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PubMed2003

Coadministration of swainsonine and doxorubicin attenuates doxorubicin-induced lethality in mice.

This study in mice concerns the protective effectiveness and mechanisms of action by which a coadministered regimen of an immunomodulatory alkaloid swainsonine (8alphabeta-indolizidine-1alpha,2alpha,8beta-triol) protects against lethality induced by a single bolus intraperitoneal injection of LD50/14 doxorubicin. This swainsonine coadministration treatment regimen has been identified previously in our laboratory as the superior of the two optimal conditions for diminishing lethality in mice due to LD50/14 doxorubicin. The anthracycline, doxorubicin is a potent and widely used cancer chemotherapeutic agent whose clinical usefulness is limited by both a dose- and time-dependent cardiomyopathy. Specifically, mice were given simultaneous injections of swainsonine or its diluent buffer, phosphate buffered saline and LD50/14 doxorubicin on day 0, followed by twice daily injections of swainsonine or phosphate buffered saline up to day +9. The survival and well being of mice were monitored daily for 70 days, which may be considered equivalent to a period of 4 to 5 years in humans. This duration has a clinical implication with respect to the late manifestation of cardiotoxicity after doxorubicin treatment. We quantified the bone marrow cellularity of mice and performed in vitro progenitor cell assays to determine the effects of swainsonine coadministration treatment regimen on bone marrow competence after doxorubicin treatment. The effects of this regimen on doxorubicin-induced changes in heart morphology and on hematologic toxicities caused by doxorubicin were determined. This swainsonine coadministration treatment regimen significantly diminished doxorubicin-induced lethality and prolonged survival and well being of mice by preventing bone marrow pancytopenia from the start of therapy. It decreased bone marrow toxicity and facilitated its restoration. It accelerated restoration of blood hematocrit and total leukocyte levels. Also it facilitated the proliferation and differentiation of bone marrow pluripotent stem cells along the different paths to progenitor lineages, and significantly preserved the mouse heart morphology. These underlying mechanisms of action for the protection by swainsonine coadministration strongly suggest a potential role for swainsonine in high dose chemotherapy with doxorubicin.

Animals↗

PubMed1995

Characterization of functions of neutrophils from bone marrow of cattle with leukocyte adhesion deficiency.

Marked differences in bone marrow cellularity were observed between cattle affected with leukocyte adhesion deficiency (LAD) and control cattle. The number of nucleated cells in bone marrow was 2.9 to 8.8 times higher in cattle affected with LAD, compared with controls. The myeloid-to-erythroid ratio of bone marrow from 3 cattle affected with LAD ranged from 2.4 to 12. Deficient CD18 expression on neutrophils isolated from bone marrow of cattle with LAD was clearly detected by flow cytometric analysis. Neutrophils from bone marrow of cattle affected with LAD appeared round and not flat, after adherence to plastic wells under agarose, whereas neutrophils from bone marrow of clinically normal cattle were firmly spread on the surface of plastic wells. In the chemotaxis under-agarose assay, many pseudopodia were detected on bone marrow neutrophils from clinically normal cattle, but were not detected on bone marrow neutrophils from cattle with LAD. Activities of chemotactic movements and phagocytosis of neutrophils isolated from bone marrow of cattle affected with LAD were documented to be severely impaired.

Animals↗

PubMed1977

Hematologic effects of a single dose of methylnitrosourea.

The hematological effects of a single dose of 50 mg/kg Methylnitrosourea (MNU),administered i.v. to CBA/J mice, are described. Special emphasis was given to the number of pluripotent (CFUS) and granulocytic committed (CFUc) stem cells found in the bone marrow and spleen. In the peripheral blood a decreased number of reticulocytes, granulocytes, lymphocytes and thrombocytes was seen. This was followed by a rapid return of reticulocytes and a very slow return of thrombocytes. The bone marrow cellularity was below normal for at least 2 weeks with a markedly reduced number of lymphocytes. A rapid decrease in bone marrow and splenic CFUS and CFUc to 20-50% of control values was observed within 3 hours in mice injected with MNU. Seven days after MNU treatment, CFUS was about 10% of normal in both tissues. Contrary to this, CFUc had undergone significant regeneration. After 3 weeks CFUS returned to normal levels. At no stage could colony stimulating activity be detected in the serum.

