Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increasing evidence supports the hypothesis that "dose" is critical to the clinical outcomes of cytotoxic chemotherapy for patients with breast cancer. Clinical trials continue to investigate whether higher doses of chemotherapy lead to proportionate improvements in the outcomes of patients. Delivery of dose-intensive chemotherapy has been facilitated by technological advancements in supportive care. Improved antiemetics have led to increased patient tolerance of the most acute symptoms of aggressive chemotherapeutic dosing. Chemotherapy-induced myelosuppression may be minimized in a lineage-specific manner by appropriate use of hematopoietic cytokines such as filgrastim (granulocyte colony-stimulating factor), sargramostim (granulocyte-macrophage colony-stimulating factor), and/or epoetin alfa (erythropoietin). However, cumulative myelotoxicity occurs with dose-intensive chemotherapy over multiple cycles despite adjunctive cytokine support. Additionally, no cytokine has yet been demonstrated to support platelet production to any clinically significant degree although several regulators of platelet production (such as thrombopoietin, IL-6, and IL-11) are in clinical trials. Many cytokines can induce the mobilization of hematopoietic progenitor and stem cells from the bone marrow into the circulating blood pool, where these cells may be harvested. Clinical use of these cytokine-mobilized peripheral blood progenitor cells (also known as PBPCs or, commonly, as blood stem cells) has documented the effectiveness of these cells to reconstitute multilineage blood production following very high-dose chemotherapy. The ease with which PBPCs can be collected and their reproducible clinical effectiveness to support patients through intensive treatment protocols have led to a virtual elimination of bone marrow as the source of cellular support for myeloablative chemotherapy in many transplant centers. Novel investigative approaches are also possible with PBPCs. In this review, the historical background of PBPCs is summarized, and the potential benefits (including economic advantages) of PBPCs to support dose-intensive chemotherapy for treating breast cancer are discussed. While dose intensification of breast cancer chemotherapy to the degree requiring PBPC support remains controversial and, in most centers, investigational, there is no doubt that PBPCs are an effective adjunct to the hematopoietic support of patients undergoing transplant-level cytotoxic treatments. Further study will undoubtedly lead to increased use of PBPCs in novel treatments for patients with breast cancer and other solid tumors.
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PMID:The emergence of peripheral blood progenitor cells to support intensive chemotherapy for patients with breast cancer. 872 88

Interleukin-3 (IL-3) is a glycoprotein produced primarily by activated T-lymphocytes. As a hematopoietic growth factor it affects the proliferation, maturation, and survival of progenitor cells of the myeloid, erythroid, and megakaryocyte lineages. Initial studies in cancer patients with normal bone marrow using IL-3 doses of > 5 micrograms/kg daily produced a doubling of the neutrophil count within 2-3 days and that of platelet counts by days 10-12. Phase I-II clinical trials have examined the response to IL-3 in various clinical states, and ongoing phase III studies are currently assessing the clinical relevance. In the treatment of relapsed lymphoma, small-cell lung cancer, and breast and ovarian cancer, IL-3 at doses of 5-10 micrograms/kg daily given mainly subcutaneously for 5-10 days has been shown to maintain chemotherapy schedules while preserving adequate granulocyte and platelet numbers in the peripheral blood. At these doses, side effects were uncommon. The translation of these observations into clinical phase III studies has been disappointing, with no clear-cut clinical advantage being observed in the treated group. This reflects the relative lack of myelosuppression seen with most current regimens for solid tumors. The role of combined treatment with IL-3 in association with granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor after cytotoxic treatment has yet to be established. However, it has been shown that they may act synergistically, resulting in significantly higher numbers of progenitor cells in the peripheral blood than when either is used alone. Combinations with IL-6 are also under study, as is the use of "cocktails" for ex vivo expansion of progenitors. This latter approach would allow single, small collections to be used for multiple infusions of progenitors and could support significant dose-intensification regimens by relieving myelosuppression. It is clear that the place of these newer cytokines in current treatment remains to be clarified.
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PMID:Is interleukin 3 active in anticancer drug-induced thrombocytopenia? 876 24

