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Successful engraftment of blood derived normal hemopoietic stem cells in chronic myelogenous leukemia.

The ability of blood-derived stem cells to restore hemopoietic function was investigated in a patient with chronic myelogenous leukemia with bone marrow cells containing the Philadelphia chromosome marker (Ph1+). After treatment with high dose cyclophosphamide, 26.3 X 10(9) blood mononuclear leukocytes, among them 26.2 X 10(5) granulocyte/macrophage progenitor cells (CFUC), were harvested by means of 5 successive leukaphereses when the bone marrow cells had converted to Ph1--. When the patient entered the aggressive phase (blast crisis), myeloablative treatment with busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg) was given, followed by transfusion of the cryopreserved blood leukocytes. Restoration of marrow and blood cellularity was completed about 20 days after this autologous blood stem cell transplantation (ABSCT). Marrow CTUC recovery was complete 2 weeks after ABSCT, and all karyotypes of the patient's marrow cells were free of the marker chromosome. The patient died of toxicity but with normal bone marrow cellularity. This report confirms the therapeutic usefulness of autologous blood-derived stem cells harvested in remission in restoring hemopoietic function after myeloablative treatment.

Adult↗

Long-term bone marrow culture profiles in patients with myelodysplastic syndromes are not explicable by defective apoptosis.

It has been suggested that increased intramedullary apoptosis may explain the paradox between peripheral blood cytopenias and the hyper- or normo-cellular bone marrow observed in the myelodysplastic syndromes (MDS). We wished to see if culture performance could be related to the presence of apoptotic cells in a group of patients with MDS (12 patients) and other patients with peripheral blood cytopenias (six patients) which caused diagnostic difficulty. There was no correlation between LTBMC or adherent cell growth and the presence of apoptotic cells in the original marrow sample. A variable degree of apoptosis was observed in both groups of patients. LTBMC profiles correlated well with diagnosis but were unrelated to the extent of intramedullary apoptosis. This suggests that apoptosis is a much more ubiquitous process in disease than previously thought.

Apoptosis↗

Stimulation of hematopoiesis in patients with bone marrow failure and in patients with malignancy by recombinant human granulocyte-macrophage colony-stimulating factor.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multipotential hematopoietin. To assess the toxicity and biological activity of recombinant human GM-CSF (rhGM-CSF) in vivo, 25 patients with malignancy or bone marrow failure were treated with rhGM-CSF (specific activity approximately 5 x 10(7) U/mg) as part of a phase 1 trial. The treatment was administered by continuous intravenous (IV) infusion daily for 2 weeks at fixed dose levels and repeated after a 2-week rest period. Over the entire dose range tested (15 to 500 micrograms/m2/d), rhGM-CSF treatment was associated with dramatic increases (two- to 70-fold) in total leukocyte counts, which consisted predominantly of neutrophils, bands, eosinophils, and monocytes. Furthermore, six of the 14 patients with one or more cytopenias that received at least two cycles of treatment had multilineage responses characterized by twofold or greater increases in platelet count to a level above 100,000, twofold or greater increases in corrected reticulocyte count, and a reduced requirement for red cell transfusions. Three of these patients became independent of both red cell and platelet transfusions for 17 to 37 weeks of follow-up. Treatment was associated also with an increase in bone marrow cellularity and frequency of cycling progenitor cells. The treatment was well tolerated; side effects included constitutional symptoms and bone pain. These results demonstrated that rhGM-CSF has a significant impact on hematopoiesis in patients with advanced malignancy and also in patients with bone marrow failure.

Adult↗

Magnetic resonance diffusion-weighted imaging: extraneurological applications.

