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R M Lemoli

Publications and source records attributed to R M Lemoli.

104 records · Page 6Linked to original sources
PubMedDate not supplied

In vitro effects of bisantrene on fresh clonogenic leukemia cells: a preliminary study on 15 cases.

In vitro clonogenic assays may be useful for determining the sensitivity of leukemic cells to chemotherapeutic agents. We evaluated the antileukemic effect of Bisantrene (an anthracene derivative now undergoing phase II clinical trials in relapsed/resistant acute non lymphoid leukemias-ANLL) using the ANLL cell clonogenic assay. Fifteen cases were studied (9 newly diagnosed, 5 relapsed and 1 refractory ANLL). Normal CFU-GM sensitivity was tested in a subset of 10 normal controls. A wide range of concentrations (from 0.01 to 10 micrograms/ml) at 3 durations of exposure (30 min, 120 min, continuous) was employed. Bisantrene proved effective in 12 out of 15 ANLL cases, inhibiting blast colony growth (50% at 1 micrograms/ml; nearly 100% at 10 micrograms/ml) in a dose-dependent, time-independent way. Three cases were unresponsive both in vitro and in vivo. Normal CFU-GM were inhibited at lower doses (50% at 0.5 micrograms/ml; 100% at 5 micrograms/ml). We conclude that: 1) Bisantrene is active in vitro on leukemic clonogenic cells at doses corresponding to plasmatic levels achievable in patients, with a parallel activity in vivo in 3 relapsed cases. It should be tested in vitro before therapeutic use in order to avoid, if possible, improper use in resistant patients. 2) Normal CFU-GM are more sensitive than clonogenic leukemic cells. This must be taken into account, in view of possible prolonged neutropenias after therapy. 3) The time-independent effect of the drug should be evaluated in the design of new therapeutic schedules.

Anthracenes↗
PubMedDate not supplied

Persistence of non clonal hematopoietic progenitor cells in blastic phase chronic myelogenous leukemia (CML). Working Party on Severe Aplastic Anemia (WPSAA) of the European Group of Bone Marrow Transplantation (EBMT).

Normal and clonal hematopoietic progenitor cells have been demonstrated to coexist in chronic-phase chronic myelogenous leukemia (CML), but few data are available on the presence of non neoplastic hematopoiesis during the blastic transformation phase. We used reverse transcription-polymerase chain reaction (RT-PCR) to investigate expression of the BCR/ABL transcript of individual hematopoietic progenitors from a CML patient in blastic phase. We demonstrate that non clonal hematopoiesis is induced to re-emerge by conventional chemotherapy containing fludarabine. In addition, we confirm that some pluripotent CD34+/CD33-/DR- cells circulating in the peripheral blood are not clonal. Our data provide an encouraging basis for further studies of in vitro purification of normal hematopoietic stem cells in advanced stage CML and of their use in the context of autologous bone marrow transplantation.

Adult↗
PubMedDate not supplied

Interleukin-11 (IL-11) and IL-9 counteract the inhibitory activity of transforming growth factor beta 3 (TGF-beta 3) on human primitive hematopoietic progenitor cells.

BACKGROUND: TGF-beta 3 has been proven to be a potent suppressor of human hematopoietic progenitor cells and its effects on hematopoiesis are only inhibitory. METHODS: In this paper we investigated the antiproliferative activity of TGF-beta 3 on highly purified bone marrow (BM) CD34+ cells and more immature CD34+/4-hydroperoxycyclophosphamide (4-HC) resistant cells. Primitive hematopoietic progenitors were stimulated by early acting stimulatory factors such as SCF, IL-11, IL-9 and the intermediate-late acting growth factors IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), alone and in combination. RESULTS: The addition of TGF-beta 3 to cultures of CD34+ cells containing IL-11, IL-9 or SCF alone resulted in 86% or more inhibition of total colony formation. Conversely, IL-3 and GM-CSF-stimulated colony growth was inhibited by 57% and 58%, respectively (p < 0.02). IL-11 and IL-9 acted synergistically or additively with IL-3 and GM-CSF on the clonogenic growth of BFU-E derived from CD34+ cells, in both the presence and absence of TGF-beta 3. Co-incubation of CD34+ cells with 2 synergistic factors (e.g. IL-11 and SCF or IL-9 and SCF), with or without TGF-beta 3, resulted in the enhancement of both CFU-GM and BFU-E growth. The percentage of CD34+ cells inhibited by TGF-beta 3 was significantly reduced when IL-11 or IL-9, but not SCF, was added to the other cytokines (e.g. IL-11 and IL-3-stimulated cultures were inhibited by 42%, compared to 57% and 90% for the CSF alone; p < 0.05). Similarly, the addition of IL-11 or IL-9 to SCF decreased the suppressive activity of TGF-beta 3 (e.g. IL-11 and SCF in combination were inhibited by 52.4%, compared to 90% or more when the same cytokines were used separately; p < 0.001). These effects were mainly observed on CD(34+)-derived BFU-E although IL-9 appeared to override TGF beta-3 on both CFU-GM and BFU-E. When tested on CD34+/4-HC resistant progenitors, IL-11, IL-9 and SCF increased the number of clonogenic cells responsive to IL-3 and GM-CSF. However, TGF-beta 3 demonstrated a greater inhibitory activity on earlier cells than on the more mature CD34+ cell fraction, and none of the study cytokines completely abrogated the activity of TGF-beta 3. CONCLUSIONS: These data confirm that TGF-beta 3 exerts its suppressive effect on hematopoietic progenitor cells according to the differentiation state of the target cells and the presence of other cytokines interacting with the cells. The permissive growth factors IL-11 and IL-9 seem to be able to partially counteract the negative regulation of TGF-beta 3.

