplant-related toxicity and engraftment.

The biological properties of IL-6 include the induction of acute phase proteins, stimulation of hematopoietic stem cell growth and thrombopoiesis. Serum levels of IL-6 were closely monitored in 66 patients before and after allogeneic (n = 37), autologous bone marrow transplantation (n = 8) or autologous peripheral blood stem cell transplantation (n = 21). Almost every patient showed elevated IL-6 serum levels during the aplastic phase. Patients then suffered from mucositis, had elevated C-reactive protein (CRP) and usually body temperatures of above 38 degrees C. It was investigated whether IL-6 serum levels, apart from inducing acute phase reactions, correlated with transplant-related complications or leukocyte and thrombocyte engraftment. By statistical analysis, a correlation was found between IL-6 and CRP and between IL-6 and fever. In contrast, no correlation was found between IL-6 and elevated serum bilirubin as a marker for hepatotoxicity. IL-6 showed a weak negative correlation with leukocyte or platelet counts. In contrast, the day of platelet engraftment correlated with the day of peak serum IL-6 value, possibly indicating an influence of IL-6 on platelet engraftment.

Bilirubin↗
PubMed1995

Cyclophosphamide/antithymocyte globulin conditioning of patients with severe aplastic anemia for marrow transplantation from HLA-matched siblings: preliminary results.

Many approaches have been taken to reducing the rate of graft failure and the incidence of graft-versus-host disease (GVHD) in bone marrow transplantation (BMT) of patients with severe aplastic anemia (SAA). The combination of cyclophosphamide with irradiation has had unequivocal success in reconstituting a sustained engraftment, but this procedure has severe associated risks such as second malignancies. Recently, cyclophosphamide (CYC) plus antithymocyte globulin (ATG) has been shown to be an effective alternative to irradiation-based programs in retransplants. Based on these experiences, the current clinical trial was started to prepare patients suffering from SAA for marrow transplantation from HLA-identical siblings with ATG plus CYC. Nine patients have been enrolled into the study so far. They received a total dose of 200 mg/kg CYC and concomitantly 120 mg/kg or 90 mg/kg ATG, followed by cyclosporine plus methotrexate as post-transplantation GVHD prophylaxis. Eight of nine patients survived without any transplant-associated complications; i.e., they had a documented stable engraftment without rejection and without acute or chronic GVHD. One patient died due to an Aspergillus sepsis prior to a definite engraftment. Although our data are preliminary because of the small number of patients enrolled and a follow-up of only 30 months, CYC plus ATG appears to be an effective preparative regimen for BMT in patients with SAA, resulting in a favorable outcome.

Adolescent↗
PubMed1995

Hematopoietic progenitor cell mobilization into the peripheral blood of mice using a combination of recombinant rat stem cell factor (rrSCF) and recombinant human granulocyte colony-stimulating factor (rhG-CSF).

A significant increase in the hematopoietic stem cell (HSC) concentration has been observed in the peripheral blood and spleen of mice treated with rhG-CSF alone or with a combination of rhG-CSF plus rrSCF. The longer the duration of cytokine treatment, the higher the stimulatory effect on stem cell mobilization. In addition, cytokine administration led to a reduced stem cell concentration in the bone marrow. The total amount of HSCs in the body did not change following cytokine administration. These data support the theory that stem cells are mobilized from the bone marrow into circulation, as opposed to expanding in blood and spleen. In sharp contrast to rhG-CSF alone, a combination of rhG-CSF plus rrSCF produced a strong increase in the self-maintenance ability of peripheral blood day 11 colony-forming units-spleen (CFU-S-11). After 10 days of cytokine treatment, long-term culture initiating cells (LTC-IC) were seen in the peripheral blood; in normal mice, the content of LTC-IC in the blood was below the detection level. The activation of stromal progenitors (cells capable of transferring the hematopoietic microenvironment) by cytokine treatment was observed here for the first time. The results suggest that a combination of rhG-CSF plus rrSCF is more effective than rhG-CSF alone in obtaining a large amount of transplantable HSCs.

Animals↗
PubMed1995

Use of cryopreserved bone marrow in allogeneic bone marrow transplantation.