Diffusion-weighted (Dw) imaging has for a number of years been a diagnostic tool in the field of neuroradiology, yet only since the end of the 1990s, with the introduction of echoplanar imaging (EPI) and the use of sequences capable of performing diffusion studies during a single breath hold, has it found diagnostic applications at the level of the abdomen. The inherent sensitivity to motion and the magnetic susceptibility of Dw sequences nonetheless still create problems in the study of the abdomen due to artefacts caused by the heartbeat and intestinal peristalsis, as well as the presence of various parenchymal-gas interfaces. With regard to focal liver lesions, a review of the literature reveals that Dw imaging is able to differentiate lesions with high water content (cysts and angiomas) from solid lesions. With regard to the latter, although there are differences between benign forms [focal nodular hyperplasia (FNH), adenoma] and malignant forms [metastasis, hepatocellular carcinoma (HCC)] in their apparent diffusion coefficient (ADC) in the average values for histological type, there is a significant overlap in values when lesions are assessed individually, with the consequent problem of their correct identification. One promising aspect is the possibility of quantifying the degree of fibrosis in patients with chronic liver disease and cirrhosis given that the deposit of collagen fibres "restricts" the motion of water molecules and therefore reduces ADC values. However, even in this field, studies can only be considered preliminary and far from real clinical applications. The retroperitoneum is less affected by motion artefacts and similarly deserves the attention of Dw imaging. Here it is possible to differentiate mucin-producing tumours of the pancreas from pseudocystic forms on the basis of ADC values even though the limited spatial resolution of Dw imaging does not enable the identification of small lesions. Dw imaging may be applied to the study of the kidney to differentiate hydronephrosis from pyonephrosis and with regard to tumours, solid from pseudocystic forms. In addition, given that renal parenchyma has significantly variable ADC values on the basis of the anatomic section and physiological conditions, the possibility of assessing functional alterations is currently being studied. Indeed, a good correlation has been found between ADC values and glomerular filtration rate. With regard to musculoskeletal applications, the absence of motion artefacts in the regions studied has enabled the development of sequences less sensitive to magnetic susceptibility and with greater spatial resolution than EPI. Attempts have therefore been made to use Dw imaging in the characterization of soft-tissue tumours although the findings so far have been disputed. Greater agreement has been found regarding sensitivity of the technique in assessing response of these tumours to chemotherapy: tumour necrosis is thought to increase ADC whereas the persistence of vital neoplastic tissue tends to lower it. One of the most promising applications of Dw imaging is without doubt the assessment of vertebral collapse where a high ADC has been shown to be associated with an osteoporotic cause and a low ADC with a neoplastic cause. Nonetheless, even here, a moderate overlap between ADC values of the two types has been encountered. Dw imaging has also been used in the assessment of bone marrow cellularity: areas of tightly packed cells show a higher ADC value than hypocellular areas. In particular, no significant difference in ADC is noted between normal hypercellular bone marrow and hypercellular bone marrow secondary to lymphomatous infiltration whereas this difference is significant between hypocellular, normocellular and haematopoietic hypercellular bone marrow. With regard to the study of joints, the limited structure dimensions, particularly cartilage, creates technical difficulties related to spatial resolution and an adequate signal-to-noise ratio, problems that can only be solved by further technological developments. Lastly, a significant difference in ADC values between degenerative and inflammatory effusion has been found, a fact that may be explained as the result of the activity of hyaluronidase present in inflammatory forms, which causes a reduction in the concentration of hyaluronic acid with a consequent decrease in viscosity.

Abdomen↗

Stimulation of granulopoiesis in patients with malignancy by recombinant human granulocyte-macrophage colony-stimulating factor: assessment of two routes of administration.

We administered Escherichia coli-derived recombinant human granulocyte-macrophage colony-stimulating factor to 61 patients with malignancy, 36 of whom had normal peripheral blood counts and 25 of whom had peripheral cytopenia due to underlying bone marrow disease, to compare the efficacy of two different routes of administration to stimulate the in vivo granulopoiesis: i.e., continuous i.v. infusion and s.c. injection. Three well-tolerated dose levels were investigated. Application of granulocyte-macrophage colony-stimulating factor resulted in dose-dependent increases in circulating neutrophils, eosinophils, and monocytes and an increase in bone marrow cellularity, irrespective of route of administration. In some patients, mild side effects, including bone pain, dyspnea, flu-like symptoms, and a decrease of platelet counts, were recorded, but they were less pronounced when the hormone was administered subcutaneously.

