Comparative erythrocyte deformability investigations by filtrometry, slit-flow and rotational ektacytometry in a long-term follow-up animal study on splenectomy and different spleen preserving operative techniques: Partial or subtotal spleen resection and spleen autotransplantation.

BACKGROUND: Partial or subtotal spleen resection or spleen autotransplantation can partly preserve/restore the splenic filtration function, as previous studies demonstrated. OBJECTIVE: For better evaluation and follow-up of the various spleen-preserving operative techniques' effectiveness versus splenectomy, a composite methodological approach was applied in a canine experimental model. METHODS: Beagle dogs were subjected to control (n = 6), splenectomy (SE, n = 4), partial and subtotal spleen resection (n = 4/each) or spleen autotransplantation groups (AU, Furka's spleen-chip method, n = 8). The follow-up period was 18 postoperative (p.o.) months. Erythrocyte deformability was determined in parallel by bulk filtrometry (Carat FT-1 filtrometer), slit-flow ektacytometry (RheoScan D-200) and rotational ektacytometry (LoRRca MaxSis Osmoscan). RESULTS: By filtrometry, relative cell transit time increased in the SE group (mostly in animal Nr. SE-3), showing the highest values on the 3rd, 9th and in 18th p.o. months. Elongation index values decreased in this group (both by slit-flow and rotational ektacytometers). In general, AU and two resection groups' values were lower versus control and higher than in SE. CONCLUSIONS: Forasmuch in the circulation both elongation by shear stress and filtration occur, these various erythrocyte deformability testing methods together may describe better the alterations. Considering the possible complications related to functional asplenic-hyposplenic conditions, individual analysis of cases is highly important.

Dietary selenium augments sarcoplasmic calcium release and mechanical performance in mice.

BACKGROUND: As an essential trace element selenium plays a significant role in many physiological functions of the organs. It is found within muscles as selenocystein in selenoprotein N, which is involved in redox-modulated calcium homeostasis and in protection against oxidative stress. METHODS: The effects of two different selenium compounds (selenate and NanoSe in 0.5 and 5 ppm concentration for two weeks) on muscle properties of mice were examined by measuring in vivo muscle performance, in vitro force in soleus (SOL) and extensor digitorum longus (EDL) muscles and changes in intracellular Ca2+ concentration in single fibers from flexor digitorum brevis (FDB) muscle.. Western-blot analysis on muscle lysates of EDL and SOL were used to measure the selenoprotein N expression. Control mice received 0.3 ppm Se. RESULTS: While the grip force did not change, 5 ppm selenium diets significantly increased the speed of voluntary running and the daily distance covered. Both forms of selenium increased significantly the amplitude of single twitches in EDL and SOL muscle in a concentration dependent manner. Selenate increased fatigue resistance in SOL. The amplitude of the calcium transients evoked by KCl depolarization increased significantly from the control of 343 ± 44 nM to 671 ± 51 nM in the presence of 0.5 ppm selenate in FDB fibers. In parallel, the rate of calcium release during short depolarizations increased significantly from 28.4 ± 2.2 to 45.5 ± 3.8 and 52.1 ± 1.9 µM/ms in the presence of 0.5 ppm NanoSe and selenate, respectively. In 0.5 ppm concentration both selenium compounds increased significantly the selenoprotein N expression only in EDL muscle. CONCLUSIONS: Selenium supplementation augments calcium release from the sarcoplasmic reticulum thus improves skeletal muscle performance. These effects are accompanied by the increased selenoprotein N expression in the muscles which could result in increased oxidative stress tolerance in case of long lasting contraction.

Myelotoxicity of carboplatin is increased in vivo in db/db mice, the animal model of obesity-associated diabetes mellitus.

