Myelosuppression and "conventional" chemotherapy: what price, what benefit?
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Antineoplastic Agents↗
Biomedical subjects
G D Demetri
Publications and source records attributed to G D Demetri.
Impact of hematopoietic growth factors on the management of small-cell lung cancer.
Hematopoietic growth factors regulate the production and differentiation of immature progenitor cells and activate mature effector cells. With recombinant DNA technology, these human proteins have been biosynthesized, and their clinical applications hold promise for beneficial therapeutic effects. The hematopoietic growth factors are generally classified in 2 groups, the colony-stimulating factors (CSFs) and the interleukins. In oncology, it has been shown that the administration of CSFs will attenuate chemotherapy-induced myelosuppression and permit administration of the planned chemotherapy doses, especially in chemosensitive tumors like small-cell lung cancer. Widespread clinical administration of the CSFs at this time without regard to the predicted risk of a given therapeutic regimen would seem to be inappropriate both therapeutically and economically. Continuing investigations should focus on important clinical end points. Until then, our ability to use the CSFs optimally, rationally, and in a cost-effective manner will remain limited.
Carcinoma, Small Cell↗
Granulocyte-macrophage colony-stimulating factor (GM-CSF): preclinical and clinical investigations.
In conclusion, hematopoietic growth factors have been shown to enhance the recovery and function of circulating WBCs after standard-dose cancer therapy or high-dose cancer therapy with ABMT, and preliminary data strongly suggests that these agents may have the ability to restore leukocyte numbers and competence in AIDS, myelodysplastic syndromes, and other marrow failure states. Phase I and II trials of GM-CSF in patients with AIDS, cancer, marrow failure states, and following bone marrow transplantation have been published, and limited phase III randomized trial experiences have been reported as well. Overall, GM-CSF represents a fascinating molecule with which to modulate human hematopoiesis in vivo. The multilineage stimulatory effects of GM-CSF that are evident in vitro have not been striking or consistent in clinical trials. However, the effects of GM-CSF on the production and function of mature neutrophils, monocytes, and eosinophils have been noted in the vast majority of clinical scenarios in which this cytokine has been tested. The clinical benefits of GM-CSF have, to date, only been proven in large-scale randomized studies of recovery from ABMT for lymphoid neoplasms. However, further data regarding the use of GM-CSF in other clinical settings have been generated, and the final results are eagerly anticipated by the oncology community. The beneficial effects of GM-CSF following ABMT consisted not only of a shorter period of absolute neutropenia, but also fewer significant infections, a diminished requirement for intravenous antibiotic administration, and a shorter overall duration of inpatient hospitalization. The use of GM-CSF in clonal disorders of hematopoiesis, such as myelodysplasia or myeloid leukemias, requires caution before such applications can be routinely recommended, and the demonstration of safety in this setting from large randomized trials will be needed. Preliminary data from small randomized trials suggests that the incidence of evolution to leukemia in patients with myelodysplasia and the number of patients with regrowth of leukemia after induction treatment in relapsed patients with AML may not be significantly different than in patients who do not receive GM-CSF. Various neutropenic conditions (eg, idiopathic or congenital) may respond clinically to hematopoietic growth factors such as GM-CSF. Patients treated for 3 to 15 months continue to respond with significantly increased granulocytes and resolution of prior infection. The subcutaneous route of administration is convenient and patients seem to accept it readily. It is difficult to determine the extent to which adjunctive therapy with GM-CSF will be cost effective.(ABSTRACT TRUNCATED AT 400 WORDS)
Acquired Immunodeficiency Syndrome↗
Granulocyte colony-stimulating factor and its receptor.
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Animals↗
The action of bryostatin on normal human hematopoietic progenitors is mediated by accessory cell release of growth factors.