Human bone marrow (BM) cells contain low levels of the DNA repair protein, O6-alkylguanine-DNA alkyltransferase, which may explain their susceptibility to nitrosourea-induced cytotoxicity and the development of secondary leukemia after nitrosourea treatment. Isolated CD34+ myeloid progenitors were also found to have low levels of alkyltransferase activity. The level of alkyltransferase in CD34+ cells or in mononuclear BM cells did not increase after incubation with granulocyte-macrophage colony-stimulating factor, interleukin-3, stem cell factor, the combination, or 5637 conditioned medium. BCNU sensitivity remained unchanged as well. In addition, O6-benzylguanine depleted alkyltransferase activity in BM cells at concentrations as low as 1.5 mumol/L after a 1-hour exposure. O6-benzylguanine pretreatment markedly sensitized hematopoietic progenitor colony-forming cells to BCNU, resulting in a reduction in the dose of drug (termed the dose-modification factor) required to inhibit 50% of the colony formation (IC50) of threefold to fivefold. Since, unlike many other cell types, proliferating early (CD34+) hematopoietic precursors do not induce alkyltransferase, myelosuppression may be the dose-limiting toxicity of the combination of O6-benzylguanine plus BCNU in clinical trials.
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PMID:Human CD34+ hematopoietic progenitors have low, cytokine-unresponsive O6-alkylguanine-DNA alkyltransferase and are sensitive to O6-benzylguanine plus BCNU. 878 20

Senescence of the lympho-haemopoietic system is associated with an increased incidence of neoplasia, autoimmune diseases and infections. Myelosuppression, either in the context of cancer chemotherapy or in the face of severe infections, commonly manifests as pancytopenia, and has an adverse impact on the prognosis of the elderly cancer patient by increasing infection and bleeding-related morbidity. The physiological basis of this blunted haemopoietic response is unclear, and has been ascribed to age-related deficits in marrow progenitor cell numbers, changes in the marrow microenvironment, decreased production of regulatory growth factors, or a combination of these mechanisms. These age-related deficits tend to be subtle and are only of clinical importance either when present cumulatively or under conditions of extreme haemopoietic stress. Furthermore, some of these deficits can be circumvented with the use of haemopoietic growth factors (HGFs). Thus, the availability in the clinic of various HGFs has had a tremendous impact on the care of the elderly cancer patient. The HGFs currently approved for use are: granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor and epoetin-alpha (recombinant human erythropoietin). However, we still need to better elucidate age-related changes in the early stages of haemopoiesis. The question of haemopoietic exhaustion, particularly under prolonged growth factor stimulation, is real and still unanswered.
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PMID:Aging and haemopoiesis. Implications for treatment with haemopoietic growth factors. 881 84

With the identification of recombinant production of the hematopoietic growth factors, these cytokines have been evaluated in the treatment of primary bone marrow failure states and after myelosuppressive chemo- or radiotherapy. Granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and erythropoietin have been approved for clinical use, and others including c-mpl-ligand (also called megakaryocyte growth and development factor or thrombopoietin) are in phase I and II trials. Most studies have been done with granulocyte and granulocyte-macrophage colony-stimulating factors; their beneficial effects are proven regarding acceleration of granulocyte recovery after chemo- and radiotherapy. In the majority of trials, this acceleration results in a reduction of infectious risks, a shortening of drug- and radiation-induced myelosuppression, and a higher chemotherapy dose intensity; however, an improved remission rate and improved long-term survival rates have not yet been definitively documented. Guidelines have been published to provide a rational basis for the use of these factors in clinical practice. It should be emphasized, however, that for many of the recommendations data from randomized clinical trials are lacking.
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PMID:Clinical use of hematopoietic growth factors. 886 99