PURPOSE: Some authors observed increased carboplatin-associated myelotoxicity in obese patients which was exclusively attributed to elevated AUC. To investigate the potential contribution of functional changes of cells primarily responsible for myelopoiesis, granulocyte-macrophage progenitors (CFU-GM) were studied in obesity-associated diabetes mellitus (DMT2). METHODS: The most frequently used animal model of human obesity with DMT2 is db/db mouse. Cellularity, frequency of CFU-GM and total CFU-GM content of femoral bone marrow were measured after 100 mg/kg dose of carboplatin in vivo. To exclude influence of pharmacokinetic changes, direct toxicity of carboplatin on CFU-GM was also determined in vitro and was compared with other anticancer agents, namely doxorubicin, 5-fluorouracil and 4-thiouridylate. RESULTS: After intraperitoneal administration of carboplatin, each measured characteristics of bone marrow function was more significantly suppressed and the induced neutropenia was more serious in db/db mice than in the controls. The increased myelotoxicity seemed to be a direct effect on myeloid progenitor cells since their increased in vitro sensitivity was found in db/db mice. This was not specific for carboplatin, a similar double to fivefold increase in myelotoxicity of each cytotoxic drug with different mechanism of action was observed. Four-thiouridylate, a promising antileukemic molecule with good therapeutic index, was by far the least toxic for CFU-GM of db/db mice. CONCLUSIONS: A serious disorder of CFU-GM progenitors was suggested in obese mice with DMT2, which eventually might lead to more severe myelotoxicity and neutropenia. Weight loss and normalization of glucose homeostasis may be important before chemotherapy of malignant diseases in obesity with DMT2.

Cellular and nephrotoxicity of selenium species.

PROJECT: Beside its useful functions at very low concentrations, selenium including supplementary Se sources pose a potential toxicological risk. The toxicity of selenium species was tested in HaCaT cell culture and related nephrotoxicity in mice. PROCEDURE: The apoptotic shrinkage and necrotic expansion of cells were measured by time-lapse image microscopy. Acute nephrotoxicity was estimated upon administration of various selenium species to mice for two weeks. To confirm or to refute the accumulation of Se in the kidney and its potential chronic effect, Se concentration in kidney tissue and histopathlology were tested. RESULTS: The comparison of selenium species showed that organic lactomicroSe did not affect cell growth at 5ppm, but inorganic nanoSe severely hampered it at lower concentration (1ppm). The in vivo Se treatment (0.5, 5, 50ppm, corresponding to 4, 40 and 400µg/kg) was misleading as it did neither affect the outward appearance nor the weight of the kidney. Se accumulation was observed after selenate, selenite, SelPlex, selenite and nanoSe administration, while lactomicroSe caused no traceable accumulation. In vivo, ex vivo and in vitro experiments reflected this order of selenium toxicity: selenate>selenite>SelPlex=nanoSe>lactomicroSe. CONCLUSION: Within the tested species lactomicroSe was the only non-nephrotoxic selenium source recommended for nutritional Se supplementation.

Protective effects of meat from lambs on selenium nanoparticle supplemented diet in a mouse model of polycyclic aromatic hydrocarbon-induced immunotoxicity.

Increased environmental oxidative stress caused primarily by chemicals like polycyclic aromatic hydrocarbons, plays significant role in human diseases. A representative compound, 7,12-dimethylbenz(a)anthracene (DMBA), was used for modeling oxidative damages including the significant decrease of the antioxidant capacity of the blood. Selenium has antioxidant effects but with a narrow therapeutic window. In our current studies to avoid accidental overdose and toxicity selenium was given to meat-producing animals. The standard rodent diet of mice was replaced by meat from lambs either on standard or selenium-enriched diet. Selenium concentration of lamb meat was enhanced three times by nano-selenium administration and an increase in the antioxidant capacity of the blood of mice was measured after the indirect selenium supplementation. Protective effects were also observed against DMBA-induced immunotoxicity. Twice the amount of white blood cells and among them three times more phagocytes survived. Similarly, in their renewal system in bone marrow twice the amount of cells survived and regenerative capacity of granulopoiesis was four times higher than in control DMBA-damaged mice. Our findings suggest functional dietary benefits of lamb meat enriched with selenium by feeding lambs with nanoparticle selenium supplements.