Animals↗

PubMed1982

Haematopoietic late effects of prolonged bleomycin treatment in mice.

In two studies, haematopoietic late effects of prolonged bleomycin treatment were evaluated in mice given serial injections of 21 mg bleomycin/m2 weekly for 31 and 44 weeks, respectively. Femoral bone marrow cellularity measured at 43, 45, and 49 weeks after discontinuation of the drug in the first and after 20 weeks in the second study was found to be significantly (P less than 0.05) lower in the treated mice than in the controls. CFU-S, BFU-E, and CFU-C contents were also reduced in the treated bone marrow, but with the exception of CFU-S in the second study, differences from control values were not significant. Additional long-term bone marrow cultures performed in the second study revealed no marked changes in the marrow proliferative activity and the self-renewal of stem cells to explain the reduced marrow cellularity and stem cell content. These last findings might, therefore, be due to a decrease in femoral size with less marrow content in the treated mice, since measurements of the tibial weights in both groups showed that the bones in the treated animals were significantly (P less than 0.05) lighter than those in the controls.

Animals↗

PubMed2000

Polycythaemia vera: bone marrow histopathology under treatment with interferon, hydroxyurea and busulphan.

Little is known about long-term effects of myelosuppressive therapy on bone marrow of patients with polycythaemia vera, since histopathology from follow-up biopsies has not been frequently reported. Thus we conducted a retrospective morphometrical analysis of diagnostic and follow-up biopsies of 62 patients, evaluating fibre content, megakaryocytes and bone marrow cellularity. 8/62 patients were treated with interferon-alpha (INF), 11/62 with hydroxyurea (HU) and 11/62 with busulphan (BU). 32/62 served as controls; they were not treated with myelosuppressive drugs but with phlebotomy only. The median observation time was 2.3 yr. Results were compared on the basis of change per time. The bone marrow of the patients with phlebotomies only was characterised by increasing cellularity of haematopoesis, number and volume ratio of megakaryocytes and fibre content. In BU- and HU-treated patients, the haematopoesis was significantly reduced. The IFN patients revealed a reduction of cellularity which was not significant. The fibre content was reduced by BU only, but not significantly. No correlation between megakaryocytes and fibres was found. It could be concluded therefore that: 1) fibre proliferation within the bone marrow was not significantly altered by IFN, HU or BU. 2) Cellularity of haematopoesis was reduced significantly by HU and BU but only partly by IFN, corresponding with haematological remission.

Adult↗

PubMed1989

Haemopoiesis in murine bone marrow and spleen after fractionated irradiation and repeated bone marrow transplantation. II. Granulopoiesis.

Granulopoiesis was studied in mice repeatedly subjected to individual doses of 3 Gy of 60Co gamma-rays at 4-day intervals up to a total dose of 24 Gy on the basis of total bone marrow cellularity follow-up and analysis of myelograms and splenograms. Half of the mice received 10(6) nuclear cells of syngeneic bone marrow after each fractional radiation dose. After an initial steep decrease, the number of granuloid cells in the spleen increased about 30-fold between days 12 and 16 of the experiment (total dose 9 and 12 Gy, respectively). This increase was temporary and between days 20 and 24 (total dose 15 and 18 Gy, respectively) a steep decrease again occurred. At a low level (below 10% of the control value) remained the granuloid cells in the spleens of bone marrow recipients until the end of the experiment (day 37, total dose 24 Gy). The behaviour of the granuloid compartment of haemopoiesis thus contrasts with findings in the erythroid compartment (see Hofer et al., 1989b) when high numbers of erythroid nuclear cells remained in the spleens of bone marrow recipients until the end of the experiment. On the whole, the influence of repeated bone marrow transplantation on granulopoiesis in the bone marrow and spleen is positive. Of the 22 comparisons made between bone marrow recipients and mice only irradiated, 14 differences are statistically significant, always in favour of bone marrow recipients.