Since enrichment of human bone-marrow hematopoietic progenitors is becoming more feasible and since purified growth factors are now available, we sought to study the action of growth factors on CD34-positive enriched cultures of human bone-marrow cells. We tested the effect of recombinant human (rh) granulocyte-macrophage colony-stimulating factor (GM-CSF), rh interleukin-3 (IL-3), or a unique biologic response modifier, bryostatin 1, on the growth of purified CD34 cells obtained by limiting dilution in single-cell cultures. We have shown previously that bryostatin 1 stimulates both myeloid and erythroid progenitors of human origin in vitro. In this study both IL-3 and GM-CSF supported colony formation from 500, 100, or single-cell cultures at equivalent plating efficiences, suggesting a direct action of these factors on hematopoietic cell growth. Conversely, bryostatin 1 did not support the growth of CD34 cells in single-cell cultures, and the cloning efficiency increased with increasing the number of cells in the culture. To test whether the indirect action of bryostatin 1 might be mediated through the production of growth factors by accessory cells, studies were performed using antibodies directed against human IL-3 and GM-CSF in culture with bryostatin 1 and normal human bone-marrow cells. Results are consistent with the hypothesis that bryostatin 1 could have a stimulatory effect on the accessory cell populations to produce either IL-3 or GM-CSF. Further support for this notion was obtained by demonstrating that T cells, which are cells known to be able to produce IL-3 and GM-CSF, are stimulated by bryostatin 1 to express messenger RNA (mRNA) for specific growth factors, including GM-CSF. These results provide further support that bryostatin 1 may be a useful clinical agent to stimulate hematopoiesis in vivo.
Antibodies↗
The biology of GM-CSF: regulation of production and interaction with its receptor.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a small glycoprotein growth factor which stimulates the production and function of neutrophils, eosinophils and monocytes. GM-CSF can be produced by a wide variety of tissue types, including fibroblasts, endothelial cells, T cells, macrophages, mesothelial cells, epithelial cells and many types of tumor cells. In most of these tissues, inflammatory mediators, such as interleukin 1, interleukin 6, tumor necrosis factor or endotoxin, are potent inducers of GM-CSF gene expression, which occurs at least partly by post-transcriptional stabilization of the GM-CSF mRNA. The biological effects of GM-CSF are mediated through binding to cell surface receptors, which appear to be widely expressed by hematopoietic cells and also by some non-hematopoietic cells, such as endothelial cells. Receptor expression is characterized by low number (20-200/cell) and high affinity (Kd = 20-100 pM). At least two different functional classes of GM-CSF receptor have been identified. The neutrophil GM-CSF receptor exclusively binds GM-CSF, while interleukin 3 competes for binding of GM-CSF to a second class of receptors detected on some leukemic cell lines, such as KG1 and MO-7E. Signal transduction involves activation of a tyrosine kinase and possibly G protein-coupled stimulation of Na+/H+ exchange. The exact relationship of the two receptors needs further clarification.
Animals↗
Expression of ras oncogenes in cultured human cells alters the transcriptional and posttranscriptional regulation of cytokine genes.
Autonomous production of cytokines such as the hematopoietic colony-stimulating factors (CSFs), IL-1, or IL-6 has been demonstrated in numerous human and murine neoplasms, and may be involved in the pathogenesis of several paraneoplastic syndromes such as leukocytosis, fever, and hypercalcemia. Because of the high frequency with which mutations in ras protooncogenes have been detected in human tumors, as well as evidence linking ras gene products to activation of certain cellular functions, we investigated whether ras mutations might influence the regulation of cytokine genes. Normal human fibroblasts transfected with a mutant val12 H-ras oncogene expressed increased levels of mRNA transcripts encoding granulocyte-CSF (G-CSF), granulocyte-macrophage-CSF (GM-CSF), and IL-1 beta compared with controls. Human mesothelioma cells transfected with a mutant asp12 N-ras oncogene exhibited similar alterations in cytokine gene expression. Estimates of transcriptional activity by nuclear run-on analysis revealed a selective increase in transcription only for the IL-1 gene. Analysis of mRNA half-life demonstrated a marked increase in the stability of numerous cytokine transcripts, including G-CSF, GM-CSF, IL-1, and IL-6. The addition of anti-IL-1 neutralizing antibody to cultures of cells expressing ras mutants did not block the expression of any of the cytokines examined, suggesting that the baseline expression of GM-CSF, G-CSF, and IL-6 was not a secondary event due to the increased transcription of IL-1. These results indicate that mutations in ras genes may alter expression of several cytokine genes through both transcriptional and posttranscriptional mechanisms.
Cells, Cultured↗
Hematopoietic growth factors and high-dose chemotherapy: will grams succeed where milligrams fail?
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Antineoplastic Agents↗
Cellular interaction regulating the production of colony-stimulating factors.
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Animals↗
Expression of a novel 3.5-kb macrophage colony-stimulating factor transcript in human myeloma cells.