Adolescent↗

Prolonged T1 relaxation of the hemopoietic bone marrow in patients with chronic leukemia.

Eleven patients with chronic leukemia (7 with chronic lymphocytic leukemia and 4 with chronic myeloid leukemia) were evaluated with magnetic resonance (MR) imaging and T1 relaxation time measurements by use of a 1.5 tesla whole body MR scanner. Bone marrow biopsies were obtained from the posterior iliac crest (within 72 hours of the MR examination) in order to provide data on bone marrow cellularity and differential counts. The patients with chronic leukemia all showed a significant prolongation of the T1 relaxation times compared with the normal range for hemopoietic bone marrow.

Adult↗

Effects of low-dose total-body irradiation on canine bone marrow function and canine lymphoma.

Low-dose total-body irradiation, 150 rad given in 10 fractions over 5 weeks, is a useful treatment modality for favorable-prognosis lymphomas. Little is known, however, about the effects of this regimen on normal bone marrow. Six healthy beagle dogs and 5 dogs of various breeds with lymphoma were treated with total-body irradiation. Three of the 5 lymphomatous dogs achieved remissions of limited duration. No changes in hemograms or in bone marrow cellularity (as assessed by needle marrow biopsies) could be detected during or after treatment. Bone marrow progenitor cells were studied weekly during treatment and for 4 weeks thereafter using in vitro growth assays for GM-CFC and M-CFC. These studies demonstrated significant reductions (P less than 0.001) of granulocyte and macrophage progenitor cells with subsequent recovery toward normal pre-irradiation and sham irradiation values. Two additional dogs were injected with sublethal doses of Salmonella typhosa endotoxin 2 weeks after completion of the irradiation regimen. Their bone marrow GM-CFC responses were dramatically blunted compared to nonirradiated controls whereas their peripheral leukocyte responses and serum CSF levels were comparable to nonirradiated controls. These studies suggest that total-body irradiation may induce bone marrow injury that may be clinically significant if patients so treated are further stressed by infections or myelosuppressive drugs.

Animals↗

Immunosuppression in weanling and adult Sprague-Dawley rats induced by acute exposure to 3,3',4,4'-tetrachloroazoxybenzene.

The acute immunomodulatory effects of the environmental and occupational contaminant, 3,3',4,4'-tetrachloroazoxybenzene (TCAOB), were investigated on selected immune parameters in weanling and adult Sprague-Dawley rats. Significant immunotoxic effects were found 17 days after 4 doses of 25 mg/kg TCAOB, administered i.p. The main non-immune toxic effects were decreased body, kidney, heart and testis weights, and a simultaneous increase in liver weight. The immune parameters showing significant suppression were: thymic weight, splenic plaque forming cell populations and function, pertioneal macrophage chemiluminescence, and bone marrow cellularity. Weanling animals were affected by TCAOB to a greater extent than adults on both the multiple and single dose regimens. The immunotoxic effects were found to be qualitatively similar to those of its isosteric analog, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The results demonstrate that TCAOB is a very potent immunotoxic compound and may have long-term effects after a single exposure. This study is the first investigation into the effect of TCAOB on immune functions.

Aging↗

Cellular and morphological changes in lymphoid organs after a single injection of interleukin 1 alpha in the mouse.

