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PubMed1988

Effects of deuteration on hematopoiesis in the mouse.

Mice ingesting 30 to 50% D2O (heavy water, deuterium oxide) developed a dose-dependent depression of formed peripheral blood elements in 4 to 9 days. The principal mechanism of anemia and thrombocytopenia is impaired hematopoiesis. Despite pancytopenia in the peripheral blood, bone marrow cellularity and morphology remained normal. Upon replacement of D2O with tap water, platelet and neutrophil concentrations returned to normal within 48 to 72 hr. In contrast, blood lymphocyte concentrations remained low for several weeks. B-lymphocytes may be more affected by deuteration than other lymphocyte subsets. In vivo reticuloendothelial cell function, as assessed by 51Cr-labeled sheep erythrocyte clearance, was unaffected by D2O. Although a dose-dependent decrease in fluid intake occurred during deuteration, hematocytopenia was not a consequence of dehydration. In view of the known kinetics of D2O in biological systems, the rapid response of myeloid elements to deuteration must be due primarily to the solvent (nonmetabolic) isotope effect. Prolonged deuteration has proven toxic when included in regimens for treatment of neoplasia, including leukemia, in animal models. The present study shows that modulation of hematopoiesis by D2O is possible without invoking the toxicities associated with prolonged deuteration.

Animals↗

PubMed2006

Combination exposure to zidovudine plus sulfamethoxazole-trimethoprim diminishes B-lymphocyte immune responses to Pneumocystis murina infection in healthy mice.

We have previously shown that zidovudine plus sulfamethoxazole-trimethoprim exposure decreases immune cell populations in the bone marrow of healthy mice by inducing apoptosis. The hypothesis of the current work was that this toxicity would have an adverse impact on the immune response. To determine this, BALB/c mice were treated with zidovudine, sulfamethoxazole-trimethoprim, the combination of both drugs, or vehicle only (control) via oral gavage for 21 days. On day 4 after dosing completion, the mice were infected intratracheally with 1x10(7) Pneumocystis murina organisms. Immune cell populations (in lung digest, bronchoalveolar lavage fluid, tracheobronchial lymph node, and bone marrow samples), the lung Pneumocystis burden, and serum Pneumocystis-specific antibody titers were determined at days 6, 10, and 20 postinfection. While total bone marrow cellularity was recovered by day 6 postinfection in the combination exposure group, B-cell numbers did not recover until 10 days postinfection, primarily due to the persistent depletion of the late pre-B-cell phenotype. The numbers of CD4+ and CD8+ T cells, as well as the numbers of total B cells and activated B cells in tracheobronchial lymph nodes, were decreased at days 10 and 20 as a result of zidovudine plus sulfamethoxazole-trimethoprim exposure compared to the numbers in the control group. No significant differences in lung lavage or lung digest cell populations were observed. There was a trend of a delay in Pneumocystis clearance in the combination treatment group, and Pneumocystis-specific serum immunoglobulin G titers were reduced at day 20 postinfection. Together, these data indicate that the combination of zidovudine and sulfamethoxazole-trimethoprim adversely affects the humoral immune response to Pneumocystis.

Animals↗

PubMed1993

Tumor inhibition and hematopoietic stimulation in mice by a synthetic copper-ATP complex.

The hematologic effect of [Cu3(ATP)(2)6H2O]2-, a synthetic copper-ATP complex (Cu-ATP) having antitumor activity, was investigated in normal and Ehrlich ascites carcinoma-bearing mice. Cu-ATP (25 mg/kg) induced appreciable tumor inhibition and prolonged host survival which were accompanied by elevated levels of hemoglobin, platelet and lymphocytes while total WBC count and bone marrow cellularity remained unaffected. In normal mice the compound elicited marrow and splenic hypercellularity with a greater number of granulocyte progenitors and elevated levels of peripheral WBC, RBC and platelets. In addition, the total number of CFU-S of these treated animals was increased and these pluripotent stem cells differentiate preferentially towards granulocyte lineage. The results indicate that Cu-ATP does not adversely affect hematopoiesis while it inhibits tumor growth; on the contrary, it has a stimulatory effect on murine granulocytopoiesis.

