Synergistic effects of thrombopoietin and granulocyte colony-stimulating factor on neutrophil recovery in myelosuppressed mice

Severe suppression of the hematopoietic system is a major factor in limiting chemotherapy dose escalation. To determine whether a combination of human recombinant granulocyte colony-stimulating factor (G-CSF) and thrombopoietin (TPO) would alter recovery of platelets, red blood cells (RBCs), or neutrophils after myeloablative therapy, myelosuppressed mice were treated with sc injections of TPO (90 micrograms/kg), G-CSF (250 micrograms/kg). TPO plus G-CSF or vehicle and complete blood counts were measured. Marrow and spleen cells were obtained at various times and assayed for erythroid, myeloid, and megakaryocytic progenitors. The prolonged neutropenia in vehicle controls (14 days) was significantly shortened in mice treated with G-CSF or TPO for 14 days. The combination of TPO plus G-CSF further reduced the duration of neutropenia. TPO and TPO plus G-CSF treatments also significantly shortened thrombocytopenia compared to vehicle. Recovery of RBCs was also enhanced in mice treated with either G-CSF or TPO, or the combination. Furthermore, treatment with G-CSF and/or TPO hastened myeloid, erythroid, and megakaryocyte progenitor recovery compared to vehicle controls. These results show that the combination of TPO plus G-CSF acts synergistically to accelerate neutrophil recovery in myelosuppressed mice and does not compromise the platelet or RBC response to TPO therapy.     

Clinical use of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in neutropenia associated with malignancy

G-CSF and GM-CSF have been shown in each clinical setting to reduce the duration of neutropenia, with the exception of the scant data available in the unrelated bone marrow transplant setting. These growth factors also have been shown to have no leukemogenic effect during the observation periods of the trials discussed. In MDS, one major randomized trial has demonstrated a reduction in incidence of infection. This has not yet been demonstrated in AML and allogeneic BMT. Data from ongoing and future trials will be helpful in elucidating their effect on treatment-related morbidity and overall survival.     

Protective effects of granulocyte colony-stimulating factor on endotoxin shock in mice with retrovirus-induced immunodeficiency syndrome

Mice with retrovirus-induced murine acquired immunodeficiency syndrome (MAIDS) were hypersensitive to lipopolysaccharide (LPS)-induced lethal shock accompanied by marked elevations of systematic interleukin 1beta (IL-beta) and interferon gamma (IFN-gamma) after LPS challenge. Pretreatment with 10 microg of recombinant human granulocyte colony-stimulating factor (rhG-CSF) protected MAIDS mice from hypersensitivity to LPS-induced lethal shock and this protection was concomitant with suppression of IFN-gamma production.     

Histopathology of cutaneous reaction to granulocyte colony-stimulating factor: another pseudomalignancy

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor (HGF) with many applications in cancer therapy. The most important applications are reduction in the incidence of febrile neutropenia, acceleration of neutrophil recovery after chemotherapy or bone marrow transplantation, and mobilization of progenitor cells. Many cutaneous adverse reactions associated with HGF have been reported in recent years, including injection site reactions, pyoderma gangrenosum, Sweet's syndrome, cutaneous leucocytoclastic vasculitis, and widespread folliculitis. The presence of large histiocytes on the dermis between collagen bundles has been proposed as a characteristic histopathologic finding in cutaneous eruptions secondary to granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. We report on a patient with a high-risk ductal infiltrating carcinoma of the breast who received high-dose chemotherapy (HDC) with peripheral blood progenitor cell (PBPC) rescue. The patient received G-CSF after PBPC for a faster granulocyte recovery. She developed a cutaneous eruption located on back, buttocks, axillae, groin and sites where electrocardiography electrodes had been placed. From the histopathological point of view, the eruption was characterized by the presence of numerous large, atypical histiocytes in the dermis with several mitotic figures, mimicking involvement of the dermis by a malignant process.     

