Search PubMed⌕ Search

Biomedical subjects

Z Estrov

Publications and source records attributed to Z Estrov.

At least 91 records · Page 5Linked to original sources
PubMed1996

Human recombinant interferon-inducible protein-10 inhibits the proliferation of normal and acute myelogenous leukemia progenitors.

Recombinant human interferon-inducible protein-10 (rIP-10) has been recently identified, purified and shown to suppress the multiplication of normal marrow early hemopoietic progenitors. In the present study we investigated the effect of rIP-10 on different normal and acute myelogenous leukemia (AML) progenitor populations. We first studied hematologically normal bone marrow using the delta culture assay, in which marrow low-density cells were incubated in liquid culture with recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) for 1 week, to allow the differentiation of mature progenitors, and thereafter cultured in methylcellulose in the presence of rGM-CSF and recombinant erythropoietin (rEPO). In this assay rIP-10 significantly inhibited the proliferation of normal marrow hemopoietic progenitors in a dose-dependent fashion. However, when fresh normal marrow cells were cultured in methylcellulose without preincubation in liquid culture, rIP-10 did not affect the growth of colony-forming cells. In contrast, when recombinant c-kit ligand (rKL) was added to rGM-CSF and rEPO, an increment in colony numbers was observed that was eliminated by rIP-10. Similar experiments performed with low-density, non-adherent, T cell-depleted AML marrow cells, obtained from 12 untreated adult AML patients, revealed qualitatively similar results: rIP-10 inhibited the proliferation of AML progenitors in the AML delta assay but did not affect the growth of rGM-CSF-responsive AML colony-forming cells when plated in semisolid media in the presence of rGM-CSF. When rKL was added to rGM-CSF during plating in an effort to recruit additional AML progenitor populations, there was an increment in leukemic blast colony numbers that was eliminated by rIP-10. As observed with normal progenitors, the effect of rIP-10 on these AML progenitors was concentration-dependent, statistically significant and reversible with a rIP-10-neutralizing antiserum. To delineate the mechanism of action of rIP-10 we used the thymidine suicide assay and found that rIP-10 significantly reduced the fraction of leukemic progenitors synthesizing DNA. Our data suggest the rIP-10 inhibits the proliferation of (probably immature) AML progenitor populations by reducing the fraction of cells undergoing DNA synthesis. Additional studies are needed to further elucidate the mechanism of this inhibition and to determine the potential clinical benefits of rIP-10 in future therapies for AML.

Acute Disease↗
PubMed1996

Molecular and biologic characterization of a newly established Philadelphia-positive acute lymphoblastic leukemia cell line (Z-33) with an autocrine response to GM-CSF.

We have recently established a new Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukemia (ALL) cell line, designated Z-33. This line has L2 morphology, ultrastructural characteristics of lymphoblasts and typical B lineage surface markers identical to those observed in the Ph1-positive ALL patient from whom the line was derived. In addition, a rearranged immunoglobulin heavy-chain gene (JH) band was found in Z-33 cells by Southern blot analysis, confirming B cell clonality. Cytogenetic analysis of the cell line revealed t(9;22)(q34;q11.2). Polymerase chain reaction (PCR)-amplified cDNA from Z-33 cells demonstrated an e1-az BCR-ABL junction, and the p190BCR-ABL protein was detected in them by the immune complex kinase assay. Z-33 cells produce interleukin (IL)-1 beta, IL-6, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), tumor necrosis factor (TNF)-alpha, and transforming growth factor (TGF)-beta, Neither IL-1 beta, G-CSF, TNF-alpha, nor their corresponding antibodies affected the cell line's growth. In contrast, anti-GM-CSF neutralizing antibodies suppressed Z-33 colony formation, and GM-CSF stimulated it in a dose-dependent fashion. In addition, receptor studies with biotinylated GM-CSF demonstrated specific binding to Z-33 cells, indicating that the cells express GM-CSF receptors. Taken together, our data suggest that the Ph1-positive Z-33 ALL cells produce GM-CSF, express GM-CSF receptors, and show an autocrine proliferative response to this cytokine.

Antibodies↗
PubMed1996

Role of interleukin-1 beta converting enzyme (ICE) in leukemia.