Adenosine Triphosphate↗

PubMed1991

Granulocyte kinetics in neutrophilia induced by recombinant human granulocyte colony-stimulating factor in mice.

To investigate the mechanisms of neutrophilic expansion induced by granulocyte colony-stimulating factor (G-CSF), granulocyte kinetics was studied by means of an autoradiographic method in G-CSF treated mice. Daily intraperitoneal injections of recombinant human G-CSF (rhG-CSF; 2.5 micrograms/day for 5 days) markedly increased the white blood cell count, especially granulocytes in circulating blood. Whole body bone marrow cellularity, quantitated using the radiodilution principle described by Donohue and Finch, increased from 30.0 x 10(7) cells/body (15.2 x 10(9) cells/kg) to 83.5 x 10(7) (41.8 x 10(9)) after the administration of rhG-CSF for 3 days. Generation time of myeloblasts, mitotic pool transit time, and post-mitotic pool transit time, assessed by autoradiography with 3H-thymidine, were significantly shortened in rhG-CSF treated mice compared with the control mice. Daily neutrophil production rates, calculated from these parameters, were 15. 61 x 10(7) cells/day in rhG-CSF mice and 1.93 x 10(7) in the controls. rhG-CSF had no significant effect on the survival time of granulocytes in the circulation, assessed by T1/2 of 3H-thymidine labeled granulocytes. Thus, neutrophilia induced by rhG-CSF is partly due to shortening of the generation time, mitotic pool transit time and post-mitotic pool transit time of myeloid cells.

Animals↗

PubMed1991

Post consolidation therapy for adult patients with acute myeloid leukaemia.

One hundred and sixteen adult patients aged 14-73 with previously untreated acute myeloid leukaemia received induction and consolidation chemotherapy with daunorubicin, cytosine arabinoside and thioguanine. Two novel approaches to post consolidation therapy have been investigated. Patients aged 50 years or less who had no suitable matched allogeneic donor were considered for autologous bone marrow transplantation (BMT) using bone marrow which had been cultured in vitro for 14 d. Patients over the age of 50 years with normal bone marrow cellularity and peripheral blood count were treated with a single oral dose of busulphan 100 mg/m2 (without BMT rescue) 3 months following the completion of consolidation therapy. Eighty-seven patients (75%) achieved a complete remission. Of 70 patients who completed consolidation therapy, 40 were aged less than or equal to 50 years and 30 were greater than 50 years. Forty-three patients went on to receive post consolidation therapy in first CR (autologous BMT 12, allogeneic BMT 7, busulphan therapy 24). The event-free survival at 4 years was 47% for autologous BMT, 34% for allogeneic BMT and 45% for busulphan-treated patients. The survival for the older cohort of patients who received post consolidation therapy with single dose busulphan therapy was encouraging, and this agent should be considered for future post consolidation strategies.

Acute Disease↗

PubMed1991

[A histopathological study of bone marrow in acute myeloid leukemia. Bone marrow biopsy changes before chemotherapy and comparison with bone marrow smears].

Histopathological changes of pretreatment bone marrow biopsy from 42 cases with acute myeloid leukemia (AML) were described. A considerable difference was shown between the results of aspirate smears and the findings of plastic embedded biopsy sections, particularly in bone marrow cellularity such as infiltration of inflammatory cells and presence of residual hemopoietic cells, qualitative and quantitative abnormalities of megakaryocytes suggestive of myelodysplastic features were more accurately assessed in the sections of marrow biopsy than in the aspirate smears. In three cases there was considerable infiltration of maturing but dysplastic granulocytic cells and erythroid precursors in the sections, but not in the aspirate smears. Our study shows that plastic embedded biopsy sections provide more information than aspiration smears for the diagnosis of AML.

Adolescent↗

PubMed2000

Histologic, neurologic, and immunologic effects of methylmercury in captive great egrets.

