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S Vadhan-Raj

Publications and source records attributed to S Vadhan-Raj.

At least 55 records · Page 3Linked to original sources
PubMed1993

The in vivo effects of PIXY321 therapy on human monocyte activity.

In this report we describe the time-dependent effects of PIXY321 (a synthetic hybrid cytokine) treatment (500 and 750 micrograms/m2/day for 14 days) on six sarcoma patients. Blood was taken prior to PIXY321 injection (day 0), on days 1, 7, and 14 of treatment, and 7 days posttreatment (day 21). The number of isolated monocytes quadrupuled by day 7 and sustained a significant increase through day 14. There were significant increases in the percentage of circulating monocytes relative to total mononuclear cells on days 1 and 7 of therapy. There were no significant changes in monocyte cell surface antigens (15 checked), suggesting that the increase in monocyte numbers was not due to increased numbers of immature monocytes. The basal activity of the monocytes was not markedly altered during treatment; however, they were primed for significantly increased phorbol 12,13-dibutyrate-stimulated superoxide anion production and endotoxin-stimulated release of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) on days of 1 and 7 of therapy. There was a significant increase of IL-1 beta mRNA levels (unstimulated cells) on days 1 and 7, but TNF-alpha mRNA levels increased significantly on day 1 only. Consistent with the increase in superoxide anion production, there were increases in monocyte protein kinase C (PKC) levels on all days of therapy. There was a significant increase in PKCII beta mRNA only on the first day of treatment. All significant changes in monocyte number and function produced by PIXY321 infusion were reversible, as there were no sustained effects on day 21 (7 days after therapy). These results indicate that the effects of PIXY321 may be mediated through up-regulation of PKC resulting in monocytes primed for increased functional activity in response to an appropriate second stimulus.

Antigens, CD↗
PubMed1993

The in vivo effects of rhIL-1 alpha therapy on human monocyte activity.

Pleiotropic cytokines such as interleukin-1 alpha (IL-1 alpha) have multiple effects on peripheral blood monocytes (PBMs). This study examined the ability of in vivo recombinant human IL-1 alpha (rhIL-1 alpha) therapy to enhance clinically important monocyte functions in ovarian cancer patients prior to chemotherapy. After 4 days of continuous infusion, in vivo rhIL-1 alpha therapy amplified both the number and activity of PBMs. Therapy with rhIL-1 alpha increased the number of PBMs sixfold. These monocytes had a significantly increased ability to produce superoxide anion in response to phorbol 12,13-dibutyrate stimulation. Their ability to secrete spontaneously the immunomodulatory cytokines IL-1 alpha and IL-1 beta was significantly increased, but their ability to secrete tumor necrosis factor alpha (TNF-alpha) was not significantly elevated. These effects of rhIL-1 alpha infusion on cytokine secretion by PBMs appear to be related to rhIL-1 alpha-induced increases in the mRNA levels for these cytokines. In contrast, rhIL-1 alpha therapy did not significantly alter PBM response to lipopolysaccharide (10 micrograms/ml). In summary, infused rhIL-1 alpha, in addition to its use as a myeloprotective agent, has enhancing effects on the number and activity of PBMs. The effects of rhIL-1 alpha infusion on PBM function demonstrated here should at least transiently increase the ability of monocytes to combat infection and enhance host immune response.

Carboplatin↗
PubMed1993

The effects of interleukin-1 therapy on peripheral blood granulocyte function in humans.

During a phase I trial of interleukin-1 alpha (IL-1 alpha) in patients with ovarian carcinomas, the effects of this treatment on blood granulocyte respiratory burst and locomotive responses were examined. Differences in baseline granulocyte function in patients as well as dose-related effects of IL-1 alpha treatment were observed. Patients enrolled early in the trial (low-dose patients) had significantly lower locomotive responses before treatment than their paired controls; these low responses normalized after 5 days of continuous-infusion IL-1 alpha treatment. Patients enrolled later (high-dose patients) had normal locomotive responses before treatment and IL-1 alpha treatment was associated with suppression of responses to selected stimuli at the end of treatment. Pretreatment respiratory burst responses in both low- and high-dose patient groups were essentially normal, but the rates of granulocyte H2O2 production following phorbol myristate acetate stimulation became significantly less than control values at the end of treatment. In vitro exposure of either patient or control cells to 150 U/ml IL-1 alpha did not alter their locomotive or respiratory burst responses, suggesting the observed in vivo effects were not mediated directly by IL-1 alpha. Treatment with IL-1 alpha is associated with changes in ex vivo granulocyte function that are related to the IL-1 alpha dose. Treatment with low doses of IL-1 alpha may provide a means of normalizing abnormal polymorphonuclear leukocyte function in some patients with ovarian malignancies.

