Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proliferation and differentiation of hematopoietic progenitor cells are regulated by a network of stimulatory and inhibitory cytokines. An understanding of the molecular mechanisms of growth control may provide a physiologic basis for the innovative therapy of bone marrow disorders. Among various accessory cells, bone marrow T lymphocytes are capable of stimulating, as well as inhibiting, hematopoietic progenitor cells. We have now elucidated molecular mechanisms regulating the differential expression of T cell genes encoding for the stimulatory and inhibitory hematopoietic programs. Stimulation of hematopoiesis requires granulocyte-macrophage colony stimulating factor (GM-CSF), whereas inhibition requires interferon-gamma (IF gamma). Both cytokines can be induced by interleukin-2 (IL2). The T cell IL2 receptor consists of a 75 kD chain (p75) mainly expressed on a subset of resting T cells and a 55 kD chain (p55) which is strongly expressed upon T cell activation. P55 and p75 associate on activated T cells to form a dimeric receptor molecule exhibiting high affinity for IL2. The p75 monomer has an intermediate affinity for IL2. Expression of p55 in the context of the high affinity IL2 receptor constitutes a requirement for T cell IFg release. In contrast, p75 alone is capable of mediating the production of GM-CSF. Thus, T cells may be capable of selective production of cytokines with specific effects in hematopoietic growth control. Utilizing a human peripheral blood leukocyte genomic library, we identified various clones containing the entire GM-CSF gene, including coding and regulatory regions. Cloning of the GM-CSF gene allowed clinical studies utilizing recombinant DNA-derived GM-CSF. Chemotherapy-induced neutropenia contributes to both complications of cytotoxic therapy as well as increased relapse incidence of underlying disease. In a prospective randomized study, we have demonstrated that GM-CSF abrogates neutropenia following aplasiogenic chemotherapy in children and adolescents with solid tumors, and that GM-CSF may reduce the duration of infectious episodes after cytotoxic therapy. Next, we escalated the cumulative doses of cytotoxic therapy in an ablative regimen followed by hematopoietic stem cell transplantation to treat patients with poor prognosis pediatric tumors. Morbidity of this highly toxic ablative regimen depends on the duration of myeloid aplasia. Median duration of aplasia following hyper-VAMP was 13 days with CM-CSF and 29 days without GM-CSF. In addition, we have employed p55 blocking monoclonal antibody for prevention of graft vs. host disease in bone marrow transplantation. The understanding of specific molecular mechanisms of hematopoietic immuno-regulation can thus be utilized to provide novel approaches to the treatment of bone marrow failure and cancer.
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PMID:Molecular regulation of hematopoietic cytokines: implications and indications for clinical use in pediatric oncology. 130 80

Thirty-seven patients with advanced malignancies were treated sequentially with recombinant interferon-gamma (rIFN-gamma) and recombinant interleukin-2 (rIL-2) in an outpatient dose escalation clinical trial. rIFN-gamma (0.1 or 0.25 mg/m2/day) was administered by intramuscular injection, days 1-7 and rIL-2 (12, 18, or 24 x 10(6) IU/m2/day) was administered by a 15-min intravenous bolus, days 8-12. Common toxicities encountered included fever, chills, fatigue, neutropenia, and elevations of SGOT, bilirubin, or creatinine. Hypotension and cardiac and pulmonary toxicities were rare. With repeated cycles of therapy, nausea/vomiting and diarrhea associated with the administration of rIL-2 were seen in greater frequency. There were no treatment-related deaths, and no patient required intensive care unit admission for toxicity management. A complete response was observed in one of 11 patients with renal cancer and a partial response was observed in one of seven patients with malignant melanoma. Due to problems with drug supply, further dose escalation could not be continued, and maximum tolerated doses (MTD) were not determined by strict criteria. However, the combination of rIFN-gamma, 0.25 mg/m2/day, and rIL-2, 24 x 10(6) IU/m2/day, appeared to be beyond the MTD, as three of six patients at this dose level could not complete one cycle of therapy due to toxicity. It is unlikely that higher doses of either agent would be tolerated, and for further study using this schedule, we recommend the doses: rIFN-gamma, 0.1 mg/m2/day, and rIL-2, 24 x 10(6) IU/m2/day.
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PMID:A Southwest Oncology Group Phase I study of the sequential combination of recombinant interferon-gamma and recombinant interleukin-2 in patients with cancer. 151 22