Interleukin (IL)-1 is a proinflammatory cytokine that plays a pivotal role in driving the in vitro proliferation of leukemic cells through autocrine or paracrine pathways. Both IL-1 genes, IL-1 alpha and the prominent IL-1 beta, produce 31 kDa proteins. Whereas the precursor (pro) 31 kDa form of IL-1 alpha is biologically active, pro-IL-1 beta is inactive unless cleaved to its mature form by a cytoplasmic cysteine protease termed IL-1 beta converting enzyme (ICE). Although ICE was first thought to be a unique enzyme with a single biologic activity, several investigators have demonstrated that ICE shares sequence homology with the protein product of ced-3, the gene for cell death of the nematode Caenorhabditis elegans, and can induce apoptosis in different cellular systems. However, recent data indicate that ICE is a member of an increasingly recognized family of ICE-related molecules whose other members, such as CPP32, do not cleave pro-IL-1 beta but rather are effective inducers of apoptotic cell death. We recently investigated the effect of ICE inhibition on acute myelogenous leukemia (AML) colony growth. We found that inhibition of ICE reduced the production of mature IL-1 beta and suppressed the proliferation of AML colony-forming units, confirming the central role of IL-1 beta in AML progenitor proliferation. These data suggest that the primary role of ICE in AML cells is cleavage of pro-IL-1 beta rather than induction of apoptosis and that the antileukemic activity of specific ICE inhibitors warrants further exploitation.

Animals↗
PubMed1995

Effect of interleukin-1 beta converting enzyme inhibitor on acute myelogenous leukemia progenitor proliferation.

Interleukin-1 beta (IL-1 beta) converting enzyme (ICE) is a cysteine protease that specifically cleaves precursor IL-1 beta to its biologically active form. Recent studies have also implicated ICE in the induction of apoptosis in vertebrate cells. Because IL-1 plays a major role in acute myelogenous leukemia (AML) blast proliferation, we sought to investigate the effect of ICE inhibition on AML progenitors. To do this, we used bocaspartyl (benzyl) chloromethylketone (BACMK) an inhibitor designed to penetrate cells and bind covalently to the active site of ICE. Our preliminary experiments showed that incubation of activated peripheral blood cells with 2.5 mumol/L of BAMCK downregulated production of mature IL-1 beta but had no effect on tumor necrosis factor-alpha. To test the effects of the inhibitor on AML cells, we first used the OCI/AML3 cell line. We found that these cells produce IL-1 beta and bind the biotinylated cytokine and that IL-1 inhibitors, such as IL-1 neutralizing antibodies, IL-1 receptor antagonist, and soluble IL-1 receptors, specifically inhibit OCI/AML3 proliferation, indicating that IL-1 beta is an autocrine growth factor for OCI/AML3 cells. The ICE inhibitor suppressed OCI/AML3 growth in a dose-dependent manner (at 0.4 to 4 mumol/L) and downregulated mature IL-1 beta production, as assessed by Western immunoblotting. Similar results were obtained with marrow aspirates from 16 AML patients. The ICE inhibitor suppressed proliferation of AML precursors (by up to 78%; mean, 44%) in a dose-dependent fashion at concentrations ranging from 0.4 to 5 mumol/L but not proliferation of normal marrow progenitors; the suppressive effect was reversed by IL-1 beta. Furthermore, incubation of AML cells with 4 mumol/L BAMCK downregulated the production of mature IL-1 beta, suggesting that the growth-inhibitory effect is mediated through suppression of the biologically active cytokine. Our data indicate that inhibition of ICE suppresses AML blast proliferation and suggest that ICE inhibitors may have a role in future therapies for AML.

Adult↗
PubMed1995

Interleukin-1 and its inhibitors: implications for disease biology and therapy.

IL-1 alpha and IL-1 beta are polypeptide hormones that exhibit a broad spectrum of beneficial and harmful biologic activities. Clinical trials designed to benefit from its stimulatory effects on human hematopoiesis and from its role in improving host defenses, are being currently conducted. Other in vivo studies, using IL-1 inhibitors with an attempts to block the detrimental effects of IL-1, are underway. Because of the multifunctional effects of IL-1 in human physiology and its pathogenetic role in several diseases, the capability to control the effects of IL-1 may prove to be a useful tool in medical practice.

