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Results for “bone marrow cellularity”

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PubMed1996

[Effects of interferon inducers on chemically-induced mutagenesis and carcinogenesis].

The murine bone marrow cellular chromosomal aberration technique was used to reveal anticlastogenic effects of the natural interferon inductors ridostin and larifan, as well as the synthetic ones polyguacil and amyxin. The action of the interferon inductors was timed to the maximum production of interferon in the body. Anticarcinogenic, antitumor, and antimetastatic properties of the above interferon inductors were found by using classical experimental models of carcinogenesis. Some mechanisms of antimutagenic and coupled anticarcinogenic action of interferon inductors were considered. The natural interferon inductor larifan was found to have an antipromoter activity. The treatment regimen by using interferon inductors in combination with the immunomodulator thymosin, a thymic hormone, was under discussion.

Animals↗

PubMed1992

Cytogenetic survey of 80 patients with acute nonlymphocytic leukemia.

The authors report a cytogenetic survey of 80 patients with acute nonlymphocytic leukemia. The prognostic value of chromosome aberrations has been evaluated with three methods. The first one showed that patients with NN or AN bone marrow cellularity have a significantly better prognosis than those with AA cellularity; the second method confirmed the relatively good prognosis for patients with t(8;21) and abnormal 16 and a poor one for those with rearrangements of chromosomes 5 and/or 7. The authors also noted, surprisingly, that patients with hyperdiploidy had a significantly poorer prognosis than those with hypodiploidy and especially pseudodiploidy. The third method showed that patients with very complex karyotypes and a worse outcome than those with simple changes. Finally, they discuss the prognostic value of unusual and/or undeciphered chromosome changes detected in 18 patients, with a mean survival of 9.6 months, showing that these changes have a negative prognostic significance.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2002

Assessment of growth and differentiation processes in myelodysplastic syndromes by PCR analysis of Galpha16 and 5'-lipoxygenase.

Development of further diagnostic and prognostic tools in myelodysplastic syndromes (MDS) is warranted. In this study we tested two molecular markers in bone marrow of MDS patients: Galpha16, a hematopoiesis-specific G protein alpha subunit serving as an intracellular marker of hematopoietic activity, and 5'-lipoxygenase (5-LO), a putative differentiation marker. The results were correlated with clinical and laboratory features and outcome. Bone marrow mononuclear cells were evaluated by block cycler PCR in 32 patients for Galpha16 and in 25 patients for 5-LO. In 12 patients cDNA analyzed by the block cycler method was quantified by real-time quantitative (RTQ) PCR for both Galpha16 and 5-LO. The results confirmed concordance of the two methods. All FAB and WHO subtypes were positive for at least one of the two genes. Strikingly, only 1 of 11 patients with refractory anemia with ringed sideroblasts was positive for Galpha16. No correlation between Galpha16 or 5-LO and bone marrow cellularity or cytogenetic risk factors (IPSS) was detected. Only combined evaluation of Galpha16 and 5-LO expression showed a correlation with extent of anemia and thrombocytopenia. A relationship between the two markers and preleukemic duration was found. Our findings show that both Galpha16 and 5-LO can be expressed in MDS, reflecting proliferation and differentiation processes in this disease. Different expression patterns of the two molecules indicate that proliferation and differentiation of hematopoietic cells may occur independently. These parameters could constitute a new class of risk factors in MDS. Determination of Galpha16 and 5-LO expression may provide a tool for observing growth and maturation in these diseases.

Acute Disease↗

PubMed1994

Effects of 5-fluorouracil or total-body irradiation on murine bone marrow microvasculature.

