摘要:

Interleukin-1 (IL-1) produces many direct and indirect effects in hematopoiesis. IL-1 stimulates hematopoietic progenitors, and enhances production of other cytokines. Experimental data suggest a role in ameliorating the myelosuppression that occurs following cytotoxic chemotherapy. Recombinant human interleukin-1 has now entered clinical trial. We conducted a phase I trial of IL-1βalone, and following a myelosuppressive dose of 5-fluorouracil in patients with cancer. A prominent neutrophilia was noted within several hours, with a later, more sustained thrombocytosis. Hypotension was dose-limiting. We observed fewer days of neutropenia following 5-FU plus IL-1 compared to IL-1 alone, but the difference did not reach statistical significance. Early results from other investigators suggest a possible protective effect from chemotherapy-induced myelosuppression. Preclinical data suggest that combinations of IL-1 and lineage specific growth factors may produce synergistic hematologic effects.

ISSN:1042-8194    

DOI:10.3109/10428199309145750

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Multiple myeloma represents a B cell malignancy characterized by a monoclonal proliferation of plasma cells. A striking feature of the disease is the tendency of the malignant plasma cells to affect mainly the bone marrow environment and to invade the peripheral blood only in the terminal stage. The growth of myeloma plasma cells is believed to be regulated by a functional interplay between the tumor cells and the bone marrow stroma, involving the action of various cytokines. This growth control is most probably mediated by close cellular contact of the myeloma cells and marrow stromal components. Therefore it can be assumed that myeloma plasma cells possess the ability to interact with the bone marrow stroma. Until now the adhesive mechanisms that may underlie this interaction, remain undetermined. We investigated the expression of several adhesion molecules on bone marrow plasma cells in myeloma patients and normal controls. Normal as well as malignant plasma cells were found to be strongly positive for the intercellular adhesion molecule ICAM-1, the fibronectin receptor VLA-4 and the lymphocyte homing receptor CD44. In addition, a much weaker expression of the second fibronectin receptor VLA-5, the laminin receptor VLA-6 and the vitronectin receptor CD51 was demonstrated. In contrast to normal plasma cells, myeloma cells can also express the neural cell adhesion molecule N-CAM. In this report we discuss the possible role of adhesion molecules in the pathogenesis and clinical evolution of multiple myeloma.

ISSN:1042-8194    

DOI:10.3109/10428199309145751

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Several immunomodulatory approaches have been explored with the aim of inducing a graft versus tumor effect (GVT) in autologous bone marrow transplantation (ABMT). Granulocyte-macrophage colony stimulation factor (GM-CSF) has been reported to induce antibody dependent cellular cytotoxicity (ADCC) via stimulation of peripheral blood neutrophils, lymphocytes, and monocytes. We investigated the role of GM-CSF in inducing ADCC via bone marrow (BM) macrophages against murine and human tumor cells both in vitro and in vivo.Our data shows that stimulation of murine BM macrophages with GM-CSF induced a potent ADCC against a murine melanoma in vitro. Treatment of tumor bearing mice with a combination of GM-CSF and antibody against melanoma resulted in a significant reduction in the dissemination of melanoma both in a nontransplant as well as in a transplantation setting. Adoptive transfer of BM macrophages obtained from animals undergoing treatment with GM-CSF plus antibody significantly reduced the spread of tumor in secondary recipients; this effect was seen only in mice undergoing bone marrow transplantation. GM-CSF treatment of human BM macrophages induced a significant ADCC against a human melanoma and a lymphoma in vitro, as well as against a human lymphoma implanted in nude mice. Treatment with GM-CSF alone or with antibody alone was ineffective in controlling the dissemination of tumors both in transplantation as well as in nontransplant situations. These observations indicate that treatment with GM-CSF plus tumor specific monoclonal antibodies after ABMT may induce a GVT effect and bring about the eradication of residual disease.