Animals↗
PubMed1995

Cytokine expression in adherent layers from patients with myelodysplastic syndrome and acute myelogenous leukemia.

We have previously shown that long-term cultures of adherent layers derived from patients with chronic myelogenous leukemia in blast crisis express high levels of interleukin (IL)-1 beta and that this cytokine may participate in disease progression. In this study, we analyzed cytokine expression in bone marrow adherent layers derived from patients with myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). IL-6 messenger RNA (mRNA) was expressed in adherent layers established from four of nine MDS patients, and from 10 of 17 AML patients (including all four individuals in whom AML had evolved from an antecedent MDS state). Similarly, IL-1 beta mRNA was expressed in adherent layers derived from two of nine MDS patients and from three of 17 AML patients. Cultures from two of 10 AML patients who expressed IL-6 also expressed granulocyte (G) colony-stimulating factor (CSF) mRNA. In contrast, IL-1 beta, IL-6, and G-CSF mRNA were not discernible in adherent layers from any of 14 normal volunteers. Transforming growth factor-beta 1, macrophage (M) CSF, IL-7, and leukemia inhibitory factor mRNA as well as IL-6 protein were constitutively expressed in adherent layers derived from both MDS patients, AML patients, and normal bone marrows, whereas IL-1 alpha, tumor necrosis factor-alpha, and GM-CSF were not expressed in either the normal-, MDS- or AML-derived adherent layers. These results indicate that cultured stroma from a subset of MDS and AML patients produce IL-1 beta and/or IL-6. Although, exposure of adherent layers to exogenous IL-1 beta was able to induce IL-6 expression, in 9 of the 14 samples constitutively expressing cytokines, IL-6 transcript levels were elevated without a concomitant increase in IL-1 beta, suggesting that IL-6 transcription was independently dysregulated.

Adolescent↗
PubMed1995

Elevated plasma thrombopoietic activity in patients with metastatic cancer-related thrombocytosis.

BACKGROUND AND PURPOSE: High platelet counts are occasionally seen in patients suffering from progressive malignant disorders. While granulocyte colony-stimulating factor (G-CSF) has been implicated in paraneoplastic leukemoid reactions, the stimulus for thrombocytosis is unknown. Our purpose in this study was to determine if plasma from cancer patients with thrombocytosis contains a factor or factors with thrombopoietic activity. METHODS: We tested the effects of plasma obtained from 5 individuals with advanced tumors and high platelet counts and from 4 patients with advanced cancer and normal platelet counts on megakaryocytic differentiation of two megakaryoblastic cell lines (Dami and HEL). Differentiation was evaluated by assessing the expression of the platelet-specific cell-surface antigens CD41 (HUPL-mI) and glycoprotein IIb-IIIa using an immunocytochemical staining score. In addition, plasma samples from 7 of the 9 patients and from 5 additional cancer patients with thrombocytosis were assayed for the levels of interleukin (IL)-3, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, and IL-1 beta protein using an enzyme-linked immunosorbent assay (ELISA). RESULTS: Expression of platelet-specific cell-surface antigen was increased in HEL cells after exposure to plasma from all 5 of the cancer patients with thrombocytosis, and in Dami cells after exposure to plasma from 4 of the 5. Similar, but less significant, results were found when these cells were incubated with control combinations of recombinant GM-CSF plus IL-6 or of IL-3 plus IL-6. Platelet-specific cell-surface-antigen expression was not increased in HEL or Dami cells after exposure to the plasma from the 4 cancer patients with normal platelet counts or to normal control plasma. ELISA revealed elevated levels of IL-6 in the plasma from 4 patients with thrombocytosis (38, 40, 63, and 99 pg/mL). In addition, GM-CSF concentration was high in 3 of these 4 patients (33, 47, and 127 pg/mL), and the G-CSF level was elevated in 1 (543 pg/mL). IL-1 beta and IL-3 levels were undetectable. CONCLUSIONS: Our data suggest that the thrombocytosis observed in individuals with advanced malignant disease is mediated by a humoral mechanism. Levels of IL-6, GM-CSF, and G-CSF are elevated in some of these patients, but the plasma concentrations are generally lower than those required for in vitro induction of megakaryocytic differentiation. Plasma from patients with paraneoplastic thrombocytosis may therefore contain thrombopoietins that have not yet been identified, and which might have clinical usefulness.