Relapse continues to be a problem after bone marrow transplantation (BMT) for hematologic malignancies, particularly in recipients of autologous or T-cell-depleted allogeneic grafts and in patients with advanced disease. Interferon (IFN) has shown antiproliferative activity in several malignant hematologic diseases and potentially may be of benefit when administered early after BMT when the number of residual cells is minimal. We tested in a phase I study the maximum tolerated daily dose of recombinant IFN alpha-2b in patients who had received a transplant for a disease at high risk for relapse (acute myeloid leukemia or non-Hodgkin's lymphoma beyond first remission, advanced myelodysplastic syndrome, acute lymphoblastic leukemia at any stage, chronic myeloid leukemia in accelerated or blast phase. Recombinant IFN alpha-2b was started at a dose of 0.5 x 10(6) IU/m2 and escalated by 0.5 x 10(6) IU/m2 in groups of three or four patients. The intention was to administer IFN as soon as stable engraftment after BMT was achieved (defined as an absolute neutrophil count of greater than 2.0 x 10(9)/L and platelet count greater than 100 x 10(9)/L for 5 consecutive days) and continued for 2 months. A total of 14 patients were enrolled after autologous (n = 3) or allogeneic (n = 11) BMT. Dose-limiting toxicity was myelosuppression. Significant (grade 2 to 4) neutropenia and thrombocytopenia led to discontinuation or dose reduction in five of eight patients receiving 1.5 x 10(6) or 2 x 10(6) IU/m2 IFN. Mild to moderate (grade 1 or 2) anorexia, weight loss, and fatigue occurred in the majority of patients independent of the IFN dose. De novo acute GVHD responsive to steroid treatment developed in 3 of 11 allograft recipients. Natural killer (NK) cell function was low before IFN treatment and was not improved with the cytokine. Conversely, interleukin-2-activated NK cells showed normal function even before starting IFN and no change was seen during IFN treatment. Clonogenic hematopoietic progenitor studies showed depression of all progenitor lines (colony-forming unit [CFU]-granulocyte, erythroid, monocyte, megakaryocyte, CFU granulocyte-macrophage, burst-forming unit-erythroid) by IFN at all dose levels except at 0.5 x 10(6) IU/m2. Considering this result and the incidence and severity of marrow depression seen at doses greater than 1.0 x 10(6) IU/m2, we would consider this the maximum dose safely tolerated if IFN alpha-2b is administered in this setting for a prolonged course on a daily basis.
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PMID:Treatment with recombinant interferon (alpha-2b) early after bone marrow transplantation in patients at high risk for relapse [corrected]. 174 91

A phase I trial was performed to assess the immunomodulatory activities, maximum tolerated doses, and the toxicity of recombinant interleukin-2 (rIL-2) administered in combination with doxorubicin to patients with refractory malignancies. Therapy was administered to successive cohorts of four to six patients who were treated at three different dose levels (1A, 1B, 2A). Levels 1-2 refer to doxorubicin (40 or 60 mg/m2) given as an intravenous (i.v.) bolus on day 1, and levels A-B refer to rIL-2 (1.0 or 3.0 x 10(6) U/m2) given as a continuous i.v. infusion on days 2-5, 9-12, and 16-19. Cycles were repeated every 28 days. Seventeen patients were entered in the trial. Dose limiting toxicity consisted of neutropenia, and the maximum tolerated dose (MTD) of the combination was doxorubicin 40 mg/m2 and rIL-2 3.0 x 10(6) U/m2. No objective responses were observed. Lymphocytosis related to rIL-2 occurred and flow cytometry demonstrated significant increases in the following subsets: CD3+CD25+HLADr+ and CD11b-CD16c+CD8-. Natural killer cell activity and lymphokine-activated killer (LAK) cell precursors were increased in patients treated at dose levels 1A and 1B (40 mg/m2 doxorubicin), but no consistent changes in LAK activity were noted. No clinical responses were seen and the overall toxicity of this combination was moderate to severe. Administration of doxorubicin prior to rIL-2 does not enhance the immunologic effects of rIL-2.
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PMID:Phase I trial of continuous infusion interleukin-2 and doxorubicin in patients with refractory malignancies. 176 77