This study was designed to investigate the changes in the murine bone marrow microvasculature following treatment with 5-fluorouracil (5-FU) or total-body irradiation (TBI). Seventy 8- to 12-week-old C3H male mice received either 5-FU at a dose of 150 mg/kg intravenously (i.v.) or TBI at a dose of 8 Gy in two fractions 4 hours apart. Femurs from the treated mice were studied by vascular casting, using mercox, and by routine histology at days 5, 21, and 90. On day 5, the sinusoids were markedly swollen, and many were fused with one another. This was accompanied by significant reduction in the bone marrow cellularity. The central sinus was grossly dilated in both TBI- and 5-FU-treated groups. The pronounced sinusoidal dilatation on day 5 appears to be a mechanical effect due to hematopoietic cell loss resulting in relative negative pressure outside the sinusoids. On day 21, the sinusoidal swelling had subsided, and the overall vascular volume appeared to be restored to normal. However, there was a large variation in the shape and size of the sinusoids, and those present were not uniformly distributed. This may be due to the result of mechanical pressure from the reconstituted hematopoietic cells. Whether these changes in the shape and distribution of sinusoids have functional significance--for instance, release of the hematopoietic cells into the circulation--remains to be established.

Animals↗

PubMed1986

Hematologic remission and cytogenetic improvement induced by recombinant human interferon alpha A in chronic myelogenous leukemia.

We treated 17 patients who had Philadelphia-chromosome-positive chronic myelogenous leukemia (4 of whom had not received therapy and 13 of whom had been treated with hydroxyurea or busulfan for less than six months) with recombinant human interferon alpha A (Roferon-A). The interferon was given as 5 X 10(6) units per square meter of body-surface area per day intramuscularly during induction therapy. Fourteen patients responded to the treatment, of whom 13 had a hematologic remission and 1 had a partial hematologic remission. The median number of white cells in those patients declined from 60.9 X 10(3) to 3.4 X 10(3) per microliter, and the median number of platelets decreased from 476 X 10(3) to 231 X 10(3) per microliter. Among the five responding patients who had splenomegaly before treatment, the spleen size returned to normal in four and decreased by 75 percent in one, although it remained enlarged. Bone marrow cellularity declined from a median of 92.5 percent to a median of 57.5 percent. In six of the patients with hematologic remission, complete suppression of Philadelphia cells was observed on at least one examination. Of the 14 patients who responded, 11 have received the interferon therapy for 9 to 15 months. One patient relapsed during the treatment, and the treatment has been temporarily interrupted in two patients because of toxicity. These data are preliminary and will need further confirmation, but they suggest that recombinant human interferon alpha A is effective in inducing hematologic remission in most patients with benign-phase chronic myelogenous leukemia and in suppressing the Philadelphia chromosome in some of these patients.

Adolescent↗

PubMed1992

The toxic and hematologic effects of interleukin-1 alpha administered in a phase I trial to patients with advanced malignancies.

PURPOSE: A phase I trial was undertaken because interleukin-1 alpha (IL-1 alpha) possesses antiproliferative, immunostimulatory, antiinfection, myeloprotective, and myelorestorative properties that could be beneficial in cancer treatment. PATIENTS AND METHODS: In this phase I trial, IL-1 alpha was administered intravenously (IV) during a 15-minute period daily for 7 days to patients with advanced solid malignancies. RESULTS: The maximum-tolerated dose (MTD) of IL-1 alpha alone was 0.3 microgram/kg. A second group of patients received indomethacin plus IL-1 alpha based on preclinical studies, which indicated that indomethacin could abrogate IL-1 alpha-induced hypotension; however, the MTD of IL-1 alpha plus indomethacin was 0.1 microgram/kg lower than IL-1 alpha alone. Fever, chills, headache, nausea, vomiting, and myalgia were common but were not dose-limiting. Hypotension resulted from a marked decrease in systemic vascular resistance and required pressors at 0.3 and 1.0 micrograms/kg IL-1 alpha. Dose-limiting toxicities included hypotension, myocardial infarction, confusion, severe abdominal pain, and renal insufficiency. IL-1 alpha treatment caused a significant, dose-related increase in the total WBC count (mainly segmented neutrophils and neutrophilic bands). Bone marrow cellularity increased because of enhanced numbers of relatively mature myeloid cells and megakaryocytes. Platelet counts decreased during therapy but were significantly elevated above baseline values 1 to 2 weeks posttreatment; this may have been an effect of IL-6 that was shown to be induced by IL-1 alpha treatment. Significant increases in triglycerides, cortisol, C-reactive protein, thyroid-stimulating hormone and decreases in cholesterol, testosterone, and protein-C were observed with treatment. CONCLUSION: We conclude that at doses of IL-1 alpha that can be given safely to cancer patients, significant, potentially beneficial hematopoietic effects occur.