Macrophage CSF (M-CSF) induces proliferation of monocyte/macrophage progenitor cells and can also activate some functions of mature cells. Three different human M-CSF cDNA (4.0, 3 to 3.5, and 1.5 kb) which are the result of alternative splicing of the single M-CSF gene have been cloned. Each of these cDNA encode a biologically active M-CSF. M-CSF transcripts are expressed in normal fibroblasts and other mesenchymal cells, and also in some hematopoietic cells such as monocytes. Normal human cells examined to date express only the 4.0-kb transcript. In contrast, a 3.5-kb M-CSF transcript was continuously expressed in two multiple myeloma cell lines (RPMI 8226 and U266/AF10) and in a bone marrow specimen of a patient with multiple myeloma. The myeloma cell lines secreted biologically active M-CSF. Resting and activated normal B lymphocytes and other B cell neoplasms examined did not express the 3.5-kb transcript, but could be induced to express the 4.0-kb transcript and to secrete M-CSF. Myeloma cells appear to be unique among hematopoietic cells in their expression of the 3.5-kb M-CSF transcript.
B-Lymphocytes↗
Expression of colony-stimulating factor genes by normal human mesothelial cells and human malignant mesothelioma cells lines in vitro.
We investigated normal human mesothelial cells and human malignant mesothelioma cell lines for the ability to produce hematopoietic colony-stimulating factors (CSFs) in culture. Early passage cultures of normal diploid human mesothelial cells spontaneously expressed detectable levels of M-CSF mRNA transcripts, but lacked detectable transcripts for GM-CSF or G-CSF. Exposure of normal mesothelial cells to epidermal growth factor (EGF), lipopolysaccharide (LPS), or tumor necrosis factor (TNF) induced expression of G-CSF mRNA. The combination of EGF and TNF induced threefold more G-CSF transcripts than did either factor alone. GM-CSF transcripts were induced only by the combination of TNF and EGF. Interleukin-1 beta (IL-1 beta) transcripts were induced by EGF, TNF, or LPS and were inhibited by hydrocortisone (HC). All malignant mesothelioma cell lines tested also spontaneously expressed M-CSF transcripts. However, in contrast to normal mesothelial cells, two of four malignant mesothelioma cell lines also autonomously expressed G-CSF and GM-CSF transcripts without TNF, EGF, or LPS stimulation. Secretion of biologically active CSFs was confirmed by testing media conditioned by the various cell types examined. The detection of biologically active CSFs correlated well with the presence of detectable CSF transcripts by Northern analysis. These data indicate that (a) normal human mesothelial cells spontaneously express detectable levels of M-CSF mRNA in culture; (b) EGF is an essential cofactor for optimal induction of G-CSF and GM-CSF expression; (c) exposure of normal mesothelial cells to inflammatory mediators such as LPS and TNF increases the levels of transcripts for CSFs and IL-1 beta; and (d) as compared with normal human mesothelial cells, some cell lines of human malignant mesothelioma exhibit aberrant gene expression for multiple cytokines, including G-CSF, GM-CSF, IL-1 beta, and IL-6.
Colony-Stimulating Factors↗
Isolation and chromosomal localization of cDNAs encoding a novel human lymphocyte cell surface molecule, LAM-1. Homology with the mouse lymphocyte homing receptor and other human adhesion proteins.
A cDNA encoding a new human lymphocyte cell surface molecule has been isolated and shown to identify a fourth member of a recently discovered family of adhesion proteins. This lymphocyte-associated molecule (LAM-1) is uniquely composed of multiple distinct domains, one domain homologous with animal lectins, one homologous with epidermal growth factor, and two short consensus repeat units similar to those found in C3/C4 binding proteins. This cDNA clone hybridized with RNAs found in B cell lines and T lymphocytes, but not with RNA from other cell types. The amino acid sequence of LAM-1 is 77% homologous with the sequence of the mouse lymphocyte homing receptor, suggesting that LAM-1 may function in human lymphocyte adhesion. The LAM-1 gene is located on chromosome 1q23-25, as is another member of this adhesion family, suggesting that this new family of proteins may be encoded by a cluster of "adhesion protein" loci.
Amino Acid Sequence↗
Regulation of granulocyte- and monocyte-colony stimulating factor mRNA levels in human blood monocytes is mediated primarily at a post-transcriptional level.