P-selectin glycoprotein ligand-1 deficiency augments G-CSF induced myeloid cell mobilization.

The effect of granulocyte colony-stimulating factor (G-CSF) was investigated in P-selectin glycoprotein ligand-1 (PSGL-1) deficient (PSGL-1(-/-)) and wild-type (PSGL-1(+/+)) mice to establish the role of this mucin in myeloid cell mobilization. G-CSF activates tissue proteases that cleave adhesion molecules, thus enhances the mobilization of myeloid cells and haematopoietic stem cells. Cytopenia was induced with a single dose of cyclophosphamide. In PSGL-1(-/-) animals, we observed a delayed extravasation of mature myeloid cells from the peripheral vessels into the tissue compartments and their faster mobilization from the bone marrow. Subsequently, animals received G-CSF twice a day for 4 days. Neutrophil and monocyte counts increased upon completion of G-CSF treatment and both values were significantly higher in PSGL-1(-/-) mice; 47.7 versus 28.3 G/l for neutrophils and 4.1 versus 2.0 G/l for monocytes. The ratio of atypical myeloid cells was also elevated. Analyzing the causes of the above differences, we identified a 4-fold increase in the colony-forming unit (CFU-GM) counts of the peripheral blood in PSGL-1(-/-) mice, compared to wild-type animals. A significantly elevated number of CFU-GM was detected also in the femurs of PSGL-1(-/-) mice, 4 and 5 days after cyclophosphamide treatment and these values paralleled with the elevation of CD34+/CD117+ stem cell counts in the peripheral blood. Our data suggest, that in the absence of PSGL-1, G-CSF was more potent in elevating absolute myeloid cell numbers by acting on cell release from the bone marrow, maturation from circulating precursor cells in the peripheral blood and prolonged retainment in the circulation.

The potential of materials analysis by electron rutherford backscattering as illustrated by a case study of mouse bones and related compounds.

Electron Rutherford backscattering (ERBS) is a new technique that could be developed into a tool for materials analysis. Here we try to establish a methodology for the use of ERBS for materials analysis of more complex samples using bone minerals as a test case. For this purpose, we also studied several reference samples containing Ca: calcium carbonate (CaCO(3)) and hydroxyapatite and mouse bone powder. A very good understanding of the spectra of CaCO(3) and hydroxyapatite was obtained. Quantitative interpretation of the bone spectrum is more challenging. A good fit of these spectra is only obtained with the same peak widths as used for the hydroxyapatite sample, if one allows for the presence of impurity atoms with a mass close to that of Na and Mg. Our conclusion is that a meaningful interpretation of spectra of more complex samples in terms of composition is indeed possible, but only if widths of the peaks contributing to the spectra are known. Knowledge of the peak widths can either be developed by the study of reference samples (as was done here) or potentially be derived from theory.

Toxicity of cytotoxic agents to granulocyte-macrophage progenitors is increased in obese Zucker and non-obese but insulin resistant Goto-Kakizaki rats.