Given the limitations of bone marrow transplantation (BMT), alternative approaches to deliver dose-intensive regimens without stem cell support are needed. Administration of hematopoietic growth factors before high-dose chemotherapy (priming) may reduce myelosuppression directly, delaying the onset of neutropenia by expanding the mature neutrophil compartment, and shortening the duration of neutropenia by expanding progenitor cell mass. Priming may also render progenitor populations mitotically quiescent after growth factors are withdrawn, thereby making them less sensitive to the cytotoxic effects of chemotherapy. It is also possible, however, that growth factor priming may worsen aplasia when used with dose-intensive regimens by either depleting early progenitor pools or recruiting progenitor populations into cycle. To determine the safety and hematopoietic efficacy of growth factor priming, 13 patients with hematologic malignancy or breast cancer were treated with granulocyte-macrophage colony-stimulating factor (GM-CSF) (250 micrograms/m2 twice daily subcutaneously) until the white blood cell (WBC) count reached either a plateau or 100,000 cells/microL. Forty-eight hours after the last dose of GM-CSF, chemotherapy was begun using high-dose etoposide and cyclophosphamide. All patients received GM-CSF after chemotherapy. Two patients were withdrawn during GM-CSF priming because they developed urticarial rashes. The maximum median increases in WBC and absolute neutrophil count (ANC) during GM-CSF priming were 7.1- and 4.4-fold, respectively. Only one patient achieved the original target WBC of 100,000/microL. The kinetics of leukocyte expansion were slow; a median of 13 days was needed to reach the maximum WBC. Furthermore, much of the leukocyte expansion was caused by an increase in eosinophils, which would not be expected to accelerate hematopoietic recovery. GM-CSF priming did not appear to have a significant impact on hematopoietic recovery after high-dose etoposide and cyclophosphamide, as there was no significant difference in 1) recovery to an ANC > 500/microL compared to a historical control group that received no growth factor (median of 29 and 30 days, respectively; p = 0.4), 2) number of days with an ANC < 500/microL (median of 19 and 20 days, respectively; p = 0.11), and 3) number of days to an untransfused platelet count > or = 50,000/microL (median 36 and 32 days, respectively; p = 0.23). The failure of GM-CSF priming may be a result of its modest stimulation of hematopoiesis or the expansion of a committed progenitor cell population that is exquisitely sensitive to this regimen.
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PMID:Granulocyte-macrophage colony-stimulating factor (GM-CSF) priming of high-dose etoposide and cyclophosphamide: a pilot trial. 891 81

The safety and efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) as adjuvant therapy for interferon alpha (IFN-alpha) treatment has been evaluated in 20 non-cirrhotic patients with chronic hepatitis C virus (HCV) infection. Adjuvant therapy with GM-CSF plus IFN-alpha was associated with less myelosuppression than with IFN-alpha alone (P < .01), although the rate of local adverse reactions increased. GM-CSF adjuvant therapy led to a 50% biochemical response (transaminase values within the normal range at therapy end) and to reductions in HCV RNA concentrations (median HCV RNA reduction of 99%, range 8-100%), which were similarly observed in single IFN-alpha recipients (median HCV RNA reduction of 91%, range 38-100%). However, HCV RNA became undetectable in three biochemical responders to the GM-CSF adjuvant therapy, but in only one biochemical non-responder to IFN-alpha alone. The use of GM-CSF as adjuvant therapy is safe and, although it has not improved the biochemical response, it might potentiate the virologic response to IFN-alpha treatment alone.
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PMID:Granulocyte-macrophage colony-stimulating factor as adjuvant therapy for factor as adjuvant therapy for interferon alpha treatment of chronic hepatitis C. 916 22