To determine if interleukin-2 (IL-2) would inhibit gastrointestinal bacterial translocation, mice were gut-decontaminated and recolonized with Escherichia coli C25; some groups were pretreated with 200 mg/kg cyclophosphamide. IL-2 (1.68 mg/kg) or sterile diluent was injected twice daily for 3 or 5 days, and mice were sacrificed the next day. High cecal levels of E. coli C25 were present in all mice. The overall incidence of E. coli C25 translocation to mesenteric lymph nodes was not reduced by IL-2. The median numbers of translocated E. coli C25/g of mesenteric lymph node were significantly (P less than .005) higher after both 3 days (659 vs. 117) and 5 days (550 vs. 50) of treatment with IL-2 with cyclophosphamide and after 5 days (1784 vs. 225) of IL-2 without cyclophosphamide. IL-2 prevented neutropenia and exacerbated lymphopenia caused by cyclophosphamide. The in vitro growth of E. coli C25 was not affected by up to 10(5) units/ml IL-2. Ileal and cecal structures assessed by light and electron microscopy were not altered by IL-2. Thus, IL-2 unexpectedly enhanced the translocation of E. coli C25 from the gastrointestinal tracts of both cyclophosphamide-pretreated and normal mice.
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PMID:Interleukin-2 enhances the translocation of Escherichia coli from the intestines to other organs. 183 71

We have evaluated the effect of Interleukin-2 [IL-2] after Cyclophosphamide (C) chemotherapy in 41 patients with metastatic cancer. IL-2 was given as a continuous infusion priming cycle 36 hours after C at 1 gm/m2 intravenously. In 39 evaluable patients, there were no complete remissions [CR], 2 partial remissions [PR], and 1 had a minor response [MR]. Stable disease for 30 days was seen in 16 patients whereas 20 progressed. The durations of partial and minor responses were brief, ranging from 1-6 months. Grade 3-4 neutropenia was seen in 41%. This was more severe than seen with IL-2 alone or IL-2 combined with lower doses of C. The marrow suppression was due to the chemotherapy. This combination of IL-2 and C appears to be reasonably well tolerated by patients, but toxicity is greater and the response rate is no better than results achieved by IL-2 alone. Responses of 26 patients with renal cancer appear to be inferior to our historical data using IL-2/LAK cells without C. Immune monitoring demonstrated changes expected with C chemotherapy (i.e., a non-selective decline in immune function). C induced no further differences in IL-2 induced changes in immune function.
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PMID:Continuous infusion of interleukin-2 and cyclophosphamide as treatment of advanced cancers: a National Biotherapy Study Group Trial. 191 Jun 23

Fanconi anaemia (FA) is a recessively inherited disorder associated with a typical physical appearance and a spectrum of clinical and laboratory characteristics. Parental heterozygotes of FA patients are superficially normal in appearance and lack overt laboratory abnormalities. Furthermore, they are indistinguishable from normal subjects on chromosome analysis. In order to determine if any of the clinical or laboratory abnormalities seen in FA patients were detectable to a lesser degree in heterozygotes, we carried out detailed skeletal measurement and laboratory investigation on 16 obligate FA heterozygotes and compared the results with 40 normal control subjects. Skeletal proportions in FA heterozygotes showed significant differences from normal subjects in the ratio of the height to the inter-acromial distance (p less than 0.001), and in having significantly shorter forearms (p less than 0.05). Apart from two patients with presumed iron deficiency, haemoglobin levels were normal, but three patients showed neutropenia (less than 1.5 X 10(9)/l). Foetal haemoglobin measurements were significantly higher (p less than 0.01) and natural killer cell subsets lower (p less than 0.05) in heterozygotes. Significantly reduced mitogenetic responses to phytohaemagglutinin and interleukin-2 of peripheral blood lymphocytes in heterozygotes was also demonstrated. These results suggest that heterozygotes show minor physical and haematological abnormalities consistent with partial expression of the Fanconi gene in the heterozygote.
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PMID:Physical and laboratory characteristics of heterozygote carriers of the Fanconi aplasia gene. 226 25