Use of cryopreserved donor bone marrow may facilitate scheduling of allogeneic bone marrow transplantation (BMT) by affording independence of a fixed time for bone marrow donation. The potential risk of damage to hematopoietic stem cells by cryopreservation resulting in delayed engraftment or graft failure has to be taken into account, however. To address these issues, the outcome of 19 matched related BMT (1992-94) performed with cryopreserved donor bone marrow was analyzed and compared with 19 related BMT (1990-93) receiving fresh donor bone marrow (control group). Time to engraftment of patients receiving cryopreserved bone marrow was not different from the control group (ANC > 0.2 x 10(9)/l 15.5 +/- 3.8 days vs 15.8 +/- 5.0 days; ANC > 0.5 x 10(9)/l 17.3 +/- 4.1 days vs 17.9 +/- 5.0 days, respectively). We did not find the previously described trend toward a lower incidence of acute GVHD in patients receiving cryopreserved bone marrow compared with patients receiving fresh bone marrow (acute GVHD > or = II 78 vs 64%). Furthermore, the two groups did not differ in the incidence of chronic GVHD (55 vs 38%) or day 100 survival (74 vs 68%). We conclude that in allogeneic BMT cryopreserved bone marrow cells can be safely used without jeopardising or prolonging time to engraftment.

Adolescent↗
PubMed1995

Deteriorating free radical-trapping capacity and antioxidant status in plasma during bone marrow transplantation.

Organ toxicity in BMT may in part be due to free radical damage. Therefore the 'Total Radical-trapping Antioxidant Parameter of plasma' (TRAP), individual plasma antioxidants, serum iron and linoleic acid, a main substrate of lipid peroxidation, were monitored before and after BMT, and they were compared with values obtained from healthy controls. Seven patients (3 AML, 3 CML, 1 multiple myeloma) receiving 16 mg/kg busulfan, 30-45 mg VP-16 and 120 mg/kg cyclophosphamide were investigated. TRAP values declined during chemotherapy by about 40% (day -9: 1019 +/- 245 mumol/l, mean +/- s.d.; day 0: 660 +/- 164 mumol/l; P < 0.05). The concentration of uric acid, one of the main antioxidants in plasma, decreased markedly (day -9: 339 +/- 108 mumol/l, day 0: 148 +/- 61 mumol/l; P < 0.05) and paralleled TRAP values. Vitamin E and bilirubin did not change from day -9 to 0 whereas vitamin C increased (day -9: 46 +/- 16 mumol/l, day 0: 89 +/- 44 mumol/l; P < 0.05). Serum iron rapidly increased within the pre-transplantation period, reaching values normally seen only in iron overload (day -9: 11.8 +/- 5.2 mumol/l, day 0: 40.6 +/- 6.5 mumol/l; P < 0.05). Linoleic acid levels were normal at the start and decreased substantially (27.0 +/- 1.6 wt% at day -9; 15.7 +/- 4.9 wt% at day 0; P < 0.05), indicating possible lipid peroxidation during high-dose chemotherapy. In conclusion, complex monitoring of the antioxidant status before and after BMT revealed a breakdown of plasma antioxidant defence and of radical-vulnerable lipids, which was associated with high circulating levels of iron.

Adult↗
PubMed1995

Transplantation of allogeneic rhG-CSF mobilized peripheral CD34+ cells from an HLA-identical unrelated donor.

We describe the case of a 41-year-old female who underwent allogeneic blood cell transplantation with CD34(+)-enriched cells from an HLA-matched unrelated donor for AML in second CR. The conditioning regimen consisted of TBI (12 Gy), VP16 (1800 mg), cyclophosphamide (7200 mg), and ATG (7200 mg). GVHD prophylaxis consisted of CsA and a short course of MTX. Receiving G-CSF from day +1, engraftment occurred on day +19 after stem cell infusion. Starting on day +10, GVHD grade II (skin and liver) developed that responded to high-dose steroid therapy. The patient died on day +38 due to suspected cerebral aspergillus infection. This case demonstrates the feasibility of primary transplantation of CD34(+)-enriched allogeneic peripheral stem cells from a matched unrelated donor leading to engraftment of donor cells.

Adult↗
PubMed1994

Pharmacokinetics of undiluted or diluted high-dose etoposide with or without busulfan administered to patients with hematologic malignancies.