Captive great egret (Ardea albus) nestlings were maintained as controls or were dosed with methylmercury chloride at low (0.5), and high doses (5 mg/kg, wet weight) in fish. Low dosed birds were given methylmercury at concentrations comparable to current exposure of wild birds in the Everglades (Florida, USA). When compared with controls, low dosed birds had lower packed cell volumes, dingy feathers, increased lymphocytic cuffing in a skin test, increased bone marrow cellularity, decreased bursal wall thickness, decreased thymic lobule size, fewer lymphoid aggregates in lung, increased perivascular edema in lung, and decreased phagocytized carbon in lung. High dosed birds became severely ataxic and had severe hematologic, neurologic, and histologic changes. The most severe lesions were in immune and nervous system tissues. By comparing responses in captive and wild birds, we found that sublethal effects of mercury were detected at lower levels in captive than in wild birds, probably due to the reduced sources of variation characteristic of the highly controlled laboratory study. Conversely, thresholds for more severe changes (death, disease) occurred at lower concentrations in wild birds than in captive birds, probably because wild birds were exposed to multiple stressors. Thus caution should be used in applying lowest observed effect levels between captive and wild studies.

Analysis of Variance↗

PubMed2005

[Retrospective observation of curative effects on MDS refractory anemia with combination of all-trans retinoic acid, 1, 25-dihydroxyvitamin D3 and androgen].

This study was aimed to examine whether a combination of all-trans retinoic acid (ATRA), 1, 25-dihydroxyvitamin D(3) and androgen possesses the therapeutic value for the MDS-refractory anemia (MDS-RA), and to analyze the mechanisms in detail. 62 cases receiving a scheme of combination of ATRA, 1, 25-dihydroxyvitamin D(3) and androgen (group A) were monitored. The remaining 33 cases (group B) were provided with vitamin supplementation, chalybeate drugs, and one or two of the combination. Bone marrow aspiration and biopsy were performed for collecting the specimens at the baseline and afterwards. The conditions of the patients were monitored by means of weekly complete blood counts and the monthly examination, including toxicity test, physical examination, electrocardiography, and biochemistry panel. The results showed that after treating for 8 weeks in group A, 4 out of 62 patients showed complete remission and 12 patients showed partial remission according to the defined response criteria, and 43 patients (69.35%) showed hematological improvement (HI). The further treatment for 16 out of 62 patients (25.81%), 13 failures (10 deaths, 2 RAEB and 1 RAEB-T) and 3 transformations (M(2), M(3), M(5)) with a median survival interval of 26.25 months, were observed and interrupted for some reasons. However, partial remission was observed only in 3 patients in group B, and HI amounted to 51.51%. Furthermore, the disease progression was observed in 12 out of 33 patients (36.36%) with a median survival interval of 16 months, 9 failures (including 6 deaths, 2 RAEB and 1 RAEB-T) and 3 transformations (M(2), M(3), M(4)). The overall ratios of survival for 3 and 5 years in group A, which received the combination, reached to 69.24% and 53.72% respectively, in comparison with 52.23% and 31.34% in the patients of group B (log-rank, P = 0.016). The following requirements, if were met, would be significant for prognosis: the combination regiment, no transformation, children, no complication, female, 90-120 g/L of hemoglobin concentration, normal cellular bone marrow and uni-cytopenias (P < 0.05). Moreover, Cox regression showed that therapy, transformation and age are all the independent factors (P < 0.05). It is concluded that the combination of above mentioned 3 drugs may be effective and safe treatment for the patients with MDS-RA. Its relevant mechanisms can be involved in the combination, that elicits a wide range of pharmacological effects, such as differentiation, anti-tumor-promotion, anti-apoptosis, anti-angiogenesis, anti-cachexia and immunoregulation.

Adolescent↗

PubMed1993

[Transient pure red cell aplasia in an adult with acute parvovirus B19 infection: observation of PVB19 DNA by polymerase chain reaction, viral antibody and erythroid cells in the bone marrow].