Adult↗

PubMed2000

Immunomodulatory activity of Withania somnifera.

Administration of an extract from the powdered root of the plant Withania somnifera was found to stimulate immunological activity in Babl/c mice. Treatment with five doses of Withania root extract (20 mg/dose/animal; i.p.) was found to enhance the total WBC count (17125 cells/mm(3)) on 10th day. Bone marrow cellularity (27x10(6) cells/femur) as well as alpha-esterase positive cell number (1800/4000 cells) also increased significantly (P<0.001) after the administration of Withania extract. Treatment with Withania extract along with the antigen (SRBC) produced an enhancement in the circulating antibody titre and the number of plaque forming cells (PFC) in the spleen. Maximum number of PFC (985 PFC/10(6) spleen cells) was obtained on the fourth day. Withania extract inhibited delayed type hypersentivity reaction in mice (Mantoux test). Administration of Withania extract also showed an enhancement in phagocytic activity of peritoneal macrophages (76.5 pigmented cells/200) when compared to control (31.5/200 cells) in mice. These results confirm the immunomodulatory activity of W. somnifera extract, which is a known immunomodulator in indigenous medicine.

Adjuvants, Immunologic↗

PubMed1987

A trial of recombinant alpha 2 interferon in the myelodysplastic syndromes: I. Clinical results.

Interferon has been reported to have differentiation promoting effects in certain model systems. Because of this and other potentially beneficial effects, a trial of recombinant alpha 2 interferon was undertaken in myelodysplastic syndromes. The study population consisted of 14 patients, subclassified as two refractory anemia (RA), one RA with ring sideroblasts (RARS), nine RA with excess blasts (RAEB), and two chronic myelomonocytic leukemia (CMMoL). The planned dosage schedule was 2.0 MU/M2 t.i.w. sc x 2 weeks q 4 weeks for at least two cycles. No patient achieved the prospective remission criteria, which included sustained blood count improvements. Transient improvements of platelet counts of greater than 50% in baseline were noted in six patients, and a transient antileukemic effect was noted in one patient with CMMoL. Myelodysplastic syndrome patients were found to be sensitive to the count suppressing effects of alpha 2 interferon with greater than 25% suppression of granulocytes, platelets, or reticulocytes transiently noted in 11 patients and decreasing bone marrow cellularity noted in two while on treatment. Because of these effects, dosage adjustments were frequently instituted in the RA, RARS, and RAEB patients. The average dosages and durations of treatment received were thus 1.48 MU/M2 x 19.4 injections for patients with RA, RARS, and RAEB and 2.25 MU/M2 x 27 injections for the CMMoL patients. Progression to acute myeloid leukemia or RAEB in transformation was noted in five patients, and increasing leukocytosis was noted in one CMMoL patient while on protocol. It cannot be determined at this time whether these transformations were accelerated by alpha 2 interferon or represent selection bias in this study population. Although some evidence of beneficial effects was noted, alpha 2 interferon in this dosage and schedule is not a useful treatment for myelodysplastic syndromes.

Bone Marrow↗

PubMed1995

Alteration in the frequency, severity and duration of chemotherapy-induced mucositis in hamsters by interleukin-11.