Analysis of Variance↗
PubMed1993

Role of granulocyte-macrophage colony-stimulating factor as adjuvant therapy for fungal infection in patients with cancer.

A pilot study was conducted to evaluate the role of granulocyte-macrophage colony-stimulating factor (GM-CSF) as adjuvant therapy for fungal infections in patients with cancer. GM-CSF was added to amphotericin B in the treatment of cancer patients with proven major-organ or disseminated fungal infection. The dose of GM-CSF ranged from 100 to 750 micrograms/(m2.d). Of eight evaluable patients, six had a neutrophil response to GM-CSF. Four of these patients were completely cured of the fungal infection, and two had a partial response. However, a capillary-leak syndrome developed in three patients, an adverse effect suggesting that the dose of GM-CSF was excessive.

Adult↗
PubMed1993

Differential responses of myeloid progenitor cells from patients with myeloid leukemia and myelodysplasia to the costimulating effects of steel factor in vitro.

Steel factor (SLF, c-kit ligand), a potent costimulating cytokine in vitro for myeloid progenitor cells from normal donors, is currently being evaluated in clinical trials for effects on hematopoiesis. Based on a preliminary observation that colony-stimulating factor (CSF)-responsive myeloid progenitor cells (CFU-GM) from a few patients with acute myeloid leukemia (AML) did not respond to the costimulating effects of SLF, we evaluated responsiveness of bone marrow or blood CFU-GM from 26 patients with either AML, chronic myeloid leukemia (CML) or myelodysplastic syndrome (MDS) to the effects in vitro of SLF and/or granulocyte-macrophage CSF (GM-CSF). Cells from all 26 patients responded to the stimulating effects of GM-CSF, but marked heterogeneity was detected in each disease category to the costimulating effects of SLF. Nine of 13 patients with AML, 2 of 6 patients with CML and 4 of 7 patients with MDS had clonogenic cells that did not respond significantly to the costimulating effects of SLF. In a more limited study of cells from patients with MDS, it was noted that if the CFU-GM of that patient did not respond to SLF enhancement of CSF-induced colony formation, neither did the erythropoietin (Epo)-dependent erythroid (BFU-E) or multipotential (CFU-GEMM) cells of that patient (3 cases of refractory anemia [RA] evaluating bone marrow and in 1 case blood progenitors as well). If CFU-GM responded, BFU-E and CFU-GEMM responded (bone marrow from 1 patient with chronic myelomonocytic leukemia [CMMol]). Clinical criteria did not readily distinguish between patients who had SLF-responsive vs. -nonresponsive clonogenic cells. While the mechanistic reason for this heterogeneity in responsiveness is not clear, these differences should be carefully considered for possible clinical trials with SLF in patients with acute and chronic myeloid leukemia and MDS.

Adult↗
PubMed1993

The effects of treatment with PIXY321 (GM-CSF/IL-3 fusion protein) on human polymorphonuclear leukocyte function.