Increased risk of anticancer chemotherapy in seriously obese patients is known. Obesity may be among factors that predict treatment-related toxicity during chemotherapy. We investigated whether functional changes in granulopoiesis may also contribute to increased myelotoxicity in addition to the known alterations of pharmacokinetic parameters in obesity. Hemopoiesis - as measured by cellularity, frequency of granulocyte-macrophage progenitors (CFU-GM) and total CFU-GM content of the femoral bone marrow - did not differ in obese, insulin resistant Zucker rats compared with Wistar rats. Nevertheless increased sensitivity of their CFU-GM progenitor cells to cytotoxic drugs was found by culturing them in vitro in the presence of carboplatin, doxorubicin and 5-fluorouracil. All drugs were more toxic on CFU-GM progenitor cells of insulin resistant Zucker rats than on CFU-GM cells of the control strain. This might be based on metabolic disorders, at least in part, because we could demonstrate a similar increase in toxicity of the studied anticancer drugs to the CFU-GM progenitors originated from the non-obese but insulin resistant Goto-Kakizaki rats in the same dose ranges. After in vivo administration of rosiglitazone, an insulin sensitizer, the anticancer drug sensitivity of CFU-GM progenitors of Goto-Kakizaki rats was decreased concurrently with improvement of insulin resistance. Although the increased treatment-related myelotoxicity and mortality are well-known among obese patients with malignant diseases, only the altered half lives, volumes of distribution and clearances of cytotoxic drugs are thought to be the underlying reasons. According to our knowledge the results presented here, are the first observations about an impaired granulopoiesis in obese animals.

Subacute toxicity of nano-selenium compared to other selenium species in mice.

Sixteen groups of mice were fed diets containing different selenium species to compare their toxicity. Inorganic sodium selenate and sodium hydroselenite, elementary nanoSe, organic Sel-Plex, and Lacto-MicroSelenium were administered for 14 d at concentrations of 0.5, 5, and 50 ppm Se, equivalent to 0.5, 5, and 50 mg Se/kg food, corresponding to an estimated 4, 40, and 400 µg/kg body weight/d Se uptake, respectively. At the end of the treatment, body, liver, spleen, kidney, heart, and brain weights were measured, mice were subjected to necropsy, and histological examinations were performed on the liver. At lower Se doses (0.5 and 5 ppm) a moderate reduction was observed in the number of bone marrow and white blood cells and in granulocyte-macrophage colony-forming units (GM-CFUs) relative to the untreated control group of mice. A comparison of lowest toxic doses of sodium selenite in mice (0.5 ppm) and mallard (10 ppm) indicates that birds are more resistant to Se than rodents. In mice, a small but measurable weight loss was observed after 5 ppm selenate and LactoMicroSe treatment. The most significant changes took place after 50-ppm administration in body and spleen weight, hematology, and liver histology. Toxicity was more pronounced when inorganic Se was applied than after subacute application of Sel-Plex, nanoSe, or LactoMicroSe. To summarize the effects, the authors' 14-d murine subacute toxicity study showed that the toxicity of Se species decreased in the following order: selenate > selenite > nanoSe > Sel-Plex > LactoMicroSe.

In vitro and in vivo activity of 4-thio-uridylate against JY cells, a model for human acute lymphoid leukemia.

We have previously reported the in vitro anti-proliferative effect of 4-thio-uridylate (s(4)UMP) on OCM-1 uveal melanoma cells. Here, we assessed the efficacy of s(4)UMP on JY cells. Treatment of JY cells with s(4)UMP suppressed their colony forming activity and induced apoptosis; healthy human bone marrow granulocyte-macrophage progenitor cells were 14-fold less sensitive to the nucleotide. In vivo effectiveness of s(4)UMP was determined using xenograft SCID mouse model. s(4)UMP decreased the cell number and colony forming activity of the total cell content of the femur of SCID mice transplanted with JY cells without affecting the bone marrow of healthy mice. These results suggest that s(4)UMP alone or in combination with other clinically approved anti-leukemic remedies should be further explored as a potential novel therapeutic agent.

Modulation of adenosine-induced responses in the guinea-pig trachea during long-term caffeine treatment: possible role of epithelium.