Ninety-five young, male Golden Syrian hamsters were randomly divided into five equally sized groups. One group served as a placebo control while the animals in the others received one of four doses of interleukin-eleven (IL-11) twice daily given by subcutaneous injection beginning on the first day of chemotherapy (day 0) and continuing to day 14. Mucositis was induced with 5-fluorouracil using a standard regimen of 60 mg/kg, intraperitoneally on days 0 and 2 followed by superficial mucosal irritation on day 4. Animals were evaluated daily beginning on day 6. Mucositis was assessed using a standardised technique in which randomly numbered daily mucosal photographs were scored by three blinded independent observers at the conclusion of the experiment. IL-11 favourably affected the frequency, severity and duration of mucositis. This phenomenon appeared to be dose dependent. Hamsters receiving 30 and 100 micrograms per day of IL-11 demonstrated significantly (P < 0.05) lower mucositis scores than did either the control or animals receiving 3 or 10 micrograms per day, although the latter had marginal beneficial effects. Additionally, survival was significantly better for hamsters receiving higher doses of IL-11 (85%) compared to the placebo control (46%). IL-11 administration also favourably affected weight loss. While stimulation of platelet production was noted in animals receiving IL-11, a lack of difference in bone marrow cellularity between test and control animals suggests that the mechanism by which IL-11 modifies mucositis is mediated at the epithelial or connective tissue level rather than through the marrow. The kinetics of IL-11 alteration of mucositis induction supports such a hypothesis. Further investigation is currently underway to establish a definitive mechanism by which IL-11 protects the oral mucosa.

Animals↗

PubMed1992

Increased yield of myeloid progenitor cells in bone marrow harvested for autologous transplantation by pretreatment with recombinant human granulocyte-colony stimulating factor.

Pretreatment with haemopoietic cytokines prior to marrow harvest may result in improved quality of bone marrow harvested for autologous bone marrow transplantation (BMT). Such improvements may reduce the risk for graft failure and decrease time to engraftment. Patients undergoing autologous BMT received recombinant human G-CSF (rhG-CSF) immediately prior to marrow harvest. rhG-CSF was administered as daily subcutaneous injections for 5 days at 5 micrograms/kg body weight. Comparison of bone marrow samples before and after rhG-CSF treatment showed an increased bone marrow cellularity and a ninefold increase in the number of marrow leucocytes per volume aspirated. The mean marrow myeloid:erythroid ratio increased from 2.6 to 4.0. The mean numbers of immature (CD38 positive) and proliferating (CD71 positive) myeloid cells increased significantly from 41.6 to 50.8% and from 17.0 to 34.8%, respectively. Other subsets studied, including CD34 positive stem cells, were unchanged. The relative numbers of day 7 and 14 granulocyte-macrophage colony-forming units (day 7/14 GM-CFU) were unchanged. Long-term marrow cultures revealed that the numbers of 'long-term culture initiating cells' were unchanged after rhG-CSF treatment in spite of the ninefold increase in cellularity. To date, five of the patients have been transplanted with autologous marrow harvested after rhG-CSF treatment. Time to trilineage engraftment was unchanged compared with historical controls. We conclude that pretreatment with rhG-CSF prior to marrow harvest may improve the graft by increasing the total number of myeloid lineage restricted progenitor cells, resulting in stable but not accelerated myeloid engraftment of autologous marrow.

Bone Marrow Transplantation↗

PubMed1988

Stimulation of myelopoiesis in patients with aplastic anemia by recombinant human granulocyte-macrophage colony-stimulating factor.

Aplastic anemia is a syndrome in which pancytopenia occurs in the presence of hypocellularity of the bone marrow. To assess the biologic activities of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) in aplastic anemia, we gave GM-CSF (60 to 500 micrograms per square meter of body-surface area) to 10 patients with moderate or severe disease, by continuous intravenous infusion daily for two weeks, and repeated the treatment after a two-week rest period. The treatment increased the white-cell count (1.6- to 10-fold) in all patients, primarily because of an increase in the numbers of neutrophils (1.5 to 20-fold), eosinophils (12- to greater than 70-fold), and monocytes (2- to 32-fold). Rates of hydrogen peroxide production in purified granulocyte fractions increased during GM-CSF treatment. Increases in bone marrow cellularity, myeloid precursor cells, and myeloid:erythroid cell ratios accompanied the white-cell response. Despite the in vivo response of the white-cells, the concentration of colony-forming cells remained the same. Measurable concentrations of interleukin-2 (2 to 15 units per milliliter) were found in the serum of 8 patients, and high levels of erythropoietin (81 to 1200 IU per liter) were found in 10 patients. The predominant side effects were constitutional symptoms. These results indicate that recombinant human GM-CSF is effective in stimulating myelopoiesis in patients with severe aplastic anemia and may benefit some patients in whom the disorder is refractory to standard forms of therapy.