A 35-year-old female was referred to our hospital for fever and anemia. Physical examination was unremarkable. Complete blood count revealed microcytic hypochromic anemia and reticulocytopenia. The bone marrow cellularity was normal. Some giant pronormoblasts were seen but other erythroid cells were absent. No stainable iron was seen. Parvovirus B19 (PVB19) DNA was detectable by polymerase chain reaction. Anti-PVB19 IgM-antibody was also positive in the serum on admission. Antibodies against rubella, measles, mumps, EB virus and HBs were negative and HBs antigen was also negative. Thus the diagnosis of iron deficiency anemia complicated with pure red cell aplasia secondary to PVB19 infection was made. The PVB19 DNA was still positive on days 6 and 11, suggesting that PVB19 virus persists as long as 3 weeks after the onset of PVB19 infection. However, the erythroid cells had recovered by day 6 after admission suggesting that the development of IgM antibody successfully protected the erythroid cells from infection by the residual PVB19. Hence, careful observation for PVB19 DNA and the antibody may be necessary if immunodeficient patients developed anemia of unknown etiology.

Acute Disease↗

PubMed1988

Permanent loss in stem cell self renewal capacity following stress to the marrow.

A technique of irradiating the entire mouse except for one hind limb was developed to provide repeated proliferative demand on the stem cell pool. Animals received 200 cGY weekly for a total dose of 3,400 to 4,000 cGy. During irradiation, shielded bone marrow cellularity was similar to that of unirradiated controls. Shielded marrow colony-forming unit (CFUs) content increased while marrow CFUs self renewal capacity decreased as compared with unirradiated age-matched controls. Following irradiation experimental animals were monitored monthly for 10 to 12 months for marrow cellularity, CFUs content, and self renewal capacity. Shielded marrow cellularity and CFUs content remained elevated over age-matched controls throughout the period of observation. These findings are compatible with the requirement of the shielded hind limb to provide hematopoietic support for the remainder of the animal. Shielded marrow self renewal capacity, a measurement reflecting primitive hematopoietic stem cell function, remained depressed and did not recover with time. These experiments provide evidence for there being limitations on the self renewal capacity of the stem cell compartment. While the small amount of shielded marrow had sufficient capacity to support the animal its average self renewal capacity was permanently reduced.

Animals↗

PubMed1985

Changes in hematopoietic stem cells in bone marrow of mice with Plasmodium berghei malaria.

An impaired erythropoietic response to anemia has been noted in human patients with malaria and in rodents experimentally infected with Plasmodium berghei. We have attempted to characterize the erythropoietic response in mice with a fatal P berghei infection, with particular emphasis on changes in marrow hematopoietic stem cells. Mice infected with P berghei had dramatic decreases in bone marrow cellularity, erythroblasts, BFU-E, and CFU-E as early as 24 hours postinfection and before there was any change in hematocrit. With development of anemia, marrows became erythropoietic with some expansion of the CFU-E compartment, but the BFU-E pool remained depleted and reticulocyte response was inadequate. There was no significant change in CFU-S from marrows of malaria-infected mice one day after infection. The lethality of malaria infection may take three weeks to be revealed, but it may be determined within hours of the infection by the irreparable changes in marrow erythroid stem cells.

Animals↗

PubMed2001

Elevated vascular endothelial growth factor (VEGF) serum levels in idiopathic myelofibrosis.