Adult↗
PubMed1995

Leukemia inhibitory factor binds to human breast cancer cells and stimulates their proliferation.

Leukemia inhibitory factor (LIF) is a cytokine that was originally described as a differentiation factor of a murine myeloid leukemia cell line and subsequently found to be an important mediator of embryonic development. Although extensively studied in the hematopoietic system, its effects on solid tumors are generally unknown. In the present study we investigated the role of LIF in human breast cancer cells. Using the reverse transcriptase-polymerase chain reaction, we found that the human breast carcinoma MCF-7 cell line expressed the message for both LIF receptor and its signal-transducing protein gp130, suggesting that these receptors might be biologically active. Binding studies with radiolabeled LIF demonstrated that MCF-7 cells interacted with this cytokine, and the ligand binding was specific and time, dose, and temperature dependent. In addition, a Scatchard analysis of the data revealed a single class of high-affinity (Kd 0.27 nM) receptors with a density of approximately 430 sites per cell. MCF-7 cells exposed to LIF internalized and degraded the ligand. LIF stimulated the growth of MCF-7 as well as other estrogen-dependent and independent breast cancer cell lines, but the effect on normal breast epithelial lines was less significant. Likewise, it stimulated colony formation by breast cancer cells obtained from five different breast cancer patients in a dose-dependent fashion. These results overall suggest that human breast tumor cells express functional LIF receptors that play a role in breast cancer cell proliferation.

Base Sequence↗
PubMed1995

Dosing of thioTEPA for myeloablative therapy.

High-dose thioTEPA is used frequently in myeloablative regimens for marrow transplantation, but the need for dose adjustments in obese patients has not been explored. We determined the pharmacokinetics of thioTEPA and its metabolite TEPA during first-dose infusion of thioTEPA 150-250 mg/m2 given daily for 3 days in combination with busulfan and cyclophosphamide, and evaluated the results for correlations with toxicity and dosing strategies. The study included 15 adults undergoing marrow transplantation for hematologic malignancies. Plasma samples were obtained at various times over a 24-h period, and concentrations of thioTEPA and TEPA were measured by gas chromatography. At 22-24 h after initiation of a 4-h infusion, the mean +/- SE plasma concentration of thioTEPA was 124 +/- 63 ng/ml, while that of TEPA was 235 +/- 69 ng/ml. For CFU-GM and BFU-E growth in vitro, the IC50(s) of thioTEPA were 83 ng/ml and 16 ng/ml, respectively, and the IC50(s) of TEPA were 141 ng/ml and 47 ng/ml, respectively. Using a two-compartment model, the mean thioTEPA Vc was 47.4 +/- 4.7 1/m2, t1/2 alpha 19 +/- 5 min, t1/2 beta 3.7 +/- 0.5 h, and plasma clearance 302 +/- 21 ml/min per m2. The mean AUCs were 6.9-16.2 mg h/1 for thioTEPA and 8.9-21.2 mg h/1 for TEPA, while the mean peak concentrations were 0.95-2.08 micrograms/ml for thioTEPA and 0.88-1.90 micrograms/ml for TEPA. There was a significant association of grades 2-4 maximum regimen-related toxicity (RRT) with TEPA peak > 1.75 micrograms/ml and with combined thioTEPA and TEPA AUC > 30 mg h/1 (5/6 vs 0/9, P = 0.01 for both comparisons), suggesting that drug exposure was an important determinant of toxicity and, potentially, efficacy. ThioTEPA Vc correlated best with adjusted body weight (r = 0.74, P = 0.0015). In an evaluation of 74 adults receiving thioTEPA 750 mg/m2 in combination with busulfan and cyclophosphamide, the maximum RRT for patients at ideal weight was significantly greater than that for obese patients dosed on ideal weight (mean RRT grade 1.7 vs 1.0, P = 0.004) but did not differ from the maximum RRT for obese adults dosed on actual or adjusted weights. We recommend that for obese patients thioTEPA be dosed on adjusted body weight. Measurements at time-points after 24 h are needed to determine when thioTEPA and TEPA concentrations are below myelosuppressive levels and safe for marrow infusion.