Adolescent↗

PubMed2004

Inhibition of angiotensin I-converting enzyme induces radioprotection by preserving murine hematopoietic short-term reconstituting cells.

Angiotensin I-converting enzyme (ACE) inhibitors can affect hematopoiesis by several mechanisms including inhibition of angiotensin II formation and increasing plasma concentrations of AcSDKP (acetyl-N-Ser-Asp-Lys-Pro), an ACE substrate and a negative regulator of hematopoiesis. We tested whether ACE inhibition could decrease the hematopoietic toxicity of lethal or sublethal irradiation protocols. In all cases, short treatment with the ACE inhibitor perindopril protected against irradiation-induced death. ACE inhibition accelerated hematopoietic recovery and led to a significant increase in platelet and red cell counts. Pretreatment with perindopril increased bone marrow cellularity and the number of hematopoietic progenitors (granulocyte macrophage colony-forming unit [CFU-GM], erythroid burst-forming unit [BFU-E], and megakaryocyte colony-forming unit [CFU-MK]) from day 7 to 28 after irradiation. Perindopril also increased the number of hematopoietic stem cells with at least a short-term reconstitutive activity in animals that recovered from irradiation. To determine the mechanism of action involved, we evaluated the effects of increasing AcSDKP plasma concentrations and of an angiotensin II type 1 (AT1) receptor antagonist (telmisartan) on radioprotection. We found that the AT1-receptor antagonism mediated similar radioprotection as the ACE inhibitor. These results suggest that ACE inhibitors and AT1-receptor antagonists could be used to decrease the hematopoietic toxicity of irradiation.

Angiotensin-Converting Enzyme Inhibitors↗

PubMedDate not supplied

An immunotoxicity screening study on salmeterol in rats.

Salmeterol, a long-acting beta 2-adrenoreceptor agonist without known immunotoxicity, was studied in a 28-day repeated dose toxicity test in Wistar rats. Several immunotoxicity screening parameters were incorporated in the study protocol to investigate the immunotoxic potential of the compound. Male rats were orally treated with 0, 0.2, 2 and 20 mg salmeterol/kg body weight/day. At the 20 mg/kg/day dose level, intubation errors occurred because the animals tried to resist intubation. Some of these animals died intercurrently. Therefore, the magnitude of the dose was lowered to 10 mg/kg/day at day 9 of treatment. Body weight and bone marrow cellularity were not affected. Hematological parameters were not altered either, except for platelet counts, that were decreased at all dose levels. Also liver weights were decreased at all dose levels tested. Absolute thymic weights were decreased at the 2 and 20/10 mg/kg/day dose levels. No treatment-related (histo)pathological lesions were seen in the (non)lymphoid organs. Serum IgM levels were increased at the 0.2, and IgG at the 2 and 20/10 mg/kg/day dose levels, respectively. B cell numbers in the spleen were decreased at all dose levels tested. The data indicate that the test battery applied to salmeterol is able to detect low immunotoxic potential. Further research is needed to elucidate whether salmeterol interferes with immune responses in rats upon antigenic challenge.

Adrenergic beta-Agonists↗

PubMed2000

Histological alterations in bone marrow in patients with late engraftment after autologous bone marrow transplantation.