Animals↗

PubMed1997

Overexpression of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma by bone marrow cells from patients with myelodysplastic syndromes.

To clarify whether regulatory cytokines inhibit hematopoiesis in patients with myelodysplastic syndromes (MDS), malignancies characterized by the formation of cytopenias despite the presence of cellular bone marrow, expression of TNF-alpha and IFN-gamma by bone marrow cells was investigated using specific reverse transcriptase-polymerase chain reaction assays. An enhanced expression of the mRNA for TNF-alpha was observed in most of the samples from MDS patients (11/14, 79%), whereas no enhancement was observed in bone marrow samples from AML (0/6), CML (0/2) or control cases (0/8). The expression of IFN-gamma was also enhanced in some of MDS cases (5/12, 42%) while AML (0/5), CML (0/2) and control cases (0/6) showed very low levels of IFN-gamma mRNA expression. Immunohistochemical examination confirmed the scattered presence of TNF-alpha or IFN-gamma producing cells in the bone marrow of MDS patients. The majority of these cells were CD68-positive macrophage lineage cells. These results suggested that disruption of hematopoiesis in MDS might be caused by enhanced production of inhibitory regulatory cytokines especially TNF-alpha and occasionally IFN-gamma by bone marrow macrophages.

Adult↗

PubMed1988

Effect of short-term splitting of gamma-ray doses on changes in haemopoietic stem cell number in bone marrow and on mortality of whole-body irradiated mice.

Split-dose irradiation of mice with two doses of 0.5 Gy given at 2 to 5 h interval damages haemopoietic stem cells (CFU-S) less than single exposure to 1 Gy. Also in comparison with whole-body single exposure of mice to a high sublethal dose of 7 Gy, splitting this dose into two doses of 3.5 Gy given at 4-h interval brought about more rapid recovery of CFU-S in femoral bone marrow and of bone marrow cellularity. At 360 days after irradiation with 7 Gy gamma-rays, a secondary decrease in CFU-S was apparent in bone marrow, which was more profound in the single-exposure group than in the group given split doses amounting to 7 Gy. The protective effect of short-term dose splitting was also evident in an investigation of mortality of irradiated mice. The LD50/30 value in mice exposed to a single dose of gamma-rays (8.3 Gy) increased to 10.5 Gy, when the dose was split (two doses, 4-h interval).

Animals↗

PubMed1975

[Bone marrow scintigraphy in anemia caused by impaired hemopoiesis. Respective values of technetium colloids and indium-transferrin].

Thirty-six patients with different types of bone marrow failure have been studied by double scintigraphy, with 99mTc-colloids and 111In.-transferrin. The observed results are compared to those obtained by bone marrow biopsy and ferro-kinetic studies. Despite our imperfect knowledge of the physiology of indium, and the non-selectivity of this tracer for the erythropoietic line, the good correlation observed in most cases between scintigraphy with 111In. and ferro-kinetics and bone marrow histology is an argument which favours the clinical use of this tracer. A striking difference between the results of scintigraphy with Tc-colloids and scintigraphy with 111In. was noticed in chronic erythroblastopenias, and in most of the aplastic anemias, primitive or due to partial leukemic involvement of the bone marrow. It is suggested that this double study may have an interest for the prognosis in these cases. In patients with lymphoma, treated by radiotherapy and/or chemotherapy, In. and Tc scintigraphies show an extension of active bone marrow to normally inactive zones. It indicates a severe defect of the normally active zones, and appears to be a contra-indication for any supplementary chemotherapy. In myeloid metaplasias, this study may be useful for the choice of treatment, by giving precise indications on the degree of splenic erythropoiesis and of bone marrow cellular depletion.

Anemia, Aplastic↗

PubMed1995

Haematopoietic radioprotection by Cremophor EL: a polyethoxylated castor oil.