We investigated the effects of a single i.v. injection of recombinant human interleukin 1 alpha (IL-1 alpha) on the morphology and the cellularity of several lymphoid organs in normal mice. The injection of 100 U of IL-1 alpha resulted in maximal neutrophilia and leukocytosis at 1 h. By 72 h, the numbers of mononuclears, but not that of polymorphonuclears, returned to baseline levels. Absolute increase in mononuclears was paralleled by relative lymphopenia. Changes in the peripheral blood coincided with rapid decrease in the spleen cellularity and white pulp volume (especially the marginal zone), and an increase in the red pulp volume. Bone marrow cellularity was increased at 1 h, but returned to control levels by 6 h after IL-1 injection. Thymus cell depletion and cortex atrophy were maximal at 6 h and could be observed throughout the experiment. These findings indicate that leukocytosis induced by a single i.v. injection of IL-1 alpha in normal mice is concomitant with a rapid cell depletion of the spleen and thymus. Morphological and cellular changes in lymphoid organs may represent the mobilization of immunocompetent cells during the development of the inflammatory response.

Animals↗

Diagnostic criteria of the myeloproliferative disorders (MPD): essential thrombocythaemia, polycythaemia vera and chronic megakaryocytic granulocytic metaplasia.

Philadelphia chromosome-positive essential thrombocythaemia (Ph(+)-ET) and chronic granulocytic leukaemia (Ph(+)-CGL) constitute a separate malignant disease entity, whereas essential thrombocythaemia (ET), polycythaemia vera (PV) and chronic megakaryocytic granulocytic metaplasia (CMGM) belong to the Philadelphia chromosome-negative (Ph-) myeloproliferative disorders. The megakaryocytes in Ph(+)-ET and Ph(+)-CGL are abnormal and small with round nuclei, showing little lobulation. Both the number and size of megakaryocytes in Ph-ET, -PV and -CMGM are typically increased. Enlarged megakaryocytes with mature cytoplasm and multilobulated nuclei and their tendency to cluster in a normal or slightly increased cellular bone marrow represent the hallmark of ET. In reactive thrombocytosis the size and morphology of increased megakaryocytes are normal. The characteristic increase and clustering of enlarged mature and pleomorphic megakaryocytes with multilobulated nuclei and proliferation of erythropoiesis in a moderate to marked hypercellular bone marrow with hyperplasia of dilated sinuses is the diagnostic hallmark of untreated PV. In secondary polycythaemia, in which increased cellularity of the erythroid cell line may be present, the number, size and morphology of megakaryocytes remain small and normal. CMGM, including early stages without myelofibrosis and advanced myelofibrotic stages of agnogenic myeloid metaplasia, appears to be a distinct neoplastic proliferation of neutrophilic granulopoiesis and megakaryopoiesis. The histopathology of the bone marrow in CMGM is dominated by atypical, enlarged and immature megakaryocytes with cloud-like nuclei which are not seen in ET and PV. Myelofibrosis in ET, PV and CMGM is graded in no reticulin fibrosis (MFO), early reticulin fibrosis (MF1), advanced reticulin sclerosis with minor collagen fibrosis (MF2) and advanced collagen fibrosis with or without osteosclerosis (MF3). Myelofibrosis is not a feature of ET, may occur in PV, and constitutes a prominent feature of CMGM during the natural history of the disease.

Bone Marrow↗

Low dose 5-azacytidine is ineffective for remission induction in patients with acute myeloid leukemia.

Low dose 5-azacytidine was administered to 11 patients with acute myeloid leukemia (AML) in hopes of achieving complete remissions by inducing differentiation of leukemic blasts. The patient population included both patients who had received no prior therapy (two patients), as well as patients refractory to primary therapy (five patients) and patients who had relapsed after achieving complete remission (four patients). Both previously untreated patients had a history of myelodysplastic syndrome, and two of the primarily refractory patients had leukemia following chemotherapy for other malignancies. The median age was 55 years (range 36-78 years). Twenty-one courses of 5-azacytidine were administered as 7-day continuous infusions at a dose of 75 mg/m2/day. Significant nonhematologic toxicity was not observed. No patient had a response as defined by bone marrow remission or improvement in transfusion requirement for red blood cells or platelets. Although some patients developed bone marrow hypocellularity (six courses in five patients), none became aplastic, and eight courses in six patients were associated with increased bone marrow cellularity percentage of blasts. Five courses in three patients were inevaluable (one central nervous system hemorrhage, one central nervous system leukemia, three courses in one patient who refused bone marrow aspiration). It is unlikely that low dose 5-azacytidine will be of benefit to patients with AML, and there was no evidence of clinically significant induction of differentiation noted.