The responses to adenosine were studied on isolated, methacholine-precontracted tracheal strips of guinea pigs in the course of long-term caffeine or solvent treatment. Guinea pigs were fed caffeine for 10 weeks (average serum caffeine concentration: 39.1 +/- 3.9 microM). In epithelium-intact tracheal preparations (EITPs), sensititization to adenosine-induced relaxation (AIR) developed. It attained a maximum in week 1 of caffeine treatment, and then its level diminished and disappeared completely by weeks 4 - 6. In epithelium-denuded tracheal preparations (EDTPs), an increase in the sensitivity to adenosine was observed from week 1 to week 10 (a 4 - 6-fold reduction in EC50). Use of a coaxial bioassay system confirmed the role of epithelium in this process. The enhancement of the AIR of the EITPs was not modified by inhibitors of cyclooxygenase and lipoxygenase. Following depletion of the neuropeptides by acute capsaicin pretreatment, the AIR of the EITPs was strongly enhanced after caffeine treatment for 6 weeks. In chronically caffeine-treated EITPs, the inhibition of neutral endopeptidase led to dramatic reduction of the AIR. On the basis of the results by inhibiting nitric oxide synthase, it can be supposed that nitric oxide released from EITPs of long-lasting caffeine-treated animals operated as a constrictor agent. Our results show that chronic caffeine treatment gives rise to an initial sensitization to adenosine of the EITPs, this being followed by the development of a specific adaptive process in the epithelial cells, which counterbalances the increased tracheal sensitivity to adenosine.

Spleen autotransplantation. Morphological and functional follow-up after spleen autotransplantation in mice: a research summary.

In 1986, we started the research on spleen surgery aimed at saving the splenic mass after its traumatic injury, with elaboration of special resection and autotransplantation techniques. The researches started on mongrel dogs and were continued on inbred mice and beagle dogs with complex histological, imaging, and laboratory investigations, following-up the function and the regeneration of autotransplanted spleen chips. Performing research on mice provided more immunological methods, such as lymphocyte subsets, immunoglobulin levels, and monitoring the phagocytic functions. Researches showed evidence also on the presence of apoptosis, furthermore, stem cell studies on regeneration and functional restoration of the spleen chips are in progress. Our results contributed to two multidisciplinary guidelines in Hungary: (1) One of them is under preparation and underlines the importance of spleen saving methods after traumatic splenic injury; (2) The second guideline shows that hemorheological changes can be early indicators of the increased sensitivity to postsplenectomy infections.

Long-lasting partial remission by Interferon-alpha treatment in a child with essential thrombocythemia.

Essential thrombocythemia (ET) is a clonal myeloproliferative disorder characterized by sustained thrombocytosis, isolated hyperplasia of megakaryocytic lineage, and association with thrombotic or bleeding episodes. It is extremely rare in childhood and frequently presents without evident clinical signs. We describe a 3-year-old girl with severe headache and dizziness suffering from ET, who was treated with Interferon-alpha-2a (IFN) based on the potent effect of this agent to inhibit myeloid colonies induced by phytohemagglutinin A stimulated leukocyte conditioned medium (PHA-LCM). Bone-marrow-derived mononuclear cells of this patient did not exhibit spontaneous colony formation but responded to recombinant human (rh) erythropoietin (EPO), rh granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage (GM)-CSF, and stem-cell factor in addition to PHA-LCM. After 65 months of in vivo IFN treatment, the patient experienced a sustained partial remission with platelet counts varying between 400 and 600 x 10(3)/microl.

Differential regulation of umbilical cord blood and leukemic B cells by interferon-alpha (IFN-alpha): observations in cultured cells.

