Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0854467 (myelosuppression)
 5,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the absence of appropriate growth factors, for example interleukin-3 or GM-CSF, cultured bone marrow stem cells die by a process known as apoptosis or programmed cell death. Apoptosis may occur in vivo when concentrations of specific growth factors are limiting and may be a means of regulating cell numbers. Growth factors are also essential for proliferation of bone marrow stem cells but differentiation can occur, provided there is a survival stimulus in the absence of growth factors. Combinations of growth factors may be synergistic in stimulating the survival and proliferation of multipotent stem cells. Although neither stem cell factor, nor GM-CSF alone can significantly induce the proliferation of stem cells, the combination induces the proliferation of these cells. Committed progenitor cells such as granulocyte-macrophage colony-forming cells, however, are stimulated to proliferate by GM-CSF alone, while stem cell factor in combination with GM-CSF results in only a slight additive effect. To date, most research has concentrated on the growth stimulatory factors. GM-CSF has an important role in the reversal of chemotherapy-induced myelosuppression in cancer patients and in other bone marrow disorders. A number of growth inhibitory molecules have now been identified, such as macrophage inhibitory protein-1 alpha. In the future, it is possible that improvements in cure rates may be achieved in cancer patients by combining the growth inhibitory factors with the stimulatory factors. Inhibitory factors may be given before chemotherapy to prevent toxicity and stimulatory factors may be given afterwards to treat neutropenic patients.
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PMID:Growth factors and the molecular control of haematopoiesis. 787 50

Myelosuppression is often the major limiting factor that prevents timely administration of cytotoxic chemotherapeutic agents, particularly in chemoresponsive malignancies. A study was designed to assess the role of GM-CSF in preventing myelosuppression in patients with intermediate-grade non-Hodgkin's lymphoma receiving combination chemotherapy (Cyclophosphamide, Vincristine, Prednisone and Epirubicin or Mitozantrone, +/- Bleomycin). A total of 24 patients were entered and data collated from 20 of them are amenable to analysis. All patients received the first chemotherapy cycle without GM-CSF and the second with GM-CSF (250 mg/m2 subcutaneously twice daily for 5 days commencing on the 5th day following chemotherapy). By entering only those patients who had suffered myelosuppression following chemotherapy, an internal control was established. GM-CSF administration significantly reduced the degree of neutropenia and leucopenia. The mean nadir white blood cell (WBC) and absolute neutrophil counts (ANC) were 2.88 x 10(9)/L and 0.97 x 10(9)/L in cycle 1 as compared to 5.95 x 10(9)/L and 2.92 x 10(9)/L respectively, in cycle 2 (p = 0.05 and 0.02, respectively). Eight patients (40%) had febrile neutropenias and 13 patients (65%) experienced a treatment delay by a median of 8 days during cycle 1. Six patients (30%) had febrile neutropenias and 2 patients (10%) had a treatment delay of 3 days during cycle 2. Reversible toxicity was seen in the majority of patients: bone pains (60%), skin rashes (35%), arthralgias (25%), and altered taste sensation (10%). No patient developed the capillary leak syndrome. This study demonstrates the efficacy of GM-CSF in preventing chemotherapy-induced myelosuppression.
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PMID:A phase II study of recombinant granulocyte macrophage colony stimulating factor in patients with non-Hodgkin's lymphoma. 795 Sep 23

The response rate of patients with metastatic colorectal cancer to the 4-drug combination [5-Fluorouracil (5-FU), dacarbazine, vincristine and bis-chloronitrosourea given 5 weekly (FIVB)] was better than the response rate to 5-FU. The dose limiting toxicity of the FIVB was myelosuppression. The present study investigates the effect of FIVB given with GM-CSF so that drug cycles could be given every 4 weeks. Thirty-five ambulatory patients with measurable metastatic colorectal cancer were treated with FIVB plus GM-CSF 4 weekly. All patients were evaluable for toxicity. Among the 163 cycles given only 4 were delayed because of leucopenia and 8 cycles were delayed because of gastrointestinal (GI) toxicity. A 50% dose reduction was given to 10 patients who had Grade 2 and 3 GI toxicity. Four of the 35 patients developed thromboembolic complications, 2 of which were lethal. Two patients were not evaluable for response as they were removed from study early because of toxicity. There were 2 complete responses and 6 partial responses. The median time to treatment failure was 3.8 months and median survival time 9.9 months. The addition of GM-CSF to FIVB decreased the expected leucopenia allowing drug treatment to be given 4 weekly to most patients. GI toxicity was dose limiting. Despite the increased dose intensity that could be delivered (to two thirds of patients), response rates were not definitely increased, no survival benefit was seen and important thromboembolic complications occurred.
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PMID:FIVB plus GM-CSF in metastatic colorectal cancer. 796 Jun 6