An increase of angiogenesis has been shown in idiopathic myelofibrosis with myeloid metaplasia (MMM) by microvessel density count method but evaluation of circulating angiogenic factors is still incomplete. In 31 patients affected by MMM and in 12 healthy subjects we evaluated the serum levels of VEGF (vascular endothelial growth factor) and correlated VEGF with clinical and laboratory features of disease. We found that MMM patients had circulating VEGF concentrations much higher than controls (Median 1208 ng/ml vs 138 ng/ml, P < 0.0001). No correlation was found between VEGF and Hb, WBC, PLT, LDH, creatinine, bone marrow cellularity, fibrosis, splenomegaly, hepatomegaly, and therapy. However, in the subgroup of patients with a normal or low VEGF concentration, a direct correlation between VEGF and platelet count (r = 0.90, P = 0.002) was detected. Moreover, patients with a platelet count < 300 x 10(9)/l had VEGF serum levels lower than patients with a higher PLT count (median VEGF 864 vs 1557 pg/ml, P = 0.001). In six patients and in eight controls we also had the opportunity to measure VEGF in the plasma and we calculated that VEGF concentration was much higher in platelet-rich than in platelet-poor plasma and that platetets of MMM patients contained four times more VEGF than those of healthy controls. These results indicate that VEGF is overproduced in MMM, thus confirming an increased angiogenic activity. Platelets are probably a major source of VEGF in MMM but not the only one.

Adult↗

PubMed1998

In vitro and in vivo hematopoietic activities of Betafectin PGG-glucan.

Betafectin PGG-glucan is a novel beta-(1,3)glucan that has broad-spectrum anti-infective activities without cytokine induction. Here we report that PGG-glucan also has both in vitro and in vivo hematopoietic activities. In vitro studies with bone marrow target cells from the C3H/HeN mouse revealed that although PGG-glucan alone had no direct effect on hematopoietic colony-forming cell (CFC) growth, when combined with granulocyte colony-stimulating factor (CSF) or granulocyte-macrophage CSF, it increased CFC numbers 1.5- to 2.0-fold over those obtained with CSFs alone. Bone marrow cells cultured for high-proliferative-potential CFCs in the presence of interleukin (IL)-1, IL-3, macrophage CSF, and stem cell factor (SCF), or cultured for erythroid burst-forming units in the presence of IL-3, SCF, and erythropoietin, also exhibited enhanced growth in the presence of PGG-glucan. The synergistic effect of PGG-glucan was specific and could be abrogated by anti-PGG-glucan antibody. The ability of PGG-glucan to modulate hematopoiesis in vivo was evaluated in myelosuppressed rodents and primates. C3H/HeN female mice were intravenously administered saline solution or PGG-glucan (0.5 mg/kg) 24 hours before the intraperitoneal administration of cyclophosphamide (200 mg/kg), and the recovery of bone marrow cellularity and granulocyte-macrophage progenitor cells was evaluated on days 4 and 8 after cyclophosphamide treatment. At both time points, enhanced hematopoietic recovery was observed in PGG-glucan-treated mice compared with saline-treated control mice. In a final series of in vivo experiments, we evaluated the ability of therapeutically administered PGG-glucan to enhance hematopoietic recovery in cyclophosphamide-treated cynomolgus monkeys. Monkeys received intravenous infusions of cyclophosphamide (55 mg/kg) on days 1 and 2, followed on days 3 and 10 by intravenous infusion of PGG-glucan (0.5, 1.0, or 2.0 mg/kg). Compared with those in saline-treated monkeys, accelerated white blood cell recovery and a reduction in the median duration of neutropenia were observed in PGG-glucan-treated monkeys. These studies illustrate that PGG-glucan has both in vitro and in vivo hematopoietic activities and that this agent may be useful in the prevention and/or treatment of chemotherapy-associated myelosuppression.

Animals↗

PubMed2005

Chronic zinc deficiency in mice disrupted T cell lymphopoiesis and erythropoiesis while B cell lymphopoiesis and myelopoiesis were maintained.