Enhancement of cytosine arabinoside cytotoxicity by granulocyte/macrophage colony-stimulating factor and granulocyte colony-stimulating factor in a human myeloblastic leukemia cell line

Enhancement of the cytotoxicity of cytosine arabinoside (ara-C) by granulocyte/macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF), and the mechanisms involved, were studied in the AML-193 human leukemia cell line. AML-193 cells require GM-CSF and G-CSF(CSFs) for optimum growth, and 24 h deprivation of CSFs decreased DNA synthesis measured in terms of 3H-thymidine incorporation. The DNA synthesis gradually recovered upon addition of CSFs. To examine the sensitivity to ara-C under different growth conditions, two groups of cell suspensions, one pretreated with CSFs after 24 h deprivation (CSFs(+) cells), and the other held continuously under CSFs-free conditions (CSFs(-) cells), were exposed to 1.0 microgram/ml of ara-C for 16 h. In clonogenic assays, CSFs(+) cells showed higher sensitivity to ara-C than CSFs(-) cells. These cell groups showed no significant difference in ara-C triphosphate accumulation or retention, though the amount of ara-C incorporated into the acid-insoluble fraction was two times greater in CSFs(+) cells than CSFs(-) cells, and that difference became even clearer in the retention pools. These data suggest that the enhancement of cytotoxicity by CSFs was due to the promotion of ara-C incorporation into DNA as a result of an increase of the cell fraction in the S phase.     

Timing of recombinant human granulocyte colony-stimulating factor administration on neutropenia induced by cyclophosphamide in normal mice

Chagas' disease is an infectious disease that affects millions of people in Latin America and is increasingly seen outside endemic areas. A substantial number of patients develop gastrointestinal disorders secondary to lesions of the enteric nervous system. The purpose of this article is to review the current knowledge about gastrointestinal manifestations of Chagas' disease, including disorders other than the well-known gross dilations of esophagus and colon.     

A case of multiple myeloma producing granulocyte colony-stimulating factor

A case of multiple myeloma (IgA-lambda) with marked granulocytosis, which measured up to 9.9 x 10(4)/mm3, is described. Matured neutrophils were predominant and blasts were not found in the peripheral blood. The serum granulocyte colony-stimulating factor (G-CSF) was notably elevated. The disease ran a chronic course and granulocytosis and elevated serum G-CSF continued. The patient developed atelectasis and bronchopneumonia, and died of respiratory failure. At autopsy, bone marrow showed marked myeloid hyperplasia in varying states of differentiation. The enlarged spleen also disclosed numerous myeloid cells of varying differentiation. Small aggregations of atypical plasma cells were present in the marrow and spleen. Immunohistochemically, atypical plasma cells were positive for anti-G-CSF antibody, which indicated G-CSF secretion from the myeloma cells. To our knowledge, this is the first reported case of G-CSF-producing multiple myeloma.     

Successful use of granulocyte colony-stimulating factor to correct neutropenia in chronic lymphocytic leukaemia

Uniparental isodisomy is defined as the inheritance of two copies of the same parental chromosome and can result in defects when it produces homozygosity for a recessive mutation or in the presence of imprinting. We describe the detection of a chromosome 6 uniparental isodisomy in a 9 year old girl, discovered during a search for an HLA identical sib. HLA typing, erythrocyte phenotyping, and genotypes of microsatellite polymorphisms were compatible with a paternal isodisomy of chromosome 6, with normal biparental origin of the other chromosomes. Paternal cells were not responsive to the patient's cells in mixed lymphocyte cultures. This fortuitous detection of a chromosome 6 isodisomy suggests that cases of chromosome 6 UPD may not be deleterious and may therefore go undetected.     

A mesenteric liposarcoma with production of granulocyte colony-stimulating factor

A 77-year-old female was admitted to our hospital because of pyrexia and a right retroperitoneal mass. Leukocytosis and other inflammatory findings were noted. Bone-marrow aspiration revealed hypercellularity with no malignant cells. An additional mass was detected sonographically in the pelvis. The serum concentration of granulocyte colony-stimulating factor (G-CSF) was highly elevated (299 pg/ml). The tumors were removed at laparotomy, and the pelvic mass was found to arise from the ileocecal mesentery. Postoperatively, white blood cell count and serum G-CSF concentrations decreased to normal levels. The mesenteric tumor showed weakly positive immunostaining for human G-CSF, and Northern and polymerase chain reaction (PCR) analyses detected CSF and its mRNA in the mesenteric tumor.     

Enhancement of delayed-type hypersensitivity to sheep red blood cells in mice by granulocyte colony-stimulating factor administration at the elicitation phase

We previously demonstrated that selective depletion of polymorphonuclear neutrophils by a mAb inhibits both the priming and effector phases of delayed-type hypersensitivity (DTH) to SRBC. To better understand the role of polymorphonuclear neutrophils in DTH, we examined the effect of granulocyte CSF (G-CSF) on DTH to SRBC in mice. G-CSF administered at the elicitation phase enhanced a DTH response that was weak in control G-CSF-untreated mice. This treatment also augmented mononuclear leukocyte recruitment in DTH in these mice. However, G-CSF administration failed to augment priming of DTH to SRBC under any conditions examined.     