Adolescent↗
PubMed1995

Role of suramin as an IL-1 inhibitor in suppression of acute myelogenous leukemia progenitor proliferation.

Interleukin-1 (IL-1) modulates both autocrine and paracrine growth-stimulatory mechanisms of acute myelogenous leukemia (AML) cell proliferation. Recent studies show that blocking the interaction between IL-1 and its receptor may suppress this proliferation. Because suramin, a polysulfonated naphthylurea originally described as an antitrypanosomal agent, was found to inhibit the binding of several growth factors to their receptor, we tested its effect on AML progenitor proliferation. We first examined the effect of suramin on murine EL-4.6.1 cells that express type I IL-1 receptors and found that suramin inhibited the binding of IL-1 to its receptor. We then tested the effect of suramin on AML progenitors using bone marrow samples from 17 patients with AML. In all experiments, suramin inhibited AML blast proliferation in a dose-dependent fashion at concentrations ranging from 30 to 240 microM. IL-1 beta (100 U/mL) partially reversed this inhibitory effect. Suramin also inhibited normal early and mature hematopoietic progenitors, as assessed by both the delta assay and the mixed colony culture assay; however, at the same concentration, suramin suppressed the colony growth of colony-forming units granulocyte-macrophage (CFU-GM) by only 45% compared with an 89% suppression of AML progenitors. IL-1 beta did not negate this inhibitory effect, which suggests that another growth inhibitory mechanism might be operative. Our data suggest that suramin may inhibit AML progenitor proliferation by blocking the interaction of IL-1 and its receptor; therefore, further studies are warranted to evaluate suramin's therapeutic potential in patients with AML.

Adult↗
PubMed1995

B-lineage lymphoid blast crisis in juvenile chronic myelogenous leukemia: II. Interleukin-1-mediated autocrine growth regulation of the lymphoblasts.

A pre-B acute lymphoblastic leukemia (ALL) cell line with monosomy 7 was established from a child with juvenile chronic myelogenous leukemia (JCML) in lymphoid blast crisis. Analysis of the growth properties of the cell line, termed 'W1' showed an interleukin-1 (IL-1) mediated autocrine pattern of cell proliferation with the following features: W1 colony growth without added growth factor was density-dependent and colony growth was augmented with serum-free autologous cell culture supernatant; exogenous IL-1 beta had a growth-promoting effect on W1 colony numbers when cells were seeded at low density; W1 cells constitutively expressed mRNA for IL-1 beta, and high levels of IL-1 beta were measured in W1 cell lysates; anti-IL-1 beta antibodies as well as IL-1 receptor antagonist markedly suppressed W1 colony growth when either was added to cultures of cells seeded without growth factors at low density; anti-GM-CSF antibodies and anti-IL-3 antibodies had no inhibitory effect on W1 colony growth. Whereas W1 colony growth was also augmented by adding IL-3, IL-4, IL-6, IL-7, GM-CSF, Steel factor and erythropoietin individually to the cultures, W1 cells did not constitutively express mRNA for any of these cytokines. W1 colony growth was markedly suppressed by exogenous TNF-alpha which contrasts sharply with the autocrine growth promoting effect of TNF-alpha on myelomonocytic elements of JCML in 'chronic' phase. The inhibitory effect of TNF-alpha on W1 cells was not due to downregulation of IL-1 production. The IL-1-dependent growth of W1 cells appeared to be unique because none of five other pre-B lineage ALL cell lines established as controls showed an autocrine growth loop via IL-1. W1 cells provide a valuable opportunity to examine the relationship of monosomy 7, B-lineage acute lymphoblastic leukemia, aberrant genetic expression of cytokines and their receptors, and IL-1 mediated autocrine cell growth in cancer.

B-Lymphocytes↗
PubMed1995

Accurate quantitation of residual B-precursor acute lymphoblastic leukemia by limiting dilution and a PCR-based detection system: a description of the method and the principles involved.