OBJECTIVE: The purpose of this study was to determine the impact of chronic zinc deficiency (ChrZD) on T and B cell lymphopoiesis, myelopoiesis and erythropoiesis in mice. METHODS: Young adult mice were fed a zinc adequate (ZA) or ChrZD synthetic diet for 34, 45, and 50 days. The cellular composition of the thymus and marrow were determined to assess the impact of ChrZD on lymphopoietic and hematopoietic processes using flow cytometry. Body weights, serum zinc and corticosterone (Cs) were monitored. RESULTS: For ChrZD mice growth was reduced 10% and serum zinc declined 15% by d 34 compared to ZA mice. By d 50 a 25% decrease in growth and 70% depression in serum zinc was noted though there was never any significant reduction in diet intake. Corticosterone rose 2.5 fold by d 34 and remained elevated in ChrZD mice indicating induction of the stress axis. At d 34 the thymus of ChrZD mice was normal but by d 50 there was a 50% cell loss and a 10% reduction in the proportion of Pre-T cells. Most importantly there was a 60% increase in Pre-T cells undergoing apoptosis in ChrZD mice. Pro-T, T helper, and T cytolytic populations were more resistant to ChrZD. Bone marrow cellularity and granulocyte, monocyte, and lymphocyte compartments remained unchanged in ChrZD mice. However, the erythroid compartment was reduced by 35% at d 50. CONCLUSIONS: The thymus was the most sensitive primary tissue to ChrZD. By d 50 it had atrophied by 36% with significant loss of Pre-T cells via apoptosis such that T-cell lymphopoiesis was disrupted. Significant reductions were also noted in the erythropoietic population by d 50. Conversely the marrow maintained myelopoiesis and B cell lymphopoiesis for the 50 d period indicating greater ability to survive a chronic zinc deficiency and exposure to Cs. The anemia and T cell lymphopenia associated with ChrZD in both rodents and humans may result from a greater sensitivity of their precursor cells to zinc deficiency and elevated Cs.

Animals↗

PubMed1982

[Prognosis in aplastic anemia].

In catamnestic examinations of patients with aplastic anaemia 11 cases had to be excluded from a primarily diagnosed total number of 112 because these proved to be cases of preleukaemia. In the rest of 101 patients there was a highly significant positive correlation (p less than 0.001) of the survival time to the bone-marrow cellularity and to the average values of corrected reticulocytes and granulocytes calculated from findings of 0,4, and 8 weeks. For thrombocytes, however, a slightly significant positive correlation (p less than 0.05) could only be identified in the present material for the 4-weeks value. The fact that the prognosis is deteriorated by a rapid development of the disease could be made probable by means of a positive correlation between the time of the first symptom and diagnosis (p less than 0.01). With patients falling below 2 or 3 limiting values of the peripheral blood cells they were classified to the SAA group according to the proposals made by Camitta, however, by using the average values described above The survival rate which remained constant after 3 years amounted to 16% for SAA patients classified in this way, 44% for non-SAA cases with constant values of 39% beginning from the fourth year. Patients with average values of all three cell parameters falling below those limiting areas had a six months survival time of only 11%. No patients were alive after one year. The latter was also true if reticulocytes and granulocytes were affected by a diminution of only 2 parameters. Those patients, however, who had an average of reticulocytes and thrombocytes only, but no granulocytes below the limiting area within the first 8 weeks showed a mortality curve which did not differ from that of non-SAA patients. Therefore, a classification of these cases can only be made with great caution allowing for a prognosis-oriented therapy, such as indication for bone-marrow transplantation.

Adolescent↗

PubMed1994

Evaluation of toxicity of cypenhymustine, a new anticancer compound, in mice.

The toxicity of cypenhymustine, a potential anticancer compound 1 (Cancer Letters, 70 (1993) 1-6), was assessed in normal as well as in Ehrlich ascites carcinoma (EAC), Sarcoma-180 (S-180) and Dalton's lymphoma (DL)-bearing Swiss male mice by measuring drug-induced changes in (1) hematological parameters and (2) femoral bone marrow cellularity on day 9 following drug treatment at the optimum dose of 3.0 mg/kg body weight from days 1 to 7. Detailed studies were also made by noting sequential changes in the above parameters in normal and EAC-bearing mice on days 12, 15, 18 and 21, respectively. The results indicate that the compound did not adversely affect hematopoiesis. From the sequential studies, it was observed that after a mild initial decrease in hematological counts, particularly in EAC-bearing treated mice, normalcy was reached within 11-14 days after termination of drug therapy. Drug induced hepatotoxicity and nephrotoxicity were also sequentially evaluated in normal and EAC-bearing mice on days 9, 12 and 15 but no such toxicities were detected. Also, body weight, skin and hair texture, and behavioural pattern (food and water intake and activity) did not reflect any toxic reaction in the host mice at this optimum dose.