Transplantation of blood-derived stem cells is increasingly performed because when used alone or when combined with autologous bone marrow grafting, it can demonstrably shorten myelosuppression following multi-agent chemotherapy. Hematopoietic growth factors can mobilize peripheral blood stem cells from the bone marrow to therapeutically intervene in accelerating hematologic recovery. Interleukin 3 (IL-3), whose hematopoietic activities were first described some ten years ago, is one of several candidate growth factors that may prove useful in enhancing this mobilization in order to obtain adequate yields of circulating stem cells for transplantation. IL-3 used in conjunction with synergistically acting cytokines such as granulocyte-macrophage colony stimulating factor (GM-CSF) or granulocyte CSF (G-CSF) have already yielded interesting results, while new factors like stem cell factor are in the process of clinical evaluations and appear promising. However, further issues remain to be clarified to confirm the general applicability of cytokine-augmented peripheral blood stem cells in improving on-schedule delivery of high-dose myelosuppressive chemotherapy in patients with malignancies.
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PMID:IL-3 and peripheral blood stem cell harvesting. 810 Apr 63

A 45-year-old male with chronic myelogenous leukemia received cryopreserved allogeneic bone marrow from his HLA-identical sister. Bone marrow was harvested and cryopreserved prior to chemoradiotherapy since the donor had neurotic tendencies. The preconditioning regimen consisted of standard dosage of busulfan plus cyclophosphamide and total lymphoid irradiation (5Gy). A total of 3.1 x 10(7)/kg marrow mononuclear cells, containing 4.7 x 10(5) CD34+ cells/kg, and 8.0 x 10(6)/kg buffy coat cells collected from the donor at day 0 was infused. Marrow engraftment occurred by day 38 although hematological recovery was delayed and subsequent administration of GM-CSF, methylprednisolone and donor buffy coat cells were required. Mononuclear cells obtained from the patient's blood at day 28 had an inhibitory effect on CFU-GM formation of the donor's bone marrow mononuclear cells. We considered that this case suffered from a transient myelosuppression due to residual host cells after bone marrow transplantation.
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PMID:[Allogeneic cryopreserved marrow transplantation in a patient with chronic myelogenous leukemia]. 815 54

Dose intensification has the potential to increase the response frequency of chemosensitive tumors to chemotherapy. G-CSF and GM-CSF offer the possibility of dose-intensifying chemotherapy without prohibitive myelosuppression. A phase I study was undertaken to identify the maximum tolerated dose (MTD) of carboplatin that could be administered with a fixed dose of doxorubicin, 60 mg/m2, administered every 28 days. Further escalation of the carboplatin dose was then attempted, with the concomitant addition of GM-CSF 10 mg/kg per day on days 1-21. We had 21 patients, 13 with prior therapy, who were eligible. In all, 60 courses of therapy were delivered, all with doxorubicin and with carboplatin doses of 250 mg/m2, 325 mg/m2 and 400 mg/m2. At carboplatin 400 mg/m2 and doxorubicin 60 mg/m2, thrombocytopenia was dose limiting. The addition of GM-CSF did not allow further escalation. Of the 6 patients treated with carboplatin 400 mg/m2, doxorubicin 60 mg/m2, and GM-CSF, grade 4 granulocytopenia and thrombocytopenia were seen in 4 and 5 patients, respectively. The severity of thrombocytopenia was related to the calculated carboplatin AUC and also to baseline platelet count and prior therapy. In addition, the interaction of GM-CSF and chemotherapy, especially carboplatin-based, may be more complex than originally anticipated.
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PMID:GM-CSF, carboplatin, doxorubicin: a phase I study. 792 66

The cause of myelosuppression in hairy cell leukemia (HCL) has been ascribed to a reduction of the circulating progenitor cell (CPC) compartment and to suppression of hematopoiesis by TNF-alpha. The present study was performed to evaluate the inhibitory effect of hairy cells (HCs) and a possible lack of hematopoietic growth factors on the number of autologous CPCs in vitro. In initial experiments the number of circulating BFU-E, CFU-GM and CFU-mix in HCL patients was found decreased. Monocytopenia but not the number of circulating HCs correlated to the degree of colony reduction in our patients. This pointed to a lack of colony stimulating factors (CSFs) in HCL. Actually, the growth of BFU-E, CFU-GM, and CFU-mix improved upon the addition of IL-3 and GM-CSF in HCL patients but not in healthy donors. To test the suppressive role of HCs in our assay system, cultures were performed after removal of autologous HCs. The results showed that in HC-depleted cultures the numbers of BFU-E, CFU-GM, and CFU-mix were significantly higher. This inhibitory effect of HCs could partially be neutralized by the addition of monoclonal antibodies against TNF-alpha. When the assays were performed with the removal of HCs and the addition of CSFs normal progenitor cell counts were detected in most patients. We conclude that HCs mediate the inhibition of colony growth in part by TNF-alpha. Monocytopenia is related with a deficiency of CSFs in this disease. The reduced colony growth in HCL, therefore, is due to both the inhibitory effects of HCs and the deficiency of CSFs. We suppose that the CPC-compartment is actually preserved in this disease.
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PMID:Evidence of colony suppressor activity and deficiency of hematopoietic growth factors in hairy cell leukemia. 840 80