Levels of serum granulocyte colony-stimulating factor in patients with cerebrovascular diseases

The role of leukocytes in the pathogenesis of cerebrovascular disease, in particular, cerebral ischemic disease has recently become a focus of research. Several studies have reported that a positive correlation between increased functional activities of neutrophils and the risk of cerebral ischemic disease. Granulocyte colony-stimulating factor (G-CSF) is known to be not only a granulocyte proliferating factor but also a potent activator of mature neutrophils. In this study, we measured the serum G-CSF levels in 143 patients with cerebrovascular diseases and in 100 patients with other diseases, using our established enzyme-linked immunosorbent assay (ELISA) for G-CSF The minimal detection level was 20 pg/ml G-CSF. In patients with cerebral infarction, G-CSF could be detected in 18.3% and in patients with cerebral hemorrhage, it could be detected in 9.8% of analyzed samples. On the other hand, 6% of the patients with other diseases had measurable levels of G-CSF. The differences among these three groups were statistically significant according to the chi 2 test (p < 0.01). Our findings that there was a significantly high frequency of elevated levels of G-CSF among patients with cerebrovascular diseases, may indicate that the action of G-CSF as a potent activator of neutrophils plays some role in the occurrence of cerebrovascular disease, in particular, cerebral infarction.     

Recombinant granulocyte colony-stimulating factor in the long-term treatment of AIDS-related neutropenias

Neutropenia is a common finding in patients with AIDS or AIDS-related complex (ARC), and limits their survival and therapies. We administered recombinant human granulocyte colony-stimulating factor (rG-CSF) 300 micrograms/day to 15 AIDS patients with severe neutropenia (< 1000/microliters). without discontinuing zidovudine, ganciclovir or other myelosuppressive drugs (e.g. antineoplastic chemotherapy). All patients showed correction of neutropenia and/or limitation of drug myelosuppressive action. Neutrophil count was > 1000/microliters during the whole follow-up (11 months). No patient showed sepsis, opportunistic infections or side effects. These data confirm the efficacy and tolerability of rG-CSF in AIDS-related neutropenia.     

Effects of granulocyte colony-stimulating factor in cirrhotic rats with pneumococcal pneumonia

A rat model was used to study the effects of granulocyte colony-stimulating factor (G-CSF) on the pathogenesis of pneumococcal pneumonia in cirrhosis. G-CSF or 5% dextrose in water was administered subcutaneously to cirrhotic and control rats before or after transtracheal infection with type 3 Streptococcus pneumoniae. In both groups, G-CSF significantly increased the total number and percentage of polymorphonuclear leukocytes (PMNL) in peripheral blood (P < .002) and bronchoalveolar lavage fluid (P < .01). An in vivo phagocytosis assay revealed no increase in uptake of pneumococci by PMNL within the lungs of cirrhotic or control rats receiving G-CSF. G-CSF administered before infection did not protect cirrhotic or control rats, but G-CSF treatment after infection significantly reduced mortality in control (P = .04) but not cirrhotic rats. These data suggest that despite increasing numbers of circulating and pulmonary PMNL, G-CSF does not protect against fatal pneumococcal pneumonia in cirrhotic rats.     

Cyclophosphamide/granulocyte colony-stimulating factor induces hematopoietic stem cells to proliferate prior to mobilization

We isolated hematopoietic stem cells (HSC) from mice treated with cyclophosphamide (CY) and granulocyte colony-stimulating factor (G-CSF). All mobilized multipotent progenitor activity was contained in two populations: Thy-1(lo) Sca-1+ Lin- Mac-1- CD4- c-kit+ long-term reconstituting progenitors and Thy-1(lo) Sca-1+ Lin- Mac-1(lo) CD4- transiently reconstituting progenitors. CY/G-CSF treatment drove both long-term and transient multipotent progenitors into cycle, leading to a more than 12-fold expansion in the number of long-term self-renewing HSC prior to mobilization. After CY and 2 days of G-CSF treatment the number of bone marrow HSC began to decline and the number of blood and splenic HSC increased. HSC continued to proliferate in the bone marrow and spleen through 8 days of G-CSF treatment, but HSC released into the blood tended to be in G0/G1 phase. Mobilized multipotent progenitors isolated from the spleen were less efficient than normal bone marrow multipotent progenitors in engrafting irradiated mice but did not differ in colony forming unit-spleen (CFU-S) activity or single cell in vitro assays of primitive progenitor activity. The data suggest that mobilized HSC isolated from the spleen are less efficient at homing to and engrafting the bone marrow of irradiated recipient mice.