The polyethoxylated castor oil, Cremophor EL (Cremophor) is approved for human use as a vehicle for oral and intravenous administration of water-insoluble compounds. Cremophor has also previously been shown to reverse the multidrug resistance phenotype at clinically acceptable doses. This study demonstrates that doses of Cremophor in the range of 25-50 microliters/kg intravenously (i.v.) administered 1 day prior to near-lethal irradiation protected the regenerative capacity of the marrow, resulting in haematopoietic radioprotection and long-term survival of near-lethally-irradiated mice. In normal mice, Cremophor administration (1) markedly reduced the level of serum haematopoietic inhibitory activity 4-8 h following injection; (2) resulted in a transient decrease in femoral bone marrow cellularity and upregulated B220 (B cells), and 7/4 (neutrophils and activated macrophages), but not Thy-1 (T-cells) surface antigen expression in bone marrow cells within 24 h of injection; and (3) transiently elevated the incidence of both primitive and committed haematopoietic progenitor cells detected in clonal agar culture within 48 h of injection. Bone marrow progenitor cell content, and peripheral blood white cell, platelet and reticulocyte counts were unaffected. This suggests that the haematopoietic radioprotection and recovery observed in irradiated mice pretreated with Cremophor may be the result of accessory cell activation and/or modulation of accessory factors regulating haematopoietic progenitor cells. Our data suggest a potential clinical use of Cremophor as an adjunct to, or as a substitute for, cytokines to minimize myelosuppression following cytotoxic therapy.

Animals↗

PubMed1991

Bone marrow findings after treatment with recombinant human interleukin-3.

In a phase I/II study, bone marrow biopsy specimens and aspirates of 20 patients with malignant tumors but normal bone marrow (n = 6), bone marrow failure resulting from chemotherapy (n = 4), myelodysplastic syndrome (n = 5), and aplastic anemia (n = 5) were evaluated before and after patients were treated with recombinant human interleukin-3 (rhIL-3). This cytokine proved to be an effective hematopoietic growth factor with only mild side effects. The rhIL-3 treatment led to increased overall bone marrow cellularity with trilinear stimulation of hematopoietic cells, except in most patients with aplastic anemia. In all patients, significant eosinophilia and, in some instances, bone marrow fibrosis developed. In addition to the increase in the number of circulating neutrophilic granulocytes, platelets, and reticulocytes, an increase of peripheral blood monocytes and lymphocytes was observed. The histologic and cytologic findings support the concept that rhIL-3 stimulates the proliferation and differentiation of pluripotent hematopoietic progenitor cells. It appears to be a safe and efficient therapeutic modality in patients with bone marrow failure. Additional clinical studies are needed to determine which patients will profit most from rhIL-3 treatment.

Adult↗

PubMed1996

Bone marrow scintigraphy as a useful method for estimating the physiological status of bone marrow and spleen in polycythaemia vera.

Bone marrow scintigraphy is a simple and noninvasive examination useful to define the status of the bone marrow and spleen in polycythaemia vera (P.V.). Despite the absence of specificity of Indium 111 labelled transferrin (In-Tf) for myelopoietic tissue, there is a close correlation between bone marrow In-Tf uptake and bone marrow cellularity and between splenic In-Tf uptake and splenic metaplasia. The results of scintigraphy are compared to clinical data, radioactive iron kinetics, bone marrow and spleen histology and the course of the disease. The diagnostic and prognostic value of bone marrow scintigraphy is discussed, particularly at the stage of transformation of P.V. into postpolycythaemia myeloid metaplasia (Post-P.V.M.M.).

Bone Marrow↗

PubMed1999

Toxicology and pharmacokinetics of intravesical gemcitabine: a preclinical study in dogs.