Many chemotherapy regimens are associated with variable periods of myelosuppression. In cancer patients, neutropenia (less than 500 neutrophils/microL) is the most important risk factor for infections. The incidence and severity of infectious complications are related to depth and duration of neutropenia, with the highest risk if neutrophils are less than 100/microL for more than a week. The period required for neutrophil recovery is usually short with standard regimens, but prolonged after high dose chemotherapy followed by autologous bone marrow transplant (-ABMT) or peripheral blood stem cell (PBSC) infusion. Under these conditions, the administration of granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) accelerates neutrophil recovery and shortens the duration of hospitalization. In standard chemotherapy settings, prophylactic use of CSF's is a matter of debate. Several studies have reached contrasting conclusion, but, combining effectiveness and costs, it results that this use of CSF'S is not to be recommended unless the risk of infections (elderly patients, reduced marrow reserve) is high. The administration of G-CSF or GM-CSF to a febrile neutropenic patient (cfr CSF's therapy) shortens the duration of neutropenia, although no great clinical benefits are evident. Nevertheless the identification of subsets of patients with additional risk factors (i.e. absolute neutrophil count < 100/microL at the onset of fever or delayed neutrophil recovery) should be helpful in establishing the role of CSF's therapy. When prolonged periods of severe neutropenia (less than 500 neutrophils/microL) are expected, antibiotics should be prophylactically administered. Fluoroquinolones seem to be the optimal choice in heavily myelosuppressed patients (ie. bone marrow transplant recipients). Fluoroquinolones are effective in reducing the frequency of gram-negative bacteremia, but, because of incomplete coverage, gram-positive infections are becoming increasingly problematic. The association with an agent that can be absorbed orally, active against gram-positive cocci, seems to be an effective strategy. Fungal infections are an important cause of morbility and mortality in severely neutropenic patients. Safety and efficacy of antifungal triazoles and the lipid formulations of amphotericin B used prophylactically still require investigation. In patients at high risk for fungal infections, monitoring cultures are predictive for systemic mycoses and should guide prophylactic and therapeutic choices. The standard treatment of oncologic patients with potential infectious neutropenia complications is admission to the hospital and treatment with broad-spectrum intravenous antibiotics. Until third generation cephalosporin and carbapenems became available, most neutropenic febrile patients were treated with associations of an aminoglycoside plus a beta-lactam. Monotherapy with the new antibiotics has proven to be effective as an association therapy and offers advantages in terms of cost and tolerability. Whether or not vancomycin is included in the initial antibiotic regimen should be decided on the basis of epidemiological consideration (i.e. prevalence of meticillin-resistant Staphylococcus aureus or Staphylococcus mitis in certain centers). Antifungal therapy is indicated in neutropenic patients who remain febrile after one week of broad-spectrum antibiotics or have recurrent fever. Amphotericin B should be promptly administered in patients suspected of invasive mycoses. Selected patients with fever and neutropenia, that can be identified on the basis of reduced risk of severe complications, do not need hospitalization. In the first reports, outpatient treatment has proven to be effective, cost saving and well received by patients, but further studies are needed to accurately define low risk status and the optimal home antibiotic regimens.
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PMID:[Prevention and treatment of febrile neutropenia]. 923 24

Multilineage hematopoietic defects occur in patients with human immunodeficiency virus (HIV) infection and affect therapy of the disease and of associated opportunistic infections and neoplasms. Anemia and neutropenia are common in HIV patients, and can occur as a result of HIV-related myelosuppression or complications or may be secondary effects of antiretroviral or other agents used in management of the disease. With the advent of combination drug therapy for the treatment of HIV infection and prophylaxis and treatment of infectious complications, myelosuppression is frequently encountered and may be treated with synthetic hematopoietic growth factors. Erythropoietin has been shown to increase mean hematocrit levels and to reduce transfusion requirements in anemic HIV-infected patients receiving zidovudine. Granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor have been shown to increase neutrophil counts in patients with AIDS-related bone marrow failure and those receiving zidovudine, interferon-alpha, or ganciclovir. Although recent research using interleukin-2 (IL-2) has shown that use of this cytokine in AIDS patients can lead to increases in CD4 cell counts that appear to be functional, further study is needed to determine whether cytokines can play a role other than palliation in HIV-infected patients.
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PMID:Cytokine use in the management of HIV disease. 938 9

With the identification and recombinant production of the hematopoietic growth factors, these cytokines have been evaluated in the treatment of primary bone marrow failure states and following myelosuppressive chemotherapy or radiotherapy. An increasing number of clinical trials with hematopoietic factors have been performed in patients with haematological and oncological diseases. Granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin and, in phase I/II trials, thrombopoietin (TPO) are available for the clinical use. Most studies have been performed with G-CSF and GM-CSF, their beneficial effects are proven regarding acceleration of hematopoietic recovery following chemotherapy. This results in a marked reduction of infectious risks and a shortening of drug- and radiation-induced myelosuppression. CSFs are most important in mobilizing peripheral blood progenitor cells (PBPC) and have allowed high-dose therapy combined with stem cell support in gynecological malignancies, e.g. ovarian carcinoma and breast cancer. However, evidence based, clinical practical guidelines for the use of hematopoietic growth factors in gynecological malignancies are not for all circumstances available.
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PMID:[Current status of clinical indications for hematopoietic growth factors after chemo-/radiotherapy in gynecology]. 948 9


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