Alanine Transaminase↗

PubMed1992

A predictive model for the clinical response to low dose ara-C: a study of 102 patients with myelodysplastic syndromes or acute leukaemia.

The response to treatment with low-dose ara-C was studied in 102 consecutive patients; 79 with myelodysplastic syndrome (MDS) and 23 with acute myelogenous leukaemia (AML) following MDS. The aim was to find variables that could predict the response to treatment. All patients had clinical symptoms related to cytopenia. Peripheral blood values, bone marrow morphology histology and chromosomes were analysed before the start of treatment. The median survival of the patients was 9 months and a poor survival was predicted by advanced age, low platelet counts, the presence of pseudo-Pelger morphology and > or = 2 chromosomal aberrations. Thirty patients (29%) responded with either a complete remission or a significant increase in haemoglobin level. For the remaining 71%, the treatment was ineffective and in some cases hazardous. The factors associated with a poor response to treatment could be divided into two groups: one included low platelet counts and the presence of chromosomal aberrations, both signs of progressive MDS with a short survival, and the other comprised morphological findings, indicating ineffective haemopoiesis. Patients with platelet counts > 150 x 10(9)/l had a response rate of 55% compared to 23.5% in patients with subnormal platelet counts. Logistic regression identified low bone marrow cellularity, absence of ring sideroblasts and < 2 chromosomal aberrations as predictors of a favourable response in patients with platelet counts < 150 x 10(9)/l. These factors and the platelet count were combined in a predictive model which can divide patients into three groups with different probabilities of response: a favourable group, 38.6% of the patients, with a response rate of > 50%, an intermediate group, 32.7% of the patients, with a response rate of 24%, and an unfavourable group, 28.7% of the patients, with only 3% responses. While low-dose ara-C is an effective treatment for some patients, it is ineffective and hazardous for others. We present a model that can facilitate therapeutic decision making in two-thirds of patients with MDS and MDS-AML by identifying patients who should not be treated with low-dose ara-C as well as patients with a relatively high probability of response.

Aged↗

PubMed1992

Liposomal encapsulation of azidothymidine results in decreased hematopoietic toxicity and enhanced activity against murine acquired immunodeficiency syndrome.

This study has determined the effect of liposomal encapsulation on the hematopoietic toxicity and antiviral activity of 3'-azido-3'-deoxythymidine (AZT) in mice. Daily intravenous administration in the dose range 0.4 to 10 mg/kg body weight for 5 days significantly depressed bone marrow cellularity with a corresponding decrease in red blood cell, blood neutrophil, and monocyte numbers. Maximum toxicity was seen at 2 mg/kg or greater. Liposomal encapsulation of AZT and administration at 2 mg/kg abrogated the toxicity of AZT. The neutrophil inflammatory response to thioglycollate injected intraperitoneally was significantly inhibited by AZT at all doses, whereas liposomal AZT was without effect. The inhibitory activity of AZT against Concanavalin A (Con A)-stimulated splenic lymphocyte proliferation in vitro was reduced on liposomal encapsulation of AZT, while treatment of mice with liposomal AZT but not free AZT resulted in a significant reduction of Con A-stimulated proliferation. Liposomal AZT was more effective than AZT in preventing the development of plasma reverse transcriptase activity and the depletion of Thy 1.2(+)-L3T4+ T cells after infection of mice with LP-BM5 retrovirus. These results indicate that AZT-induced hematopoietic toxicity may not be a limiting factor for antiviral therapy, and that the use of liposomes to deliver AZT results in enhanced antiretroviral activity in mice.

Acquired Immunodeficiency Syndrome↗