The exact mechanism of the beneficial therapeutic action of interferon-a (IFN-alpha) in B-cell-lineage malignancies has not been adequately explained. Here we report on the differential effect of IFN-alpha2b on non-malignant B cells of umbilical cord blood and leukemic B-cell lines JY, BL-41 and BCBL-1. Leukemic cell proliferation was characterized by colony assay, whereas apoptosis was investigated by flow cytometry of propidium iodide-stained cells. The degree of differentiation was evaluated by measuring the expression level of Fcgamma receptor-II (FcgammaRII) labeled with anti-CD32-FITC monoclonal antibody using flow cytometry. IFN-alpha protected umbilical cord blood CD19-positive B lymphocytes from apoptotic cell death in vitro. IFN-alpha significantly decreased colony formation of all three cell lines, and in contrast to normal cells, induced apoptosis in JY and BL-41 and excessive necrosis in HHV-8 infected BCBL-1 cells. FcgammaRII was upregulated both in normal and in leukemic B cells as indicated by an increase both in the proportion of CD32-positive cells and the mean fluorescence intensity. From our results it seems that antiproliferative, apoptotic and differentiative effects of IFN-alpha are interrelated but distinct cellular events, which are differentially regulated in normal, leukemic and virus-infected cells of the B-cell lineage.

Effect of rosiglitazone, an insulin sensitizer, on myelotoxicity caused by repeated doses of 5-fluorouracil.

Haematopoietic colony-stimulating factors are used frequently to moderate myelotoxicity, but administration of granulocyte-colony-stimulating factor (G-CSF) prior to chemotherapy actually may worsen the toxic effects on bone marrow. This is important in the design of clinical cancer treatment protocols. Previously, we found that rosiglitazone may protect granulocyte-macrophage progenitor cells (CFU-GM) against damage caused by a single dose of 5-fluorouracil (5-FU). Our new studies are designed to evaluate whether rosiglitazone has similar beneficial effects on bone marrow preservation when administered concurrently with repeated, daily doses of 5-FU while restricting regeneration time. Myelotoxicity characterized by the decrease in cellularity, frequency of granulocyte-macrophage progenitor cells and CFU-GM content of femoral bone marrow in mice. Five-day oral rosiglitazone pre-treatment decreased the susceptibility of granulocyte-macrophage progenitors to 5-FU damage. Significantly, more CFU-GM cells survived after the single intraperitoneal dose of 5-FU (100 mg kg(-1)). The increased frequency of CFU-GM cells with their intensive proliferation allowed faster restoration of the damaged CFU-GM compartment than was seen in the case of repeated daily administration of the cytostatic drug (25 or 50 mg kg(-1)) together with rosiglitazone for 7 consecutive days. The expansion of the CFU-GM compartment was 3 times and 50 times greater in the combined-treated mice than in their counterparts treated with repeated doses of 5-FU alone, although differences in absolute neutrophil counts were not significant. In conclusion, our results indicated that rosiglitazone has protective effects on bone marrow progenitor cells even after daily 5-FU treatment but further studies are warranted to evaluate the optimal treatment schedules.

Investigation of beta-Lactamases in clinical isolates of Staphylococcus aureus for further explanation of borderline methicillin resistance.

BACKGROUND: Borderline methicillin resistance in Staphylococcus aureus is due to beta-lactamase overproduction and/or specific methicillinases. METHODS: beta-Lactamase activity in culture supernatants and in cytoplasmic membrane fractions was estimated by bioassay and by SDS-PAGE combined with nitrocefin assay. RESULTS: During the investigation of borderline methicillin-resistant Staphylococcus aureus (BORSA) strains VU94 and 822 two beta-lactamases were detected in the membranes, with molecular weights of 13 and 30 kDa. The latter could be found in the culture supernatants, too. In the presence of globomycin, this enzyme disappeared from the membrane, and the oxacillin-hydrolyzing activity of the membrane decreased to the level of susceptible strains. Both beta-lactamases were detected in the methicillin-resistant Staphylococcus aureus strain studied, but the susceptible strains possessed only the first enzyme. CONCLUSIONS: The 30-kDa beta-lactamase proved to be a methicillinase, and it can be one of the main causes of the borderline phenotype of BORSA strains. The other enzyme is one of the smallest beta-lactamases published to date.

Accelerated recovery of 5-fluorouracil-damaged bone marrow after rosiglitazone treatment.