PURPOSE: We used two different methods to administer high-dose etoposide (VP-16) during a myeloablative conditioning chemotherapy regimen before bone marrow transplantation (BMT). VP-16 was administered either diluted (0.5 mg/mL) or undiluted (20 mg/mL), with or without busulfan. PATIENTS AND METHODS: Blood samples were drawn from 17 patients during the infusion (6 hours) and thereafter daily until 2 days after BMT. VP-16 concentrations were measured in all plasma samples by high-performance liquid chromatography (HPLC) and electrochemical detection, and the results were analyzed with a pharmacokinetic data analysis system. RESULTS: All calculated pharmacokinetic parameters in the two patient groups (VP-16 administered diluted or undiluted) were similar. There were no statistically significant differences in half-lives, mean residence time (MRT), volume of distribution, total clearance, or area under the curve (AUC). VP-16 was found in blood samples from eight of 17 patients at the time of BMT. Significant differences in systemic drug exposure and systemic clearance were found when patients were grouped according to treatment with busulfan or with total-body irradiation (TBI). CONCLUSION: The two administration modes for VP-16, either diluted or undiluted, are bioequivalent in pharmacokinetic terms. The terminal half-lives were longer than expected and resulted in significant VP-16 plasma levels at the time of BMT. The biologic significance remains unclear. Busulfan and/or concomitant medication with phenytoin influence plasma clearance (clp) and systemic drug exposure significantly.

Adolescent↗
PubMed1994

Pharmacokinetics of high-dose VP-16: 6-hour infusion versus 34-hour infusion.

VP-16 was administered in high doses (30-45 mg/kg) in combination with busulfan (BU) and cyclophosphamide (CY). The anticancer activity of VP-16 is thought to be schedule-dependent. We investigated a 6-h and a 34-h infusion of VP-16 to compare pharmacokinetic parameters and toxicity. Blood samples were taken from a total of 16 patients during infusion time (6 h and 34 h, respectively) and thereafter up to 2 days after bone marrow transplantation (BMT). VP-16 concentrations were measured in all plasma samples with HPLC technique and electrochemical detection and the results were analyzed with a pharmacokinetic data analysis system. All calculated pharmacokinetic parameters in the two patient groups were essentially similar. There were no statistically significant differences in half-lives, mean residence time, volume of distribution, total clearance and area under the curve. The treatment-related toxicity was not different between groups. The major difference was the maximal concentration in the case of 6-h infusions (122 +/- 35 micrograms/ml) and in the case of 34-h infusions (23.2 +/- 4.9 micrograms/ml) and the duration of VP-16 concentrations with > 10 and > 1 microgram/ml. Drug levels above these thresholds were always longer in case of 34-h infusions. In 8 of 16 patients VP-16 concentrations were measured in plasma samples at the time of BMT ranging from 80 to 820 ng/ml. The two different schedules for VP-16 administration, either given as a 6-h infusion or as a 34-h infusion, are bioequivalent in pharmacokinetic terms.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1994

[Measurement of alloreactive anti-recipient helper T-cell precursors after allogenic bone marrow transplantation].

Acute graft-versus-host disease (GvHD) is a severe complication after allogenous bone marrow transplantation (BMT). The compatibility of major histocompatibility complex antigens (MHC) is the strongest stimulus for GvHD, which also occurs in patients with a genetically MHC-identical sibling donor. In such cases it would be helpful to recognize anti-recipient (interleukin-2-producing) T-lymphocyte precursors to detect a minor histocompatibility antigen (mH), which escapes from typing methods. To quantitate the alloreactive immune response initiating acute GvHD, we established the helper T-lymphocyte precursor test (HTL-p) as described by Theobald et al. in 'GvHD direction', using a limiting dilution assay. Serial dilutions of the donor peripheral blood mononuclear cells (PBMCs) were cultured for 14 days with constant numbers of stimulator PBMCs from the recipient, followed by an unspecific restimulation step with phytohemagglutinin (PHA) or specific restimulation with EBV-transformed blast cells from the recipient. The Il-2 production of specific T cells was assessed by addition of CTLL-16 cells, whose proliferation was measured by an ELISA. We suppose that the HTL-p test is a good tool for measuring the number of anti-recipient T-lymphocyte precursors as a predictive value for the intensity of GvHD.