Adult↗

Enhanced proliferation of functionally competent bone marrow cells in different strains of mice treated with swainsonine.

The immunomodulatory alkaloid swainsonine (8alphabeta-indolizidine-1alpha,2alpha,8beta-triol) has potential for overcoming the bone marrow suppressive effects of cancer chemotherapy and radiotherapy. An earlier study showed that multiple doses of swainsonine enhanced bone marrow cellularity in four different strains (C57BL/6; C3H-HEN; Balb/C and DBA-2 mice) of inbred mice which were not exposed to any chemotherapeutic agents or radiation. In vitro assessment of total colony formation capacity of bone marrow cells (BM CFUs) showed a 2- to 8-fold increase in swainsonine-treated mice compared to control mice that were given sham injections of physiological saline. In the current study, we have evaluated the functional competence of the bone marrow cells produced in response to swainsonine treatment of normal healthy mice. In particular, colony forming units-granulocyte-macrophage (CFU-GM), erythroid-burst forming units (BFUe) and CFU-Mix (or CFU-granulocyte-erythrocyte-monocyte-megakaryocyte (CFU-GEMM)) levels, were determined using in vitro assays. The time course of the changes in CFU-GM, BFUe and CFU-Mix (CFU-GEMM) were also followed. Our results demonstrate that swainsonine bolsters the CFU capacity of BM cells without loss of function to levels which are several folds higher than in sham-treated control mice. Swainsonine treatment caused an increase in all lineages of marrow cells without loss of function. This effect was reproduced in all four strains of inbred mice in this investigation. Examination of the peripheral blood did not reveal increase in white blood cells or changes in the hematocrit levels. The long-term effects of swainsonine treatment are not known at present. Nonetheless, swainsonine-induced increase in CFU capacity of bone marrow cells and related cells along the different differentiation paths should find clinical application in cancer treatment with chemotherapeutic agents and/or radiation.

Adjuvants, Immunologic↗

Effects of amphetamine on immune-mediated lung inflammatory response in rats.

OBJECTIVE: The present study analyzed the effects of acute amphetamine (AMPH) treatment on immune-mediated lung inflammatory response in rats. METHODS: There were four experiments. In the first and second experiments, rats were treated with AMPH (1 mg/kg) or 0.9% NaCl, and locomotor activity (experiment 1) and serum AMPH concentrations (experiment 2) were measured 1 or 12 h after treatment. In the third experiment, rats which were immunized with ovalbumin (OVA) were treated 14 days later with 0.9% NaCl or AMPH (1 mg/kg). Twelve hours after these treatments, all animals were submitted to challenge by 1% OVA inhalation being analyzed afterwards for bronchoalveolar lavage fluid (BAL), peripheral blood and bone marrow cellularity. In the fourth and final experiment, rats were treated and studied as for experiment 3, except that half of the animals within each group were previously treated with metyrapone prior to the OVA challenge. RESULTS: In the non-immunized rats, AMPH treatment induced an increase in locomotor activity synchronized to high serum AMPH concentrations 1 h after, but not 12 h after treatment. In OVA-challenged rats, AMPH treatment decreased the total number of inflammatory cells, recovered in both BAL and peripheral blood and increased the total number of bone marrow cells. These effects, observed 1 day after OVA challenge, were abrogated by previous metyrapone treatment. CONCLUSION: AMPH treatment changed HPA-axis responsiveness to the stress condition imposed by the OVA challenge decreasing lung and blood leukocytes cellularity most probably via corticosterone actions on bone marrow activity.