ISSN:1042-8194    

DOI:10.3109/10428199309145752

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

We have successfully constructed highly potent and selective anti-CD19 PAP immunotoxins using each of the three crosslinking agents, SPDP, LC-SPDP, or SMPT, to generate an intermolecular bridge between the B43 MoAb and PAP toxin moieties. These immunotoxins were selectively immunoreactive with and cytotoxic against CD19′B-lineage ALL cells. In this report, we compared (a)in vivochemical, immunological, and biological stability, (b)in uiuoimmunogenicity, and (c)in vivoanti-leukemic activity of various B43-PAP immunotoxin constructs. Our data recommend the use of SPDP and SMPT rather than LC-SPDP for generation of B43(anti-CD19)-PAP immunotoxins as clinical anti-leukemic agents. To our knowledge, this is the first comparative analysis of thein vivopharmacokinetic features, immunogenicity, and anti-leukemic activity of anti-CD19 PAP immunotoxins that were prepared with different heterobifunctional crosslinking agents.

ISSN:1042-8194    

DOI:10.3109/10428199309145753

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Various lines of evidence suggest that substantial numbers of very primitive normal hematopoietic cells persist in the marrow of most patients with CML, despite the presence of an expanded Philadelphia-Chromosome (Ph) positive population, and that normal clones might, in certain circumstances, have a proliferative advantage over leukemic populations. We have recently demonstrated in 5/8 CML patients with blastic phase (BP) that the blood progenitor cells/(BPC) harvested during early recovery from marrow aplasia were Ph-negative on cytogenetic analysis, suggesting that leukapheresis may provide a useful source of 'normal' progenitors for subsequent reinfusions. We report here an update on 40 patients with Ph + CML and 9 patients with ALL in first or subsequent relapses with associated cytogenetic translocations including t(8;14) t(4;8) t(4;11) and t(9;22). All these patients received intensive conventional chemotherapy and during early recovery from marrow aplasia, when the WBC reached 0.5–2.0×109/L, BPC were collected by 4–8 leukapheresis and tested for the persistence of the marker translocations and, when possible, for the presence of the hybrid bcr/abl transcripts by polymerase chain reaction (PCR). In seven out of 10 patients with chronic phase CML, BPC were Ph-negative and in 5 PCR negative. In both accelerated phase patients, BPC were Ph-negative but PCR-positive and in eight out of 28 blastic CML patients, BPC were Ph-negative and in two cases also PCR-negative. Six out of 9 ALL patients, lost the cytogenetic translocations. After complete recovery, 16 patients were subsequently given high-dose therapy followed by reinfusion of 'normal' BPC. Two patients in CP-CML and 2 out of six patients with ALL maintain clinical and cytogenetic remission at 3 and 10 months and 16 months respectively. All the patients transplanted in BP-CML relapsed 5–18 months post-transplant. These data suggest that intensive conventional chemotherapy can lead to a precocious overshoot of cytogenetically normal BPC.

ISSN:1042-8194    

DOI:10.3109/10428199309145754

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

A total of 41 patients who underwent autologous bone marrow transplantation without the use of granulocyte-macrophage colony-stimulating factor were retrospectively evaluated to determine whether the infusion of peripheral blood stem cells collected during the period of recovery of bone marrow from previous disease-specific chemotherapy could shorten the time to bone marrow engraftment after transplantation. Of the 41 patients, 24 patients received bone marrow only (group 1), 8 patients received bone marrow plus steady-state peripheral blood stem cells (group 2) and 9 patients received bone marrow plus rebound peripheral blood stem cells collected during the period of recovery from disease-specific chemotherapy (group 3). Infusion of rebound peripheral blood stem cells (group 3) accelerated recovery of white blood cells and neutrophils and resulted in a white blood cell count of 109/L by day 15 compared with day 25 in group 1,P0.0001), and a neutrophil count of<0.5×109/L by day 16 versus day 26 in group 1,P= 0.0034). Addition of steady-state peripheral blood stem cells (group 2) did not hasten myeloid engraftment, and recovery of platelets was not improved in either group given peripheral blood stem cells. Compared with patients in group 1, patients in group 3 required 7 fewer days of parenteral antibiotics (25 days versus 18 days, respectively;P= 0.0072) and were discharged about 3 weeks earlier than patients in group 1 (day + 41 versus day +21;P= 0.0002). These results demonstrate that infusion of peripheral blood stem cells collected during the period of recovery of bone marrow from disease-specific chemotherapy hastens recovery of white blood cells and neutrophils after transplantation. Whether administration of granulocyte-macrophage colony-stimulating factor during the rebound phase from disease-specific chemotherapy will yield peripheral blood stem cells that further reduce the time to recovery of neutrophils or hasten recovery of platelets or both, remains to be determined.