More active and well-tolerated agents are needed for the treatment of superficial bladder cancer. This study investigated intravesical gemcitabine to establish the toxicology and pharmacokinetics necessary for clinical trials. Beagle dogs (in groups of 2; n = 6) received 100 mg, 350 mg, or 1 g of drug by intravesical administration on alternate days three times/week for 4 weeks. Animals were observed for clinical signs of toxicity; gemcitabine levels and peripheral blood counts were taken three times weekly. The dogs were euthanized, and a full necropsy was performed at days 1 and 14 after the last dose. Intravesical gemcitabine was given at 100 mg (n = 2), 350 mg (equivalent to the 1000 mg/m2 human dose; n = 3), and 3.5 g (n = 1). i.v. gemcitabine was given at 350 mg (n = 2). Plasma samples drawn at time points up to 8 h were analyzed for systemic absorption and clearance of drug. Doses of 100 and 350 mg were well tolerated with no clinical side effects. Necropsies revealed normal bone marrow cellularity and normal bladder histology. At 1 g, signs of severe clinical toxicity were evident, and after only three doses, necropsies demonstrated severe bone marrow hypoplasia, cystitis, and intestinal necrosis. At all intravesical doses, significant systemic absorption was seen. The T1/2 (+/- SD) for intravesical and i.v. administration of 350 mg was 328 (+/-6.8) min and 99.3 (+/-5.2) min, respectively (P<0.001). Intravesical gemcitabine is well tolerated and has no direct bladder toxicity at doses up to 1000 mg/m2. Higher doses result in gastrointestinal, bladder, and bone marrow toxicity.

Absorption↗

PubMedDate not supplied

Stimulatory effect of intermittent feeding on hemopoietic recovery in sublethally gamma-irradiated mice.

The effect of three-week adaptation to intermittent feeding on the recovery of the hemopoietic functions of mice after sublethal gamma irradiation was investigated. Measurement of oxygen consumption, carbon dioxide output and the respiratory quotient demonstrated an increased metabolic rate in the intermittently fed animals and an accentuation of lipogenic processes. This metabolic state persisted even after irradiation. An improvement in the recovery of hemopoietic functions after irradiation was demonstrated in adapted animals, which was reflected by the increased proliferative activity of the hemopoietic cell populations (more intensive incorporation of 125I-UdR into the DNA of cells of the spleen, thymus and femoral bone marrow), by more rapid renewal of spleen weight, more rapid recovery of the femoral bone marrow cellularity and increased levels of granulocytes in peripheral blood.

Animals↗

PubMed1998

Cellular size of bone marrow cells from rats and beagle dogs.

The usefulness of cellular size measurement for differentiating erythroid and myeloid cells was investigated using rat and canine bone marrow film prepared by the Cytospin method and Wright-Giemsa staining. 1. In the erythroid series, basophilic and polychromatic erythroblasts were distinguishable in terms of cellular diameter; i.e., 99% of rat and 95% of canine polychromatic erythroblasts were distributed in a range < or = 9.5 microns, at which basophilic erythroblasts did not exist. 2. In the myeloid series, myelocytes and metamyelocytes were to some extent distinguishable by their diameters; in rats, myelocytes (75% of the population) were > or = 13.5 microns, and metamyelocytes (61%) < or = 11 microns; and in dogs, myelocytes (45%) were > or = 16 microns, and metamyelocytes (66%) < or = 12 microns. 3. With regard to the metamyelocytes and myelocytes existing in the same range, their nuclear sizes (width) allowed further differentiation; in rats, the nuclear width of myelocytes (87%) was > or = 5 microns, and that of metamyelocytes (84%) < 5 microns; and in dogs, myelocytes (96%) > or = 7 microns, and metamyelocytes (88%) < 7 microns. The present results indicate that cellular size, together with nuclear size, contribute to distinguish the active mitotic group from less- or non-mitotic group in erythroids and myeloids, thus being helpful for toxicological evaluation on chemicals.

Animals↗

PubMed1988

Phase I study of recombinant human granulocyte-macrophage colony-stimulating factor in patients with bone marrow failure and malignancy.