During a phase I trial of the genetically engineered hematopoietic growth factor PIXY321 (granulocyte-macrophage colony-stimulating factor/interleukin-3 [IL-3] fusion protein), we examined the effects of PIXY321 treatment on human polymorphonuclear leukocyte (PMN) locomotive, respiratory burst, and phagocytic responses. PIXY321 treatment was associated with transient suppression of both unstimulated locomotion and chemotaxis responses to multiple stimuli, as well as significant transient enhancement of formyl peptide-stimulated H2O2 production. No effects on opsonic phagocytosis of Staphylococcus aureus were observed. In vitro exposure of control PMN to PIXY321 resulted in suppression of unstimulated locomotion/chemotaxis and enhancement of formyl peptide-stimulated H2O2 production but had no effects on phagocytosis. When patient cells were exposed in vitro to PIXY321 during treatment, suppression of chemotaxis and enhancement of H2O2 production were observed before PIXY321 treatment, but these effects diminished during treatment. The in vivo and in vitro exposure effects of PIXY321 treatment on PMN function are similar to those of the parent molecule, granulocyte-macrophage colony-stimulating factor (GM-CSF).

Adult↗
PubMed1992

Growth characteristics and expansion of human umbilical cord blood and estimation of its potential for transplantation in adults.

We estimated whether single collections of cord blood contained sufficient cells for hematopoietic engraftment of adults by evaluating numbers of cord blood and adult bone marrow myeloid progenitor cells (MPCs) as detected in vitro with steel factor (SLF) and hematopoietic colony-stimulating factors (CSFs). SLF plus granulocyte-macrophage (GM)-CSF detected 8- to 11-fold more cord blood GM progenitors [colony-forming units (CFU)-GM] than cells stimulated with GM-CSF or 5637 conditioned medium (CM), growth factors previously used to estimate cord blood CFU-GM numbers. SLF plus erythropoietin (Epo) plus interleukin 3 (IL-3) enhanced detection of cord blood multipotential (CFU-GEMM) progenitors 15-fold compared to stimulation with Epo plus IL-3. Under the same conditions, bone marrow CFU-GM and CFU-GEMM were only enhanced in detection 2- to 4- and 6- to 8-fold. Increased detection of cord blood CFU-GEMM correlated directly with decreased detection of cord blood erythroid burst-forming units (BFU-E). In contrast, adult bone marrow CFU-GEMM and BFU-E numbers were both enhanced by SLF plus Epo plus IL-3. This suggests that most cord blood BFU-E may actually be CFU-GEMM. Cord blood collections (n = 17) contained numbers of MPCs (especially CFU-GM) similar to the number found in nine autologous bone marrow collections. To assess additional sources of MPCs, the peripheral blood of 1-day-old infants was assessed. However, average concentrations of MPCs circulating in these infants were only 30-46% that in their cord blood. Expansion of cord blood MPCs was also evaluated. Incubation of cord blood cells for 7 days with SLF resulted in 7.9-, 2.2-, and 2.7-fold increases in numbers of CFU-GM, BFU-E, and CFU-GEMM compared to starting numbers; addition of a CSF with SLF resulted in even greater expansion of MPCs. The results suggest that cord blood contains a larger number of early profile MPCs than previously recognized and that there are probably sufficient numbers of cells in a single cord blood collection to engraft an adult. Although the expansion data must be considered with caution, as human marrow repopulating cells cannot be assessed directly, in vitro expansion of cord blood stem and progenitor cells may be feasible for clinical transplantation.

Age Factors↗
PubMed1992

Abrogating chemotherapy-induced myelosuppression by recombinant granulocyte-macrophage colony-stimulating factor in patients with sarcoma: protection at the progenitor cell level.

PURPOSE: The purpose of this study was to optimize the dose, schedule, and timing of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) administration that would best abrogate myelosuppression in patients with sarcoma. PATIENTS AND METHODS: Sarcoma patients who had experienced severe myelosuppression after chemotherapy with Cytoxan (cyclophosphamide; Bristol-Myers Squibb Co, Evansville, IN), Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and dacarbazine ([CyADIC], cycle 1) were eligible. GM-CSF was administered during a 14-day period until 1 week before cycle 2 of CyADIC and was resumed 2 days after cycle 2 completion. The schedule subsequently was modified to allow the earlier administration of GM-CSF in which CyADIC was compressed from 5 days to 3 days, and GM-CSF was administered immediately after the discontinuation of CyADIC in cycle 2. To understand better the impact of GM-CSF on bone marrow stem cells, the proliferative status of bone marrow progenitors was examined during treatment. To evaluate the effects of GM-CSF on effector cells, select functions of mature myeloid cells were also examined. RESULTS: In the seven patients who were treated on the initial schedule, GM-CSF enhanced the rate of neutrophil recovery; however, severe neutropenia was not abrogated, By using the modified schedule in 17 patients, GM-CSF significantly reduced both the degree and the duration of neutropenia and myeloid (neutrophils, eosinophils, and monocytes) leukopenia. The mean neutrophil and mature myeloid nadir counts were 100/mm3 and 280/mm3 in cycle 1 and 290/mm3 and 1,540/mm3 in cycle 2 (P less than .01 and P less than .001). The duration of severe neutropenia (neutrophil count less than 500/mm3) and myeloid leukopenia (myeloid leukocyte count less than 1,000/mm3) were reduced from 6.2 and 6.8 days in cycle 1 to 2.8 and 1.4 days in cycle 2 (P less than .001). While 16 of 17 patients experienced severe myeloid leukopenia (less than 500/mm3) in cycle 1, only two of 17 experienced severe myeloid leukopenia in cycle 2 (P less than .001). Overall, severe neutropenia was abrogated in seven patients, which made them eligible for dose-escalation of Adriamycin. The fraction of cycling progenitors increased threefold on GM-CSF and decreased dramatically below the baseline within 1 day of GM-CSF discontinuation. CONCLUSIONS: The modified schedule improved the beneficial effects of GM-CSF by enhancing myeloprotection and permitting dose-intensification of chemotherapy. The increased myeloid mass and quiescent progenitors at the initiation of chemotherapy suggest that GM-CSF might allow further chemotherapy dose-rate intensification by shortening the interval between courses.

Adolescent↗
PubMed1991

The kit receptor and its ligand, steel factor, as regulators of hemopoiesis.

Mouse strains carrying mutations at the Dominant White Spotting (W) locus or the Steel (Sl) locus are anemic and display defects in pigmentation and gametogenesis. In W mutants the anemia is due to a deficiency of hemopoietic stem cells and, in Sl mutants, to a deficiency of supporting stromal cells in the bone marrow. The W locus encodes the c-kit proto-oncogene product, a cell surface receptor with protein-tyrosine kinase activity, and the Sl locus encodes its ligand, a hemopoietic cytokine known variously as Steel factor (SLF), mast cell growth factor, stem cell factor, and Kit ligand. SLF can synergize with a number of other cytokines to stimulate growth of hemopoietic progenitors in vitro and stimulates blood cell production in vivo in animals. Here we review the biological activities of SLF, with particular emphasis on its effects on hemopoietic stem and progenitor cells. We also discuss present knowledge of the molecules involved in SLF-triggered signal transduction, and speculate on potential therapeutic applications for SLF in human disease.

Anemia↗
PubMed1990

Stimulation of myelopoiesis in a patient with congenital neutropenia: biology and nature of response to recombinant human granulocyte-macrophage colony-stimulating factor.

To stimulate granulopoiesis, we gave recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF; 120 microgram/m2/d) to a patient with congenital neutropenia. The treatment resulted in marked increases in white blood cell counts (maximum, 17,400/microL), consisting mainly of eosinophils (maximum, 13,050/microL) and monocytes (maximum, 1305/microL), rather than neutrophils (maximum, 798/microL). Circulating phagocytes (97% eosinophils) derived after GM-CSF treatment were less effective in chemotaxis, slower but equally effective in phagocytosis, and more effective in H2O2 production compared with normal control neutrophils, but comparable in chemotaxis and H2O2 production to control eosinophils. Before GM-CSF treatment, the bone marrow showed a maturation defect in the neutrophilic series that persisted after treatment despite marked increases in mature cells of other lineages. In vitro agar culture of bone marrow cells before GM-CSF treatment showed a normal number of granulocyte colonies; however, maturation was limited to the metamyelocyte stage. Although the absolute number and cycling rates of myeloid colony forming cells (predominantly eosinophils) increased after treatment, the maturation defect in the neutrophilic series persisted. The finding that GM-CSF induced stimulation of proliferation, which was coupled with maturation in the eosinophilic and monocytic but not the neutrophilic components, suggests that this patient had an intrinsic cellular or humoral defect in neutrophil maturation.

Adolescent↗
PubMed1990

Stimulation of myelopoiesis in chronic lymphocytic leukemia and in other lymphoproliferative disorders by recombinant human granulocyte-macrophage colony-stimulating factor.

In an attempt to stimulate granulopoiesis, we administered recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) to 11 patients with lymphoproliferative disorders. Ten patients had neutropenia, six of whom had severe neutropenia (less than 500 neutrophils), including two with agranulocytosis. GM-CSF (60-250 micrograms/m2/day) was administered by continuous intravenous infusion daily for 14 days at 2-week intervals. Significant increases in white blood cell counts (1.3-to 11.7-fold) and neutrophils (1.7- to more than 29-fold) were seen in 10 of 11 patients, including one patient with agranulocytosis. Eosinophils (3.9- to greater than 65-fold) and monocytes (1.3- to 5-fold) increased as well. In contrast, no significant increases were seen in total lymphocytes or in different phenotypic subsets of lymphocytes during treatment. The overall proportion of myeloid and lymphoid elements in bone marrow remained stable. These results indicate that GM-CSF is effective in stimulating myelopoiesis in neutropenic states associated with lymphoproliferative disorders. Further studies will be necessary to determine whether the correction of neutropenia ultimately translates into clinical benefit.

Bone Marrow↗
PubMed1990

Alteration of the functional effects of granulocyte-macrophage colony-stimulating factor on polymorphonuclear leukocytes by membrane-fluidizing agents.

Locomotion and oxidative metabolism of polymorphonuclear leukocytes from 15 patients receiving recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) were examined in vitro. At the end of each GM-CSF treatment course, polymorphonuclear leukocyte (PMN) chemotactic responses were suppressed and no enhancement of formyl-peptide-stimulated superoxide production was observed. The priming of PMN superoxide production normally seen after in vitro GM-CSF exposure was also blunted in these cells. By using control donor PMN, two membrane-fluidizing agents, pentoxifylline and butanol, were shown to normalize suppressed PMN chemotaxis caused by in vitro GM-CSF (1 nM) exposure. Pentoxifylline, but not butanol, also reversed the effects of in vitro GM-CSF on PMN superoxide production. When PMN obtained from six patients at the end of GM-CSF therapy were exposed to pentoxifylline in vitro, the chemotactic suppression typically observed was significantly improved. The data suggest that GM-CSF may affect PMN function via mechanisms involving membrane fluidity or cell deformability or both.

1-Butanol↗
PubMed1990

Circulating myeloid progenitor cell kinetics during hematologic recovery from chemotherapy and subsequent recombinant human granulocyte-macrophage colony-stimulating factor administration.

Hematopoietic recovery from chemotherapy may be associated with an increase in circulating myeloid progenitor cell concentration (CFU-GM); these cells may be harvested by apheresis and used for autologous transplantation after high-dose cytoreductive therapy. Not all patients will demonstrate this increase, possibly due to damage to the stem cell compartment from prior chemoradiotherapy. Elevated circulating CFU-GM has also been reported in patients after short-term administration of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF); whether elevation would persist during longer duration is unknown. We measured circulating CFU-GM (by both limiting dilution in liquid culture and colony formation in semisolid media) in patients with sarcoma who began infusion of rhGM-CSF during recovery from chemotherapy. Patients with elevated circulating CFU-GM did not sustain these levels during subsequent rhGM-CSF infusion. By contrast, patients without rebound elevation of circulating CFU-GM following chemotherapy recovery did increase CFU-GM levels with rhGM-CSF administration. The proportion of marrow CFU-GM in cell cycle during chemotherapy recovery was elevated in both patient groups and remained elevated with rhGM-CSF administration. Both marrow and peripheral blood limiting dilution assays demonstrated linear growth kinetics, indicating a direct effect of the in vitro growth factor (also rhGM-CSF) on progenitor cells without excessive influence or dependence on accessory cells in culture. The use of rhGM-CSF to restore circulating CFU-GM for apheresis during recovery in patients lacking such elevation merits further study.

Antineoplastic Agents↗