Cell Division↗
PubMedDate not supplied

Hematological recovery after autologous bone marrow transplantation for high-grade non Hodgkin's lymphomas: a single center experience.

BACKGROUND: Both rhGM-CSF and rhG-CSF can accelerate hematological recovery after high-dose therapy and autologous bone marrow transplantation in patients with high grade non Hodgkin's lymphoma and reduce transplant-related morbidity after ABMT. METHODS: The clinical course of 23 non randomized patients was analyzed and compared with a historical control group of 10 patients. Ten patients received GM-CSF at a dose of 10 micrograms/kg in a 6-h IV infusion, and 13 received G-CSF at a dose of 5 micrograms/kg subcutaneously. Control patients received no GFs. RESULTS: Mean granulocytic recovery to 0.5 x 10(9)/L was obtained 13.1 +/- 3.2 days after marrow reinfusion in the G-CSF arm vs 16 +/- 2.7 in GM-CSF pts (p = 0.03) and vs 19.6 +/- 7.6 in controls (p < 0.01); this reduction led to a statistically significant shorter duration of fever and parenteral antibiotic therapy. Platelet recovery to 20 x 10(9)/L was not significantly influenced by GFs. CONCLUSIONS: These results indicate that only G-CSF accelerates hematological recovery after high-dose chemotherapy and autologous bone marrow transplantation and induces a significant decrease in terms of infection morbidity and duration of hospital stay.

Adolescent↗
PubMedDate not supplied

Characterization and selection of benign stem cells in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a clonal disorder arising from the hematopoietic stem cell, characterized by the Philadelphia chromosome (Ph) and, at the molecular level, by fusion of the BCR (breakpoint cluster region) gene and the c-ABL gene. The hallmark of CML is represented by a marked increase in the number of leukemic progenitors, as well as more mature cells, in the bone marrow (BM) and peripheral blood (PB). Despite expansion of the leukemic clone, normal Ph-negative stem cells have been demonstrated to survive in CML. Early observations of partial, but transient, restoration of Ph-negative hematopoiesis after high-dose chemotherapy have recently been extended by the use of myeloablative regimens followed by autografting with marrow or blood-derived stem cells. Moreover, treatment of early-stage CML patients with the biologic response modifier alpha-interferon (alpha-IFN) has led to the re-emergence of normal progenitor cells. Concurrently, "in-vitro" studies have reported that cultures of CML marrow in the presence of a stromal feeder-layer resulted in depletion of Ph-positive cells and predominance of Ph-negative hematopoietic precursors. Based on the assumption that normal and malignant stem cells may coexist in CML, several studies have recently been directed toward the characterization and "in-vitro" selection of benign progenitors within CML hematopoiesis. The results of those studies demonstrated that normal precursors can be phenotypically and functionally identified in the BM or PB of Ph-positive CML patients. These cells are included in the earliest identifiable hematopoietic cell compartment. Normal cells do not bear cell surface lymphoid or myeloid-lineage antigens, express high levels of the CD34 antigen, and fail to express the HLA-DR antigen. Furthermore, they possess a great capacity for adhering to marrow stroma. This cell population represents only a small minority of hematopoietic progenitors, but it retains many of the properties associated with putative hematopoietic stem cells. Thus, purification of a population of benign hematopoietic precursors that could be used for autologous bone marrow transplantation (ABMT) may be feasible in CML patients.

Hematopoietic Stem Cells↗
PubMedDate not supplied

Allogeneic hematopoietic stem cells from sources other than bone marrow: biological and technical aspects.

BACKGROUND AND OBJECTIVE: Identification and characterization of hematopoietic stem cells in peripheral blood (PB) and cord blood (CB) have suggested feasible alternatives to conventional allogeneic bone marrow (BM) transplantation. The growing interest in this use of allogeneic stem cells has prompted the Working Group on CD34-positive Hematopoietic Cells to review this subject by analyzing its biological and technical aspects. EVIDENCE AND INFORMATION SOURCES: The method used for preparing this review was informal consensus development. Members of the Working Group met three times, and the participants at these meetings examined a list of problems previously prepared by the chairman. They discussed the individual points in order to reach an agreement on the various concepts, and eventually approved the final manuscript. Some of the authors of the present review have been working in the field of hematopoietic stem cell biology and processing, and have contributed original papers published in peer-reviewed journals. In addition, the material examined in the present review includes articles and abstracts published in journals covered by the Science Citation Index and Medline. STATE OF ART: Several studies have now shown that hematopoietic stem cells collected from peripheral blood after the administration of G-CSF, or from cord blood upon delivery, are capable of supporting rapid and complete reconstitution of BM function in allogeneic recipients. Perhaps more importantly, reinfusion of large numbers of HLA-matched T-cells from PB collections or T-cells with various degrees of HLA disparity from CB did not result in a higher incidence or greater severity of acute graft-versus-host disease than expected with BM. Based on the data reviewed, operative guidelines for mobilization, collection and graft processing are provided. PERSPECTIVES: It should be remembered that despite the growing interest, these procedures must be still considered as advanced clinical research and should be included in formal clinical trials aimed at demonstrating their definitive role in stem cell transplantation. In this regard, a large European randomized study is currently comparing PB and BM allografts. However, the possibility of collecting large quantities of hematopoietic progenitor-stem cells, perhaps with reduced allo-reactivity, offers an exciting perspective for widening the number of potential stem cell donors and greater leeway for graft manipulation than is possible with BM.

Animals↗