Amphetamine↗

Effect of recombinant human granulocyte macrophage-colony stimulating factor in long-term marrow cultures from patients with aplastic anemia.

The hematopoietic system in patients with aplastic anemia (AA) shows both quantitative and qualitative deficiencies, i.e., reduced numbers of hematopoietic progenitor cells (HPC) and impaired HPC proliferation in long-term marrow cultures (LTMC). Since recombinant human granulocyte macrophage-colony stimulating factor (rhGM-CSF) has been shown to be a potent stimulator of normal hematopoiesis, both in vivo and in vitro, in the present study we wanted to assess the possibility of stimulating hematopoiesis in LTMC from 17 patients with AA, by weekly addition of rhGM-CSF (10 ng/ml). In LTMC from 11 patients (group of responders), rhGM-CSF induced a significant increase (4.8-fold, compared with untreated cultures) in the levels of myeloid progenitor cells; in contrast, in six patients (group of nonresponders), myeloid progenitors were refractory to this cytokine. In the group of responders, rhGM-CSF also induced a pronounced increment in the levels of nonadherent and adherent cells (5.99- and 5.18-fold, respectively, compared with untreated cultures). Among the different myelopoietic lineages, rhGM-CSF preferentially stimulated the macrophagic lineage; this was evident both at the progenitor and mature cell levels. Interestingly, the effect of rhGM-CSF in LTMC from AA patients was only transient. Indeed, the effects mentioned above were observed only during the first three weeks of culture; afterwards, myeloid progenitor and nonadherent cell levels in treated cultures declined, practically reaching the levels observed in untreated cultures. At the moment, we do not know whether this transient stimulatory effect is due to the production of inhibitory cytokines, by macrophages generated in response to rhGM-CSF, or to the exhaustion of the HPC pool in AA cultures. In all 17 patients, rhGM-CSF had no effect on the kinetics of erythroid or multipotent progenitor cells. These results are in keeping with clinical studies in which it has been observed that most AA patients treated with rhGM-CSF show increments in circulating monocytes and granulocytes, as well as in bone marrow cellularity. However, little or no effect is observed on erythropoiesis. The actual mechanisms involved in the in vitro effects of rhGM-CSF on myeloid progenitor cells from AA bone marrow are still not completely understood. Future studies on this issue should be encouraged, since they may help to understand the in vivo (clinical) effects of this cytokine.

Anemia, Aplastic↗

Reduced bone marrow stem cell pool and progenitor mobilisation in multiple myeloma after melphalan treatment.

The content of stem cells was analysed in bone marrow samples from 75 multiple myeloma patients. In unstimulated bone marrow the percentage of CD34+ cells was significantly reduced in 11 patients previously treated with melphalan-prednisolone (MP)(median= 0.15%) compared to median 0.87% in 31 untreated patients (P=0.0001). The bone marrow cellularity in the two groups did not differ. There was no correlation between the number of courses or total dose of melphalan and content of CD34+ cells in the bone marrow. The clonogenicity as well as the ability to expand the marrow stem cell pool during growth factor treatment were also reduced in MP treated patients compared to untreated patients. Analysis of different subsets of CD34+ cells revealed no influence on the pre B cell compartment in the bone marrow by MP treatment, but the committed stem cells (CD34+CD38+) were reduced more than the uncommitted stem cells (CD34+CD38-) in the MP treated group compared to the untreated patients. Mobilisation to and harvest of total number of CD34+ cells from peripheral blood was also reduced in the MP treated group. There was, however, no difference in the distribution between CD34+CD38+ and CD34+CD38- populations in the leukapheresis products in the untreated and the melphalan-treated group, suggesting selective mobilisation of CD34+CD38+ cells and/or differentiation of CD34+CD38-cells during growth factor stimulation. We conclude that melphalan decreased the number of stem cells in the bone marrow, the ability to expand the stem cell pool and mobilise stem cells to the pheripheral blood.

Adult↗

Orchiectomy increases bone marrow interleukin-6 levels in mice.