Bone Marrow Transplantation↗
PubMed1993

P-glycoprotein expression in normal and reactive bone marrows.

The expression of mdr1 gene product P-glycoprotein (P-gp) was investigated in 53 normal and reactive bone marrows by means of immunocytochemistry, using the monoclonal antibody (mAb) C219 and the alkaline phosphatase anti-alkaline phosphatase method. In a limited number of patients, data were confirmed by using the mAb MRK16 or a polymerase chain reaction assay for mdr1 gene expression. There was no history of prior chemotherapy or any malignancy in this group. Bone marrow aspirates were obtained as part of a routine diagnostic programme in bone marrow donors or in patients presenting with a variety of diagnoses such as unexplained gammopathy, fever, anaemia, other changes in peripheral blood smear, rheumatoid arthritis, vasculitis, or urticaria pigmentosa. Morphologically the bone marrow was normal in 23 patients, a megaloblastic erythropoiesis was seen in two patients and unspecific changes were seen in 28 patients. Twenty-seven of 53 samples were found to be positive for P-gp expression with the percentage of positive cells ranging from 2%-80% (mean = 24%). With a cutoff point of 10%, five of 23 normal (22%) and 13 of 28 reactive bone marrows (46%) were considered positive for P-gp expression. There was no obvious correlation between diagnosis or age and P-gp expression. Additional staining for the early surface marker CD-34 was performed in 12 samples, with none of them revealing more than 1% positivity. Since P-gp expression has so far been described only in CD-34 positive bone marrow cells, data suggest that P-gp expression may be reinduced in CD-34 negative cells under conditions which remain to be determined.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Effect of recombinant human granulocyte colony-stimulating factor treatment of mice on spleen colony-forming unit number and self-renewal capacity.

The aim of this investigation was to find out whether the self-renewal capacity of spleen colony-forming units (CFU-S) changed after treatment of CBF1 (CBA-LacxC57B1/6) F1 female mice with granulocyte colony-stimulating factor (G-CSF). In addition, the possibility of synergism between erythropoietin (Epo) and G-CSF in blood stem cell mobilization was studied. Twenty-five and 250 micrograms/kg/d injections of recombinant human (rh) G-CSF expanded the number of CFU-S in peripheral blood four- and 32-fold. The self-maintenance potential of CFU-S did not change significantly. The treatment of mice with 250 micrograms/kg/d rhG-CSF resulted in a two-fold increase of spleen cellularity and a 15-fold augmentation of CFU-S number, without noticeable changes in their self-renewal capacity. Moderate changes in CFU-S number were observed after Epo administration in spleen and peripheral blood; however, no significant synergistic effect of Epo was detected with either dose of rhG-CSF. The multifold increase of CFU-S number in peripheral blood following rhG-CSF administration, with no reduction in their generating potential, suggests that rhG-CSF-mobilized blood stem cells provide an appropriate source for reconstitution of the hematopoietic system.

Animals↗
PubMed1993

Intravenous pentoxifylline failed to prevent transplant-related toxicities in allogeneic bone marrow transplant recipients.

Based on encouraging results of a recently published study on the clinical usefulness of oral pentoxifylline (PTX) to reduce transplant-related toxicities, prophylactic pentoxifylline was administered to 31 consecutive allogeneic BMT recipients with hematological malignancies. Patients received PTX as a continuous infusion at increasing dose levels (0.50, 0.75, 1.00 and 1.25 mg/kg/h) starting 1 day prior to the conditioning regimen. At all dose levels, PTX was well tolerated with no significant side-effects. When compared with a historical control group of 61 consecutively transplanted allogeneic BMT recipients, PTX patients did not appear to experience less gastrointestinal (moderate and severe mucositis: 100% vs 68%, p < 0.001), hepatic (hyperbilirubinemia > 1.5 mg/dl: 84% vs 30%, p < 0.001) or renal (creatinine > 1.5 mg/dl: 16% vs 27%, NS) toxicity or to have a lower incidence of GVHD > or = grade III (21% vs 22%, NS). Using i.v. PTX, we were unable to reproduce the reduction in morbidity and mortality in patients undergoing BMT which has been described for prophylactic oral PTX.

Adolescent↗