Bone marrow histology after bone marrow transplantation has rarely been studied. Here, we reviewed the pre- and post-transplant bone marrow biopsies (BMB) of 40 acute myelogenous leukemia (AML) patients autografted in our center, 28 with normal and 12 with delayed peripheral recovery. The two groups were comparable in terms of previous therapy, disease phase and the number of infused cells, and received the same conditioning regimen. In the former group, reduced bone marrow cellularity and mild reticulin abnormalities were usual histological findings; in the latter, five patients had the same pattern, but the other seven had an almost undetectable hematopoietic parenchyma and severe reticulin derangement. One of these seven patients died of reactivated hepatitis B virus infection; the others eventually achieved peripheral recovery, with none of them experiencing a relapse. Autografted AML patients are excellent subjects for histological investigations. They account for the majority of delayed engraftments, the contribution of extramedullary components to the timing of engraftment is minimal, and leukemia relapse cannot be ruled out. These results suggest that BMB is a useful investigation in the work-up of late engraftment. A high degree of reticulin derangement with an almost undetectable hematopoietic parenchyma appear to be the morphological hallmarks of late engraftment.

Adult↗

PubMed2001

Shwachman-Diamond syndrome: clinical phenotypes.

The clinical phenotype of Shwachman-Diamond syndrome (SDS) is extremely heterogeneous, showing a wide range of abnormalities and symptoms. The main characteristics of the syndrome are exocrine pancreatic dysfunction, haematologic abnormality and growth retardation. At diagnosis, especially when made in infancy, symptoms of pancreatic insufficiency are always present. This condition could be considered as a transient pancreatic insufficiency. In fact, several studies have shown that, with advancing age, about 40-60% of patients become pancreatic sufficient. Observations on the evolution of pancreatic activity lead us to believe that the diagnosis of SDS must be considered even in the absence of signs and symptoms of pancreatic insufficiency. Intermittent neutropenia is the most common haematological finding in SDS, but more of the bone marrow cellular elements can be involved. In recent years, recombinant human granulocyte colony-stimulating factor has been used in some SDS subjects with severe neutropenia and frequent infection. The major haematological problem in the disease is the appearance of acute myeloid leukaemia; however, its prevalence is difficult to establish. Growth retardation is a typical manifestation. Weight and length are deficient at birth and remain below normal over time. Some studies show that SDS patients present short stature rather than malnutrition and this would suggest an inherent growth problem. A broad spectrum of skeletal abnormalities has been found to be associated with this syndrome. Short ribs with broadened anterior ends and metaphyseal dyschondroplasia of the long bone are the most common findings. Elevated liver enzymes and hepatomegaly are present in the first years of life with subsequent improvement without complications. Developmental delay, learning disorders and attention deficit disorders are also reported.

Bone and Bones↗

PubMed1999

DeltaMGMT-transduced bone marrow infusion increases tolerance to O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea and allows intensive therapy of 1,3-bis(2-chloroethyl)-1-nitrosourea-resistant human colon cancer xenografts.

O6-Benzylguanine (BG) is a potent inhibitor of the DNA repair protein 06-alkylguanine DNA alkyltransferase (AGT), and sensitizes tumors to BCNU in vitro and in xenografts. The combination of BG and BCNU is now undergoing phase I clinical testing. The maximally tolerated dose of BCNU given after BG is expected to be lower then the doses tolerated as a single agent owing to BG sensitization of hematopoietic progenitors. We have previously shown that retroviral expression of G156A mutant MGMT (deltaMGMT) in mouse and human marrow cells results in significant BG and BCNU resistance. In this study we evaluated the effect of deltaMGMT-transduced marrow infusion on the therapeutic index of multiple BG and BCNU treatments in tumor-bearing nude (nu/nu athymic) mice. Prior to subcutaneous implantation of BCNU-resistant SW480 human colon cancer cells, cohorts of mice were given intraperitoneal injections of nonablative doses of BG (30 mg/kg) and BCNU (10 mg/kg, one-half of the LD10) and then infused with 1-2 x 10(6) isogeneic deltaMGMT (n = 29 mice) or lacZ-transduced (n = 20 mice) marrow cells. The xenograft-bearing mice were treated with multiple cycles of BG (30 mg/kg) and BCNU (10-25 mg/kg). After three cycles, deltaMGMT mouse bone marrow was repopulated with CFU containing the provirus, and demonstrated a 2.7-fold increase in AGT activity and a 5.5-fold increase in BCNU IC90 compared with LacZ mice. After five cycles, the BCNU IC90 of CFU cells increased nine-fold over control cells, indicating selective enrichment of CFU precursor cells expressing high levels of deltaMGMT. Starting with the third cycle of therapy, tolerance to BG and BCNU was significantly improved in deltaMGMT mice compared with LacZ mice, as evidenced by preserved peripheral blood counts, bone marrow cellularity, and CFU content 1 and 2 weeks posttreatment and a significantly higher survival rate. Xenograft growth was significantly delayed in mice tolerating multiple cycles and higher dose intensity of BG and BCNU as compared with mice receiving less intensive therapy. We conclude that deltaMGMT-transduced marrow cells can improve the therapeutic index of BG and BCNU by selectively repopulating the marrow and providing significant marrow tolerance to this combination, allowing intensive therapy of a BCNU-resistant tumor.