With the use of aggressive cis-platinum-based combination chemotherapy the majority of patients with metastatic testicular cancer will be cured. Hematopoietic growth factors (HGFs), particularly G- and GM-CSF, have been investigated for the treatment of testicular cancer in order to (a) ameliorate chemotherapy-induced myelosuppression, (b) increase the dose intensity of treatment, or (c) generate peripheral blood stem cells (PBSC) as hematopoietic support for mega-dose chemotherapy. Results from in vitro and animal models have excluded a significant influence of both factors, G-CSF and GM-CSF, on tumor growth and response to cytotoxic treatment. For the group of 'good-risk' patients with metastatic testicular cancer, 85-90% of whom will reach long-term survival, the incidence of granulocytopenic infections after standard chemotherapy regimens appears to be lower than 20%. The prophylactic use of HGFs for these patients is not routinely recommended but may be considered in case of an increased risk for infections. For 'poor risk' patients, who will achieve 50% survival following standard chemotherapy, different attempts of treatment intensification have been investigated. The use of aggressive multidrug regimens is associated with granulocytopenic infections in 20-70% of patients. A randomized trial has demonstrated that the prophylactic use of G-CSF significantly reduces granulocytopenia, the number of septic infections, and the infection-related death rate. For 'poor risk' patients the prophylactic use of HGFs, particularly G-CSF due to its favorable side effect profile, is recommended. The availability of G- and GM-CSF has made it possible to develop dose-intensified chemotherapy regimens. Demonstrated particularly for GM-CSF, a 1.5 fold dose increase can be achieved by the use of a myeloid growth factor alone, and thrombocytopenia and other organ toxicity will become dose limiting. Mobilization of PBSC, either after stimulation with HGFs alone or with HGFs, following chemotherapy has been successfully used in patients with testicular cancer. For the treatment of patients with relapsed disease PBSC support followed by HGFs has allowed the use of mega-dose therapy in multiple phase-II studies. This has prompted the investigation of high-dose therapy as first-line treatment for 'poor-risk' patients. In these patients sequential high-dose treatment with cis-platinum, etoposide, and ifosfamide for four consecutive cycles, each supported by G- or GM-CSF and PBSC, is currently being investigated by the German Testicular Cancer Study Group. HGFs have substantially reduced treatment-associated morbidity and mortality in patients receiving chemotherapy for testicular cancer. They make it possible for the first time to clinically explore the true value of dose-intensified chemotherapy regimens in testis cancer, serving as a model of a highly chemotherapy sensitive disease. Enrollment of patients in prospective clinical trials evaluating the role of high-dose therapy is strongly recommended.
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PMID:Hematopoietic growth factors and treatment of testicular cancer: biological interactions, routine use and dose-intensive chemotherapy. 860 73

Diaziquone (AZQ) is a lipid soluble alkylating agent which was designed for increased CNS penetration. Its principle toxicity is myelosuppression. We conducted a phase I trial using AZQ in combination with GM-CSF to determine if the maximal tolerate dose (MTD) of AZQ could be escalated. Using GM-CSF on a standard schedule, we were unable to escalate the previously determined MTD of diaziquone with the use of this colony stimulating factor.
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PMID:Phase I trial of diaziquone (AZQ) plus GM-CSF. 861 83

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 after myelosuppressive chemotherapy or radiotherapy. A lot of clinical trials with hematopoietic factors have been performed in patients with haematologic and oncologic diseases within the last decade. Granulocyte colony-stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor [GM-CSF], interleukin-3, interleukin-2, erythropoietin and in phase I/II trials thrombopoietin [TPO] are available for the clinical use. At the present, there is a broad use of growth factors. Most studies have been done with G-CSF and GM-CSF, their beneficial effects are proven regarding improvement of hematopoietic recovery after 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 to be given to patients who would not have been able to undergo conventional bone marrow transplantation. However, an improved outcome and improved survival rates with standard chemotherapy protocols couldn't be documented by studies up to now, even though higher chemotherapy doses are possible by the use of hematopoietic factors.
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PMID:[Current status of the clinical application of hematopoietic growth factors in oncology]. 898 92


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