Twenty-five patients with malignancy and/or bone marrow failure were treated with recombinant human granulocyte macrophage colony-stimulating factor (rh GM-CSF) (specific activity 5 x 10(7) units/mg, purity greater than 95%) given by continuous intravenous infusion at various fixed dose levels (15-500 micrograms/m2/day), as part of a phase I study. Treatment was associated with marked increases in white blood cell counts (2-70 fold), consisting mainly of neutrophilic granulocytes. Significant increases were also observed in eosinophils, monocytes and lymphocytes. In addition six patients had multilineage responses characterized by increases in platelet counts (greater than 2 fold and greater than 100,000/mm3) and reticulocyte counts (greater than 2 fold). Three of these 6 patients did not require red cell or platelet transfusion for 17 to 37 weeks. Treatment also resulted in an increase in bone marrow cellularity and myeloid: erythroid cell ratio. The common side effects were constitutional symptoms and bone pain. These findings demonstrate that rh GM-CSF is well tolerated when given by continuous IV infusion and is a potent stimulator of hematopoiesis in vivo.

Bone Marrow↗

PubMed1999

Composite tissue allografts in rats: IV. Graft-versus-host disease in recipients of vascularized bone marrow transplants.

This laboratory has used a composite tissue allograft model as a vehicle for studies on a new type of bone marrow transplant, the vascularized bone marrow transplant. The model consists of a rat hind limb transplant that incorporates integumentary musculoskeletal, and lymphopoietic tissues. These transplants, in comparison with conventional marrow transplants, have the advantage of providing a syngeneic microenvironment and immediate engraftment of both mature and progenitor hemopoietic cells at the time of transplantation. The characteristics of graft-versus-host disease were studied in this model. Lewis X Brown Norway F1 (LBN RT-1(1+n)) rats received hind limbs from Lewis (LEW RT-1(1)) donors (n = 19). Animals were observed daily for signs of graft-versus-host disease. Necropsies were performed. A minority of animals developed lethal disease (7 of 19 recipients) and demonstrated cachexia with concomitant histopathologic changes of the disease. Acute and chronic groups emerged with distinct clinical courses, which are similar to other models of this disease. Recipients of vascularized bone marrow transplants (limb transplants) showed clinical and histopathologic changes of the disease. The transplants may be used as a model of graft-versus-host disease in humans. Most interestingly, the transplant has a lower incidence of disease compared with other methods of bone marrow transplantation and represents an alternative to conventional bone marrow transplantation, which deserves further exploration. It may be possible to develop a new technique for bone marrow transplantation based on this surgical approach. It is proposed that the transfer of vascularized blocks of bone/marrow into prospective recipients as opposed to cellular bone marrow transplants may be preferable.

Animals↗

PubMed1999

Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization.

Cathepsin K is a cysteine protease expressed predominantly in osteoclasts. Activated cathepsin K cleaves key bone matrix proteins and is believed to play an important role in degrading the organic phase of bone during bone resorption. Mutations in the human cathepsin K gene have been demonstrated to be associated with a rare skeletal dysplasia, pycnodysostosis. The degree of functional activity of the mutated forms of cathepsin K in these individuals has not been elucidated, but is predicted to be low or absent. To study the role of cathepsin K in bone resorption, we have generated mice deficient in the cathepsin K gene. Histologic and radiographic analysis of the mice revealed osteopetrosis of the long bones and vertebrae, and abnormal joint morphology. X-ray microcomputerized tomography images allowed quantitation of the increase in bone volume, trabecular thickness, and trabecular number in both the primary spongiosa and the metaphysis of the proximal tibiae. Not all bones were similarly affected. Chondrocyte differentiation was normal. The mice also had abnormalities in hematopoietic compartments, particularly decreased bone marrow cellularity and splenomegaly. The heterozygous animals appeared normal. Close histologic examination of bone histology revealed fully differentiated osteoclasts apposed to small regions of demineralized bone. This strongly suggests that cathepsin K-deficient osteoclasts are capable of demineralizing the extracellular matrix but are unable to adequately remove the demineralized bone. This is entirely consistent with the proposed function of cathepsin K as a matrix-degrading proteinase in bone resorption.

Animals↗