Animals↗

PubMed1990

Host natural suppressor activity regulates hemopoietic engraftment kinetics in antibody-conditioned recipient mice.

Resistance to semi-allogeneic or syngeneic hemopoietic stem cell engraftment can be reduced by treating the unirradiated host with anti-class I MHC antibody. In our previous studies we showed a direct correlation between such resistance and the level of natural suppressor (NS) activity in the host. Thus newborn mice that have high NS activity are very resistant to marrow engraftment, as are adults pretreated with CFA that increases NS activity in the bone marrow. We have now devised a method that allows us to follow hemopoietic engraftment kinetics within the marrow cavity itself by assaying individual CFU-granulocyte/macrophage progenitor cells for their host or donor origin over the immediate post-transplant period. By using this method, we find a close correlation between the rate of marrow engraftment and reduction in host NS activity. Marrow engraftment does not correlate with the reduction of either total host bone marrow cellular content or CFU-granulocyte/macrophage progenitor cell levels. NS activity is mediated by Thy-1-, partially radiosensitive, nylon wool nonadherent cells without NK activity. Adoptively transferred Thy-1-, irradiated spleen cells containing NS activity induced by pretreatment with CFA delayed engraftment kinetics in the marrow cavity. Thus hemopoietic engraftment in the marrow cavity appears to be controlled by an inhibitory regulatory activity that is reflected in the in vitro NS assay. These studies suggest new regulatory targets for selective host conditioning to eliminate resistance to marrow transplantation.

Animals↗

PubMed1991

Hematopoietic and therapeutic properties of bestatin in normal and myelosuppressed mice.

Bestatin is a potent inhibitor of aminopeptidase B, an enzyme which is found in abundance in the membrane of monocytes and macrophages. Binding of Bestatin to cells in the histiocytic linage upregulates colony stimulating activity (both in vitro and in vivo), which subsequently increases hematopoietic and hematologic values. We report that the treatment of mice with Bestatin upregulates the frequency and absolute numbers of colony forming unit--granulocyte-macrophage (CFU-GM), as well as the entry of CFU-GM into S phase (a measure of progenitor cell activity). As a result, there is an increase in bone marrow cellularity in cyclophosphamide myelosuppressed mice and an increase in the absolute neutrophil count in normal and myelosuppressed mice. The therapeutic application of this hematopoietic modulator has been demonstrated in combination cyclophosphamide and Bestatin protocols. While Bestatin has significant therapeutic activity for minimal metastatic disease, therapy models in which the hosts have greater metastatic tumor burdens requires combination chemoimmunotherapy for a significant therapeutic effect. Because myelosuppression as a therapeutic indication for Bestatin has only recently been recognized, few clinical studies have been undertaken with appropriate surrogates of hematopoietic activity. However, the preliminary clinical evidence of hematopoietic activity by this non-toxic dipeptide, as reviewed here, suggests that this may be an appropriate drug for the treatment of myelosuppressed patients. Thus, Bestatin as an orally active biological response modifier (BRM) has significant therapeutic activity for metastatic disease via multiple mechanisms including hematopoietic stimulation and macrophage activating properties.

Animals↗