ISSN:1042-8194    

DOI:10.3109/10428199309145755

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

The expression of c-kit and its ligand, the stem cell factor (SCF), was studied in five cases of acute myeloid leukemia. One of these had a trisomy of chromosome 4, where the c-kit oncogene is located. In this case, the c-kit oncogene was overexpressed, but matched by a low expression of its ligand, SCF. The molecular evaluation of the growth rate by c-myc and the histone H3 expression indicated that the growth fraction of this cell population was very low. In one of the other leukemic cell populations studied, characterized by a low expression of c-kit and an elevated expression of the SCF, the growth fraction was also very low. Our results suggest that at least for some receptor oncogenes, the simple overexpression cannot be taken as an indication that the oncogene is involved in the deregulation of cell proliferation.

ISSN:1042-8194    

DOI:10.3109/10428199309145756

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Recently, the combination chemotherapy Novantrone, Oncovin, Velban, Prednisone [NOVP] was developed by The University of Texas M. D. Anderson Cancer Center for treatment of Hodgkin's disease [HD]. Preliminary clinical results show that NOVP is as effective as the traditional Mechlorethamine, Oncovin, Procarbazine, Prednisone [MOPP] regimen in achieving remission, but with fewer side-effects. To determine if NOVP is genotoxic, we studied the induction of chromosome breaks and sister chromatid exchanges [SCEs]in lymphocytes of 42 HD patients both before and during NOVP treatment. Furthermore, in vitro bleomycin treatment was used to unmask potential single-stranded DNA breaks inducted by the therapy. Our results showed that NOVP did not cause elevated levels of chromosome or single-stranded DNA breaks, or SCEs. These results together with previous findings that NOVP caused minimal acute and gonadal toxicities suggest that NOVP is less toxic than MOPP. Therefore, this new regimen shows promise as an effective and minimally toxic regimen for treatment of HD.

ISSN:1042-8194    

DOI:10.3109/10428199309145757

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

It has recently been suggested that a combination of C-Reactive Protein (CRP) andβ-2-microglobulin (β2M) can be used to devise a simple prognostic model for patients with multiple myeloma. In this study we have measured serumβ2M, CRP and thymidine kinase (STK) in a series of 215 samples to determine their value as a monitor of disease status. A longitudinal study was also performed with 6 individual patients. CRP levels did not correlate with disease status. The mean of the stable (23.62 mg/L) and the progressive disease 23.64 mg/L) groups were almost identical,t =0.003;p= NS) with ranges of<5-150 mg/L and<5-100 mg/L respectively. There was no correlation between CRP and STK,r= 0.11) or CRP andβ2M (r= 0.05). In longitudinal studies, CRP did not necessarily reflect changes in disease activity. We conclude that CRP measurements are not valuable as a monitor of disease activity in patients with myeloma.

ISSN:1042-8194    

DOI:10.3109/10428199309145758

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

We report on a patient originally diagnosed as having monoclonal gammopathy of undetermined significance (MGUS) who progressed to develop Waldenstrom's macroglobulinaemia (WM) after 3 years. Four years later he developed chronic myelomonocytic Ieukaemia (CMMoL) which terminated in acute myeloid leukaemia (AML) after another year. We also review published reports of similar cases.

ISSN:1042-8194    

DOI:10.3109/10428199309145759

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor