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Biomedical subjects

S Vadhan-Raj

Publications and source records attributed to S Vadhan-Raj.

At least 37 records · Page 2Linked to original sources
PubMed1996

Effects of interleukin-1 alpha on ovarian carcinoma in patients with recurrent disease.

The aim of this study was to evaluate the safety and the biological effects of interleukin (IL-1 alpha) in patients' with recurrent ovarian carcinoma treated with carboplatin. In this phase I study, IL-1 alpha was administered by a continuous intravenous infusion at doses ranging 0.1-10 micrograms/m2 every 24 h for 4 days (96 h) 3 weeks before the first dose of carboplatin (400 mg/m2) in patients with potentially platinum-sensitive ovarian cancer. The maximum tolerated dose was 3 microgram/m2/day. Dose-limiting effects at 10 micrograms/m2/day were fever, chills, hypotension and fluid retention. Minor but objective antitumour effects were observed in 2 of 18 patients. 4 patients (including 1 with a minor response) had a decrease of the CA-125 serum level ranging from 33 to 39%. The trial design precluded evaluation of the duration of response to single-agent IL-1 alpha. Based on this trial design, there is evidence of minor antitumour effect to a single course of IL-1 alpha dose given prior to chemotherapy.

Adult↗
PubMed1996

Randomized comparison between antibiotics alone and antibiotics plus granulocyte-macrophage colony-stimulating factor (Escherichia coli-derived in cancer patients with fever and neutropenia.

PURPOSE: A prospective, randomized study was conducted to determine if recombinant human granulocyte-macrophage colony-stimulating factor (rh-GMCSF) (Escherichia coli-derived) could improve response rates to antibiotic therapy and shorten the duration of neutropenia in cancer patients. PATIENTS AND METHODS: A total of 107 febrile neutropenic cancer patients were randomly assigned to empiric therapy with ticarcillin-clavulanate (4 g ticarcillin + 0.1 g clavulanate i.v. every 4 hours) plus netilmicin (2 mg/kg i.v. every 8 hours) with or without rh-GMCSF (3 micrograms/kg per day i.v.). Clinical improvement, duration of neutropenia, and toxicity were monitored. RESULTS: Addition of rh-GMCSF to the antibiotics significantly improved the response rate (96% versus 82%, P = 0.03), but not the survival rate (93% versus 93%), in the evaluable patients. This difference in response rate was not significant when considering all patients in an intent-to-treat analysis. The number of patients who recovered from severe neutropenia ( < 100 cells/microliter) during the period of observation in the study was significantly greater among patients receiving the colony-stimulating factor, although the median duration of neutropenia was not affected. Superinfections and subsequent infections were not significantly different among the two treatment regimens. Side effects were more common among patients treated with the colony-stimulating factor. CONCLUSIONS: Our data do not support the routine administration of rh-GMCSF with antibiotics for patients with fever and neutropenia. Further studies should be conducted to identify those patients most likely to benefit from rh-GMCSF therapy, such as patients with persistent profound neutropenia and refractory infections.

Adolescent↗
PubMed1996

Remission of advanced uterine leiomyosarcoma with pulmonary metastases with carboplatin and paclitaxel.

A patient who had a high-grade uterine leiomyosarcoma (LMS) with extensive intra-abdominal and pulmonary metastases at the time of diagnosis underwent supracervical hysterectomy, bilateral salpingo-oophorectomy and tumor reductive surgery. She then received induction chemotherapy with paclitaxel 135 mg/m2 over 24 h and carboplatin (target AUC = 7.5 mg.ml/min) monthly for seven courses, achieving remission with a small amount of residual disease. The treatment was well tolerated except for peripheral neuropathy. Accordingly, the combination of carboplatin and paclitaxel may be considered in patients with advanced high-grade LMS of the uterus, and this regimen warrants further study in this disease.

Antineoplastic Agents↗
PubMed1996

Phase Ia/Ib trial of anti-GD2 chimeric monoclonal antibody 14.18 (ch14.18) and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in metastatic melanoma.

We performed a phase Ia/Ib trial of chimeric anti-GD2 monoclonal antibody 14.18 (ch14.18) in combination with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to determine the maximum tolerated dose as well as immunologic and biologic responses to the regimen. Sixteen patients with metastatic malignant melanoma received escalating doses of ch14.18 (15-60 mg/m2) administered intravenously for 4 h on day 1. Twenty-four hours later, subcutaneous injections of rhGM-CSF were administered daily for a total of 14 days. Significant side effects were related to ch14.18 infusion and consisted of moderate to severe abdominal and/or extremity pain, blood pressure changes, headache, nausea, diarrhea, peripheral nerve dysesthesias, myalgias, and weakness. Dose-limiting toxicity was observed at 60 mg/m2 and consisted of severe hypertension, hypotension, and atrial fibrillation in one patient each, respectively. Significant increases in white blood cell count, granulocyte count, eosinophil count, and monocyte count occurred after rhGM-CSF treatment. Significant enhancement of in vitro and in vivo monocyte and neutrophil tumoricidal activity and antibody-dependent cellular cytotoxicity along with significant elevations in C-reactive protein and neopterin were observed. Despite these immunological and biological changes, no antitumor activity was seen. In short, the combination of ch14.18 and rhGM-CSF resulted in toxicity similar to that observed with ch14.18 alone without improvement in tumor response.

Antibodies, Monoclonal↗
PubMed1995

In vivo biologic effects of PIXY321, a synthetic hybrid protein of recombinant human granulocyte-macrophage colony-stimulating factor and interleukin-3 in cancer patients with normal hematopoiesis: a phase I study.

PIXY321 is a novel fusion protein of recombinant human granulocyte-macrophage colony-stimulating factor and interleukin-3 that exhibits biologic effects of both its parent cytokines in vitro and in preclinical studies. To evaluate the clinical safety and hematopoietic effects of this hybrid cytokine, PIXY321 was administered by subcutaneous injection twice daily at doses of 25 to 1,000 micrograms/m2/day over 14 days to 24 patients with sarcoma before chemotherapy as part of a phase I trial. The treatment was associated with significant increases in white blood cell, neutrophil, platelet, and reticulocyte counts (all P < .001). The increase in neutrophil count was dose-related and was seen during treatment with the cytokine, whereas the increase in platelet count was gradual and peaked after the cessation of the cytokine treatment and was not clearly dose related. PIXY321 treatment also increased bone marrow (BM) cellularity and the percentage of BM cells in S phase (P < .001). In addition, there was a significant increase in the number of CD34+ cells and committed and multipotential progenitors in the peripheral blood. The ex vivo expansion capacity of peripheral blood and BM progenitor cells was preserved after the in vivo treatment with PIXY321. The treatment was well tolerated, with the most common side-effect being injection site reactions. The results of this study show the biologic and clinical activity of a genetically engineered fusion molecule of two hematopoietic cytokines in humans with normal hematopoietic function.

Agranulocytosis↗
PubMed1995

Human chemokines: enhancement of specific activity and effects in vitro on normal and leukemic progenitors and a factor-dependent cell line and in vivo in mice.

The myelosuppressive effects of human chemokines were evaluated in vitro on normal myeloid progenitors obtained from bone marrow and cord blood, on bone marrow progenitors from patients with acute or chronic leukemia, on proliferation of human factor-dependent cell line M07e, and in vivo on myelopoiesis in mice. Preincubation of human MIP-1 alpha, MIP-2 alpha, interleukin (IL)-8, platelet factor (PF) 4, monocyte chemotactic and activating factor (MCAF), and interferon-inducible protein-10 (IP-10) in an acetonitrile (ACN) solution significantly enhanced the specific activity of these chemokines for in vitro suppression of granulocyte-macrophage (CFU-GM), erythroid (BFU-E), and multipotential (CFU-GEMM) progenitor cells stimulated to proliferate with a colony stimulating factor plus steel factor (SLF). Combinations of any two of these ACN-treated chemokines synergized to suppress colony formation of CFU-GM, BFU-E, and CFU-GEMM at chemokine concentrations below that at which combinations of non-ACN treated chemokines are active. Cord blood progenitors, as previously reported, were in a slow or noncycling state and nonresponsive to inhibition by chemokines. However, after suspension culture with GM-CSF, IL-3, and SLF, they were placed into rapid cell cycle and were responsive to inhibition by ACN-treated chemokines. Low doses of these ACN-pretreated chemokines were active in vivo in suppressing absolute numbers and cycling status of femoral marrow CFU-GM, BFU-E, and CFU-GEMM in C3H/HeJ mice. Other chemokines, alone and in combination, including MIP-1 beta, MIP-2 beta, GRO-alpha NAP-2, and RANTES, were inactive in vitro and in vivo whether or not they were pretreated with ACN. While heterogeneity in responsiveness of CFU-GM from different patients with leukemia to suppression by ACN-treated chemokines was apparent, if the patients had CFU-GM responsive to one of the active chemokines these cells were responsive to the other active chemokines; if patient CFU-GM were not responsive to one of the chemokines, they were not responsive to the other active chemokines. M07e colony-forming cells were responsive to the growth-inhibiting effects of the active ACN-treated chemokines, alone and in combination, but these effects were rapidly reversible and sustained only by multiple daily additions of chemokines. These results should be of value in considering these chemokines for potential clinical use and for assessment of their mechanisms of action, alone and in combination.

Animals↗
PubMed1995

Effects of interleukin-1 alpha administration on pituitary-adrenal and pituitary-thyroid axes function of patients with ovarian cancer.

We monitored pituitary, adrenal, and thyroid function in 21 women who had recurrent ovarian cancer and who received interleukin-1 alpha (IL-1 alpha) before and after carboplatin. Serum cortisol, corticotropin, thyroxine, and thyrotropin were measured in the morning before and at the end of each treatment cycle. Serum corticotropin levels were suppressed in many patients despite a normal simultaneous serum cortisol; thyrotropin tended to rise with declining thyroxine levels after prolonged IL-1 alpha administration. However, serum cortisol and thyroxine remained within the normal range at all times, in all patients. Thyroid dysfunction consistent with thyroiditis was seen in one patient. We conclude that administration of IL-1 alpha as currently used in clinical studies does not create significant thyroid or adrenocortical dysfunction.

Female↗
PubMed1995

Effects of in vivo treatment with PIXY321 (GM-CSF/IL-3 fusion protein) on proliferation kinetics of bone marrow and blood myeloid progenitor cells in patients with sarcoma.

PIXY321, a stimulator of multipotent colony-forming units (CFU-GEMM), burst-forming unit-erythroid (BFU-E), and colony-forming units granulocyte/macrophage (CFU-GM) progenitor cell proliferation in vitro, is currently being assessed in phase-I/-II clinical trials. We evaluated kinetics of CFU-GEMM, BFU-E, and CFU-GM proliferation in bone marrow (BM), blood, and granulocyte (CFU-G) and macrophage (CFU-M) progenitors in BM of chemotherapy-naive patients with sarcoma-administered PIXY321 (25 to 1000 micrograms/m2/day subcutaneously for 14 days). BM and/or blood cells from three to four patients at each dosage were assessed before, during, 1 to 2 days, and 7 days following treatment with PIXY321. Cells were pulse-treated in vitro with or without high-specific activity tritiated thymidine (3H-dThr) (to assess the percentage of progenitors in S-phase of cell cycle) and cultured for immature and more mature subsets of CFU-GEMM, BFU-E, CFU-GM, and for CFU-G and CFU-M. Despite heterogeneity in baseline cycling status of progenitors in BM, administration of 125 to 500 micrograms PIXY321 to patients at least doubled (p < 0.001) cycling rates of all BM progenitors. The cycling rates of blood progenitors increased from a slow or non-cycling state to > 38% cells in cycle. Within 1 to 2 days after cessation of PIXY321 infusion, all progenitors were in a slow or noncycling phase below that of many of the pre-BM samples (immature and mature CFU-GM and mature BFU-E) or were back to background levels (CFU-G, CFU-M, CFU-GEMM, and immature BFU-E). These cycling effects were similar to those previously noted for BM CFU-GM and BFU-E in patients on clinical trial with GM-CSF. In contrast, higher dosages of PIXY321, especially 1000 micrograms, increased cycling of BM and blood progenitor cells early during treatment, but cycling rates decreased while patients were still being administered PIXY321; decreased cycling was maintained after cessation of PIXY321. PIXY321 is thus highly active in vivo as a stimulator of multipotential and more lineage-restricted progenitors. The kinetics of progenitor cell proliferation noted in this study highlight differences seen with GM-CSF and G-CSF. The effects described here could be of relevance in design of future clinical trials using PIXY321 as an adjunct treatment in patients undergoing cytoreductive therapy.

Blood Cells↗
PubMed1994

PIXY321 (GM-CSF/IL-3 fusion protein): biology and early clinical development.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) are functionally related hematopoietins with overlapping but distinct hematopoietic effects. GM-CSF supports more myeloid progenitor cells, whereas IL-3 promotes more erythroid, megakaryocytic and multipotential progenitor cells. Their complementary in vivo biological effects and cross competition for receptor binding prompted the development of PIXY321, a synthetic hybrid protein of GM-CSF and IL-3. PIXY321 binds to cell lines expressing specific receptors for either ligand, and it exhibits enhanced biological activity in human hematopoietic progenitor cell assays. In preclinical studies, PIXY321 has been shown to accelerate both neutrophil and platelet recovery in rhesus monkeys subjected to sublethal irradiation. Based on these preclinical observations, clinical trials have been initiated examining the therapeutic potential of this agent in ameliorating treatment- or disease-related hematopoietic suppression. The early results indicate that PIXY321 can stimulate multilineage hematopoiesis in vivo and enhance neutrophil and platelet recovery following chemotherapy and bone marrow transplantation (BMT). These results suggest that PIXY321 elicits the biological effects of both its component cytokines and represents a novel means of delivering two independent but interactive cytokines in combination.

Animals↗
PubMed1994

Role of granulocyte-macrophage colony-stimulating factor as adjuvant treatment in neutropenic patients with bacterial and fungal infection.

The results are presented of two preliminary studies conducted to assess the role of GM-CSF as adjuvant treatment in neutropenic patients with bacterial or fungal infections. In the first study the effect of GM-CSF on the rate of response to antibiotics was assessed. Febrile neutropenic patients (n = 91) were randomized to receive ticarcillin-clavulanate plus netilmicin with or without GM-CSF (60 micrograms/m2). Response rates were significantly higher in patients who received antibiotics plus GM-CSF (p = 0.05). An increase in neutrophil count was seen in 89% of GM-CSF patients with initial low neutrophil counts (< 100/microliters) compared with 67% of control patients (p = 0.04). In the second study the activity of GM-CSF in patients with fungal infections was assessed. Neutropenic patients with documented fungal infections received amphotericin B plus GM-CSF. Of the eight evaluable patients, six responded and four had a complete response to treatment. The neutrophil counts of the two non-responding patients did not increase substantially during GM-CSF treatment and both died of their fungal infection. The prognosis of neutropenic patients with fungal infections is usually poor and the results of this pilot study are therefore very encouraging. The two studies show that GM-CSF is able to stimulate neutrophil recovery in neutropenic patients and may improve the response to antibiotic and antifungal treatment.

Adolescent↗
PubMed1994

Effects of interleukin-1 alpha on carboplatin-induced thrombocytopenia in patients with recurrent ovarian cancer.

PURPOSE: The purpose of this study was to evaluate the clinical safety and ability of interleukin-1 alpha (IL-1 alpha) to ameliorate carboplatin-induced thrombocytopenia and thus allow patients with ovarian cancer to receive multiple cycles of chemotherapy at full doses. PATIENTS AND METHODS: IL-1 alpha was administered by continuous intravenous infusion daily at doses of 0.1 to 10 micrograms/m2/24 hours over 4 days (96 hours) before the first cycle and/or following the second cycle of carboplatin in 21 patients with recurrent ovarian cancer who had platinum-responsive disease. In cycle no. 1, patients received carboplatin (400 mg/m2) alone, while in cycle no. 2 carboplatin was followed by IL-1 alpha. RESULTS: Treatment with IL-1 alpha before carboplatin was associated with moderate leukocytosis (baseline mean, 6.15 x 10(3)/microL; maximum mean, 17.9 x 10(3)/microL; P < .001) and significant increases in platelet counts (baseline mean, 241 x 10(3)/microL; maximal mean, 392 x 10(3)/microL; P < .001). IL-1 alpha following carboplatin significantly reduced the duration of thrombocytopenia (days platelet count < 50,000, 5.1 to 2.9 days; P = .003) and increased the area under the curve (AUC) of platelets as a function of time (P < .001). The mean nadir platelet counts were 54,000/microL and 67,000/microL (P = .08) in cycles no. 1 and 2, respectively. In fact, seven of 12 patients given 3 micrograms/m2/d of IL-1 alpha had less thrombocytopenia in cycle no. 2 than in cycle no. 1. Treatment with IL-1 alpha was associated with the tolerance of multiple cycles of carboplatin at the same dose in several patients. The maximum-tolerated dose (MTD) was 3 micrograms/m2/d; fever, chills, hypotension, and fluid retention were dose-limiting toxic effects. CONCLUSION: These findings demonstrate that IL-1 alpha can enhance recovery of platelets following carboplatin therapy and suggest a potential therapeutic role for IL-1 alpha in attenuating thrombocytopenia associated with chemotherapy.

Adult↗
PubMed1994

Effects of PIXY321, a granulocyte-macrophage colony-stimulating factor/interleukin-3 fusion protein, on chemotherapy-induced multilineage myelosuppression in patients with sarcoma.

PURPOSE: To evaluate the clinical safety and ability of PIXY321, a novel fusion protein of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), to ameliorate chemotherapy-induced multilineage myelosuppression. PATIENTS AND METHODS: PIXY321 was administered by subcutaneous injection twice daily (25 to 1,000 micrograms/m2/d) over 14 days to 24 chemotherapy-naive patients with sarcoma in a phase I/II study. Three weeks from the initiation of PIXY321, the first cycle of chemotherapy with cyclophosphamide, doxorubicin, and dacarbazine (DTIC) (CyADIC) was administered over 3 days. Four weeks later, a second cycle of CyADIC was administered, followed by 14 days of PIXY321. RESULTS: Treatment with PIXY321 was well tolerated. Local skin reactions and constitutional symptoms were the main side effects. The dose-limiting toxicity was not encountered; however, headache and fatigue were more frequent at the highest dose (1,000 micrograms/m2). PIXY321 before chemotherapy elicited a modest increase in the WBC count (consisting mainly of mature neutrophils), platelets, and corrected reticulocyte counts (all P < .001). Following chemotherapy, PIXY321 at effective doses (500 to 1,000 micrograms/m2/d), significantly reduced both the degree (mean nadir, 70 v 310/microL; P = .016) and duration (mean days < 500/microL, 6.6 v 3.9 days; P = .002) of neutropenia. Cumulative thrombocytopenia was not observed during the first two cycles of CyADIC (mean nadir platelet count, 103 v 95 x 10(3)/microL, in cycles no. 1 and 2, respectively; P = NS). Compared with our historic control data, the mean nadir platelet count in cycle no. 2 was significantly higher after PIXY321 (1.7-fold, P < .05) than with CyADIC alone or with GM-CSF support. There was a suggestion for a dose response, since the mean percentage change in nadir platelet values from cycle no. 1 to cycle no. 2 increased with the PIXY321 dose (P < .02), with the peak effect observed at 750 micrograms/m2/d. CONCLUSION: These results suggest a potential clinical role for PIXY321 in attenuating the cumulative multilineage hematopoietic toxicity of chemotherapy.

Adult↗
PubMed1994

Kinetic response of human marrow myeloid progenitor cells to in vivo treatment of patients with granulocyte colony-stimulating factor is different from the response to treatment with granulocyte-macrophage colony-stimulating factor.

We previously demonstrated that granulocyte-macrophage colony-stimulating factor (GM-CSF) induced sustained increases in cycling of myeloid progenitors in patients with sarcoma. However, decreased proliferation of these cells to a slow- or noncycling state, below pretreatment levels, occurred within 1 to 2 days and maintained for at least 1 week after discontinuation of GM-CSF. To assess possible biological differences in GM-CSF and granulocyte (G)-CSF in such kinetic effects, we evaluated cycling status of marrow progenitors before, during, and after administration of recombinant human G-CSF (5 micrograms/kg/d subcutaneously [s.c.]) to six patients with sarcoma for 8 days. On the last (8th) day of G-CSF treatment, cycling rates of colony-forming units-granulocyte/macrophage (CFU-GM), burst-forming units-erythroid (BFU-E), and multipotent colony-forming units (CFU-GEMM) were enhanced 1.5- to 1.9-fold, to values of 40 +/- 10% to 58 +/- 5%. In sharp contrast to patients receiving GM-CSF, however, progenitor cells from patients off G-CSF treatment for 2 to 4 days were still rapidly proliferating. These differences in proliferative kinetics may be of use for design of clinical trials to efficaciously utilize these growth factors.

Bone Marrow↗
PubMed1993

Effects of continuous high dose rhGM-CSF infusion on human monocyte activity.

In this study we describe the time-dependent effects of a high dose (750 micrograms/ml/24 hr) continuous infusion of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on monocyte number, cytokine release, and superoxide anion production. Blood was taken from patients prior to rhGM-CSF infusion (day 0), and on days 1, 7, and 14 of infusion. The mean concentration of monocytes per ml of blood increased progressively from 4.3 x 10(5) on day 0 to 21 x 10(5) on day 14 of infusion. There was no significant change in the basal release of tumor necrosis factor alpha (TNF-alpha) or interleukin 1 beta (IL-1 beta) induced by rhGM-CSF. However, the lipopolysaccharide (LPS)-stimulated release of TNF-alpha by monocytes increased significantly on day 1 of infusion, and by day 14 had increased 8-fold. IL-1 beta release from LPS-stimulated monocytes increased slightly by day 7, and by almost 10-fold by day 14 of infusion. When maximally stimulated with phorbol dibutyrate, the monocytes demonstrated an increased (although not significant) capacity to produce superoxide anion on days 7 and 14 of infusion. No change in basal superoxide anion production was seen at any day of infusion. These GM-CSF-induced changes in stimulated cytokine and superoxide anion release could not be reproduced by treating monocytes with rhGM-CSF in vitro. In summary, a two week, high dose infusion of rhGM-CSF resulted in increases in circulating monocyte concentration, and in the stimulated release of TNF-alpha and IL-1 beta, and superoxide anion production from these monocytes. These primed monocytes could enhance the ability of neutropenic patients to fight infection.

Adult↗