Human blood monocytes secrete a number of cytokines following activation including two hematopoietic growth factors, granulocyte-colony stimulating factor (G-CSF) and monocyte/macrophage-colony stimulating factor (M-CSF). The genes for these two factors can be both coordinately and independently expressed. Treatment of monocytes with phorbol myristic acid or cycloheximide induces both genes, while lipopolysaccharide selectively and transiently induces G-CSF transcripts. Interleukin-3 or granulocyte/monocyte-colony stimulating factor selectively induce M-CSF transcripts. Using nuclear run-on transcription assays and Northern blot analysis of actinomycin D-treated cells to estimate mRNA half-life, we show that the induction of both genes is due to mRNA stabilization. In resting monocytes, the levels of transcripts for both G-CSF and M-CSF are very low. Following stimulation with phorbol myristic acid, cycloheximide, lipopolysaccharide, or interleukin-3 the estimated transcription rate of both genes does not increase. However, the half-life of M-CSF mRNA increases to approximately 2 h, whereas G-CSF mRNA half-life increases to as long as 4 h. Thus, the control of CSF gene expression in monocytes is likely to involve more than one post-transcriptional mechanism.
Colony-Stimulating Factors↗
A phase I trial of recombinant human tumor necrosis factor and interferon-gamma: effects of combination cytokine administration in vivo.
The combination of tumor necrosis factor (TNF) and interferon-gamma has synergistic bioactivity in numerous preclinical model systems. We have tested this potential synergism in vivo by administration of both cytokines to patients with advanced cancer using overlapping 24-hour continuous intravenous (IV) infusions in a phase I trial. Thirty-six patients were treated with a fixed dose of interferon-gamma (200 micrograms/m2/d) with interpatient dose escalation of TNF (from 5 to 205 micrograms/m2/d). The dose-limiting toxicity at the maximal-tolerated dose (MTD) of TNF (205 micrograms/m2) with interferon-gamma was hypotension. Other toxicities noted included an influenza-like syndrome, transient decreases in circulating leukocyte and platelet counts, subclinical evidence of disseminated intravascular coagulation, and the sporadic occurrence of acute pulmonary toxicity. The recommended phase II dose for this combination schedule is TNF, 136 micrograms/m2, with interferon-gamma, 200 micrograms/m2. The addition of interferon-gamma to TNF resulted in a greater than three-fold increase in toxicity compared with TNF administered as a single agent, supporting the hypothesis that the combination of these cytokines may induce synergistic effects in vivo.
Adult↗
Hemopoietins and leukemia.
This article summarizes research relevant to the possible association between aberrant production of hemopoietins or hemopoietin-activated signals and the neoplastic growth of leukemic cells.
Acute Disease↗
In vitro expression of colony-stimulating factor genes by human acute myeloblastic leukemia cells.
Cells from most cases of acute myeloblastic leukemia (AML) proliferate in vitro in response to one or more colony-stimulating factor (CSF). Previous studies have suggested that some AML cells can produce their own CSFs, but the frequency of this phenomenon is unclear. In this study, Northern blot hybridization was used to detect mRNA transcripts for granulocyte-monocyte CSF (GM-CSF), granulocyte-CSF (G-CSF), and macrophage-CSF (M-CSF) in 22 randomly selected cases of AML. Ten cases expressed one CSF transcript (generally M-CSF), one case expressed two CSF transcripts, and six cases expressed all three. The expression of CSF transcripts did not significantly correlate with the French-American-British classification, with the possible exception that four of the five cases expressing all three CSF mRNAs were FAB M1. Six cases had autonomous growth of clonogenic cells in agar, and all six cases expressed one or more type of CSF transcript. None of the five evaluated cases lacking all three CSF transcripts had autonomous growth. However, there were many cases in which CSF transcripts were present and no autonomous growth was observed. In response to exogenously added human recombinant CSFs, 11 of 18 cases proliferated in response to GM-CSF, 8 of 18 cases in response to G-CSF, and 0 of 10 cases in response to M-CSF. Response to a CSF was not significantly correlated with the presence or absence of CSF transcripts, particularly for M-CSF. These results show that CSF transcripts are frequently detected in AML, although with a substantial degree of heterogeneity. It is possible that CSF production contributes to unregulated growth in some cases of AML.
Cell Division↗
NCCN: New applications for erythropoietin.
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Anemia↗