Our preliminary data indicate that rosiglitazone may be myeloprotective. We investigated whether it can modify bone marrow recovery. Five-day pre-treatment with rosiglitazone significantly accelerated recovery of 5-fluorouracil-damaged bone marrow in mice. Frequency and femoral content of granulocyte-macrophage progenitors reached mean baseline faster in pre-treated groups than in 5-fluorouracil-treated controls. Consequently, neutropenia was milder. Five-day insulin pre-treatment had similar effects in vivo. Insulin supports in vitro hematopoiesis. The observed myeloprotection demonstrated the importance of insulin in vivo. Clinical use of insulin to moderate myelotoxicity is impractical but rosiglitazone, an insulin sensitizer, could offer hope. Although rosiglitazone tends to increase plasma insulin levels, the significant myeloprotection was partly due to direct effects on progenitors. In vitro rosiglitazone enhanced the survival of both murine progenitor and human mobilized blood stem cells in the presence of 5-fluorouracil, the effect of which was neutralized by a peroxisome-proliferator-activated receptor-gamma antagonist.

Potent inhibition of HIV-1 entry by (s4dU)35.

We have previously reported the potent in vitro HIV-1 anti-reverse transcriptase activity of a 35-mer of 4-thio-deoxyuridylate [(s(4)dU)(35)]. In efforts to define its activity in a more physiological system, studies were carried out to determine the stage of viral infection that this compound mediates its anti-viral effect. Results of the studies reported herein show that (s(4)dU)(35) is nontoxic and is capable of inhibiting both single and multi-drug resistant HIV strains (IC(50): 0.8-25.4 microg/ml) in vitro. Besides its previously reported anti-RT activity, (s(4)dU)(35) mediated its antiviral action by preventing virus attachment (IC(50): 0.002-0.003 microg/ml), and was stable in vitro and slowly degraded by DNAses. Competition studies and fluorescence resonance energy transfer (FRET) experiments indicated that (s(4)dU)(35) preferentially binds to CD4 receptors, but not to CD48. Confocal laser scanning microscopy (CLSM) studies showed that (s(4)dU)(35) did not penetrate into the cells and colocalized with cell surface thioredoxin. Our studies identify (s(4)dU)(35) as a potential novel HIV entry inhibitor that may have utility as either a systemic antiretroviral or as a preventing agent for HIV transmission.

Leukemic cells and the cytokine patchwork.

BACKGROUND: In leukemia, the clonal population is characterized by a hierarchical organization. Although the majority of the leukemic population is generated after post-determinic divisions, a subset of cells retain undifferentiated "blast" morphology. In addition, leukemic cells often have numerical or structural chromosomal abnormalities, aberrant gene expression patterns, and abnormal cell surface marker profiles. Despite these differences when compared to normal bone marrow and blood cells, leukemic cell survival and proliferation, just like that of normal progenitor cells, is influenced by hematopoietic growth factors. A major issue is whether differential regulation of normal and leukemic hematopoietic cells by cytokines can be exploited in antileukemic treatment or, in contrast, whether in vivo cytokine therapy may even be harmful to the patients. PROCEDURE: Here we review the results of recent experimental and clinical observations that investigated the influence of cytokines on leukemic cell growth and differentiation in vitro and in vivo. RESULTS: The majority of studies indicate that hematopoietic growth factors are involved in the regulation of proliferation and terminal differentiation of leukemic blast cells. Genetic aberrations involving cytokines or their receptors may contribute to leukemogenesis. Abundant interactions, cross-lineage stimulation, and aberrant response patterns seem to transform the complex cytokine network regulation of normal hematopoiesis into an even more interlaced "patchwork" that controls leukemic hematopoiesis. CONCLUSIONS: Since hematopoietic growth factors are present in high serum concentrations in patients with acute leukemia and myelodysplastic syndromes, consequences of possible interactions should be kept in mind even when well-defined human recombinant factors in single application are to be involved in antileukemic protocols.