Repeated analysis of peripheral blood lymphocytes (PBLs) from a patient with large granular lymphocytosis, neutropenia, and rheumatoid arthritis revealed that approximately 45% of PBLs displayed the following phenotype: CD3+, CD4-, CD8-, CD16+, HNK-1-, WT31-. This population was purified for further analysis by depletion with anti-CD4 and anti-CD8 monoclonal antibodies (MoAbs). Southern blot analysis showed preferential rearrangements of the V gamma 9 genes. Northern blot demonstrated the presence of V gamma 9 mRNA transcripts. With MoAbs directed against either the V gamma 9 peptide (Ti gamma A) or the delta chain of the gamma delta T-cell receptor (TCR delta 1), we further demonstrated that those cell surfaces expressed both V gamma 9 and a delta gene product. In addition, analysis of the gamma gene rearrangements on six clones derived from this population demonstrated a unique rearrangement on a single chromosome, strongly suggesting the monoclonality of this T-cell population. Significant cytotoxic activity against K562, U937 was observed only after an in vitro culture period with interleukin-2 (IL-2), whereas no specific inhibitory effect on autologous bone marrow (BM) CFU-G was noted.
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PMID:Clonal expansion of lymphocytes bearing the gamma delta T-cell receptor in a patient with large granular lymphocyte disorder. 254 20

Twenty patients with disseminated melanoma were treated with interferon alfa-2a, given by intramuscular (IM) injection three times a week in escalating doses from 15 to 50 X 10(6) U/m2. Of 18 patients considered evaluable, two had complete remission and in two others the disease was stabilized. Laboratory tests 6 hours after injection of interferon alfa-2a indicated a marked lymphopenia and a reduction in natural killer (NK) cell activity. Sequential changes (measured before injection of interferon alfa-2a on days 3, 10, and 31) consisted of neutropenia, thrombocytopenia, and a slight increase in OKT4 positive T cells compared with OKT8 positive T cells. NK activity against the K562 target cells was increased in most patients during the first week of treatment, returning to near or below pretreatment levels thereafter. This response contrasted with a delayed increase against melanoma target cells in 10 patients. The latter correlated with an increase in mitogen-stimulated interleukin-2 (IL2) production, and may indicate that the cytotoxic activity resulted from lymphokine-activated killer (LAK) cells. Changes in cortisol levels may explain some effects on the immune system, such as depression of IL2 and immunoglobulin production in vitro, and the differences noted in clinical responses during the present study compared with those observed with interferon alfa-2b given by intravenous (IV) injection in 5-day cycles. These results suggest that interferon alfa-2a has antitumor activity in certain melanoma patients, in particular those with metastases to pulmonary or subcutaneous sites. Assays of IL2 production and LAK activity may assist in the selection of patients who respond to interferon alfa-2a and help to optimize treatment regimens.
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PMID:Immunological effects of recombinant interferon alfa-2a in patients with disseminated melanoma. 348 11

Immunotherapy with interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells generated from autologous lymphocytes has produced significant tumor regressions in patients with advanced cancer. In the current study, we reviewed the hematologic effects associated with this therapy in our initial 42 patients. Eighty-eight percent of the treated patients developed anemia that required greater than or equal to 4 units of red cell transfusions, and 43% received at least 8 units. Only a blood loss of 2 to 3 units could be attributed to repeated phlebotomy, cytophereses, and hemodilution. IL-2 administration also resulted in thrombocytopenia as well as lymphopenia and eosinophilia. Forty-three percent of patients developed platelet counts of less than or equal to 50,000/microL, and 36% of the total group required platelet transfusions. Mild neutropenia and a rebound lymphocytosis followed discontinuation of IL-2 treatment. To explore the possible mechanisms for these hematologic effects, standard hematopoietic colony assays were conducted on serial blood samples from five patients. IL-2 produced a significant decline in circulating erythroid (BFU-E) and granulocytic/macrophage (CFU-C) progenitors, which rebounded after the discontinuation of IL-2 therapy. Infusion of IL-2 also resulted in measurable serum levels of gamma-interferon. Some of the hematologic effects of immunotherapy with LAK cells and IL-2 may be the result of IL-2-mediated suppression of hematopoiesis.
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PMID:Hematologic effects of immunotherapy with lymphokine-activated killer cells and recombinant interleukin-2 in cancer patients. 349 2


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