Interleukin-6 (IL-6) appears to be an important factor in disease states associated with bone resorption. There is both in vitro and in vivo evidence supporting the fact that androgens down-regulate interleukin-6 production. These observations, in combination with the fact that osteoblasts and bone marrow stromal cells produce IL-6, led us to hypothesize that orchiectomy-induced androgen loss will result in increased IL-6 expression in the bone microenvironment. To prove our hypothesis we assessed the effect of orchiectomy on IL-6 protein and mRNA expression in bone marrow and spleen. We found that orchiectomy was associated with increased serum IL-6 levels at 3 and 28 days postsurgery. Phorbol ester-stimulated IL-6 levels were also higher in supernatants from bone marrow and spleen cell cultures from orchiectomized mice compared with unoperated or sham-operated mice. Additionally, we found that steady state IL-6 mRNA levels were increased in bone marrow but not spleen cells. Finally, we found that orchiectomized mice had splenomegaly and increased bone marrow cellularity. Histopathology of the spleen revealed lymphoid hyperplasia accompanied by a marked mononuclear cell infiltration of the red pulp. We conclude that orchiectomy induces IL-6 expression in the bone marrow. These findings suggest that endocrine and cytokine interactions contribute to bone pathophysiology.

Animals↗

The prevention of benzene-induced genotoxicity in mice by indomethacin.

Benzene is a myelotoxin which affects hemopoietic progenitor cells leading to bone-marrow depression as well as a genotoxin which causes chromosomal abnormalities including micronucleus formation. We have demonstrated previously that benzene administered to DBA/2 or C57B1/6 mice causes bone-marrow depression and increased prostaglandin E2 levels in bone marrow; both of these effects can be prevented by the coadministration of indomethacin, a selective inhibitor of prostaglandin synthase. We report, herein, that benzene (400-600 mg/kg body weight), under conditions where it depresses bone-marrow cellularity, also induces an increase in the frequency of micronucleus formation in polychromatic erythrocytes of C57B1/6 mice which is also prevented by the coadministration of indomethacin at levels that do not inhibit cytochrome P450 or myeloperoxidase. In Swiss Webster wild-type mice doses of benzene from 400 to 1000 mg/kg were without effect on marrow cellularity, but did induce the formation of micronucleated polychromatic erythrocytes which could be prevented by indomethacin. In contrast, DBA/2 mice, a strain highly sensitive to benzene, exhibited significant bone-marrow depression at a dose of benzene of 100 mg/kg body weight. Even at this low dose, benzene is too toxic toward developing erythrocytes to allow the evaluation of micronucleus formation. The frequency of induction of micronucleated polychromatic erythrocytes by benzene thus depends on the strain of mouse used. Furthermore, micronucleus formation appears to be an early and very sensitive indicator of benzene toxicity. A possible role for prostaglandin H synthase in the geno- and myelo-toxicity of benzene is discussed.

Animals↗

Swainsonine stimulates bone marrow cell proliferation and differentiation in different strains of inbred mice.

The immunomodulatory alkaloid swainsonine (8alphabeta-indolizidine-1alpha,2alpha,8beta-triol) has potential for overcoming the bone marrow suppressive effects of cancer chemotherapeutic drugs and radiation. The effect of swainsonine on bone marrow cellularity was evaluated in four different strains (C57BL/6; C3H-HEN; Balb/C and DBA-2 mice) of inbred mice subjected to multiple doses of the alkaloid. Swainsonine treatment stimulated bone marrow cell proliferation in all strains of mice. Examination of the peripheral blood did not reveal any increase in total leukocyte count. In vitro assessment of total colony-forming unit (CFU) capacity of bone marrow cells showed a two- to eight-fold increase in swainsonine treated mice of different strains compared to their corresponding controls given sham injections of physiological saline. Swainsonine induced increase in CFU capacity of bone marrow cells should find clinical application in cancer treatment with chemotherapeutic agents and radiation.

Animals↗