The detection of residual leukemia cells in the bone marrow of patients during morphologic remission has been greatly facilitated by use of the polymerase chain reaction (PCR) to amplify leukemia-specific sequences. While the current PCR strategies for estimating the amount of residual leukemia claim a detection sensitivity of one leukemia cell amongst 10(5) or 10(6) normal cells, a rigorous assessment of the relative error associated with these techniques has not been presented. We have developed a method of estimating the amount of residual leukemia in remission marrows that is analogous to the limiting dilution assays used to determine the frequency of immunocompetent cells in a responder cell population. Using this method we measured the fraction of all-or-none (i.e. positive or negative) reactions of the PCR amplification of the leukemia-specific IgH gene rearrangement in replicate samples of serial dilutions of DNA obtained from diagnostic bone marrow specimens from 15 children with B-precursor acute lymphoblastic leukemia (ALL). A sigmoid curve representing the fraction of positive PCR reactions at a given dilution of leukemia DNA was found to be the best fit to the data. The narrowness of the log-linear region of this curve prevents the direct application of the analysis methodology that has previously been described for limiting dilution assays. However, the residual leukemia burden during morphological remission in these 15 patients and in two additional patients who experienced relapse could be estimated by the described dilution analysis method using the best-fit equation. Furthermore, the data generated for diagnostic, remission and relapse marrow samples exhibited a small interspecimen variation. The results suggest that this method can reliably estimate residual leukemia over a range of five orders of magnitude. Although the PCR reaction appears to be one of the most sensitive methods for detecting residual leukemia, all techniques based on this procedure, including our own, must exhibit limitations inherent to the amplification process. Our estimates or relative error suggest that a realistic limit for the PCR estimation of residual leukemia lies in the range of one leukemia cell per 10(5) normal cells. The suggested method is rapid, technically simple and relatively inexpensive. Furthermore, the principles that it is based upon can be applied to any PCR-based strategy.

Bone Marrow Examination↗
PubMed1995

Monitoring residual disease in acute lymphoblastic leukemia: therapeutic implications.

The polymerase chain reaction (PCR) has been applied to detect occult leukemia (ALL) cells in patients with acute lymphoblastic leukemia who are otherwise considered in complete remission by traditional morphological examination of bone marrow specimens. The combined data from the clinical studies published to date suggest that a consistent pattern for residual disease disappearance over many months exists for patients who remain in complete remission for an extended period of time. Conversely, a pattern of residual disease persistence and reappearance preceding clinical findings exists for the majority of patients who ultimately relapse. The ability to detect residual ALL disease near the end of chemotherapy or after the completion of treatment in some patients who otherwise are deemed likely to be cured of their malignancy raises the possibility that mechanisms other than leukemia cell cytotoxicity are influencing the outcome for this disease.

Antineoplastic Agents↗
PubMed1995

Interleukin-1 and its inhibitors: a biologic and therapeutic model for the role of growth regulatory factors in leukemias.

Production of growth factors may provide a mechanism for disease evolution in some leukemias. Interleukin-1 is a plelotropic cytokine with the ability to synergize with other growth factors as well as to stimulate their production and release. Autocrine and/or paracrine secretion of interleukin-1 has been implicated in the pathogenesis of both chronic and acute myelogenous leukemia. Recently, a series of both specific and nonspecific IL-1 inhibitory molecules have been identified. These include IL-1 receptor antagonist, soluble IL-1 receptors, IL-1-converting enzyme inhibitor, IL-4, IL-10 and IL-1-antisense. Early experiments demonstrating the ability of some of these molecules to inhibit acute and chronic myelogenous leukemia growth suggest that clinical trials of these compounds may provide a novel management approach in these malignancies. Here we review the potential biologic and therapeutic role of IL-1 and its inhibitors in the myeloid leukemias.

Animals↗
PubMed1994

Altered levels of interleukin-1 beta and interleukin-1 receptor antagonist in chronic myelogenous leukemia: clinical and prognostic correlates.

We have recently demonstrated that interleukin (IL)-1 beta levels are elevated in advanced chronic myelogenous leukemia (CML) and that IL-1 inhibitors can suppress CML clonogenic growth. To further assess the clinical implications of increased IL-1 beta expression in CML, we analyzed IL-1 beta and IL-1 receptor antagonist (IL-1RA) levels in leukocyte lysates from a series of CML patients and from normal volunteers. Both IL-1 beta and IL-1RA were measured by enzyme-linked immunosorbent assays (ELISAs), with the lower limits of sensitivity of the assays being 20 pg/mL and 6.5 pg/mL, respectively. The median IL-1 beta level in the 81 CML patients tested was higher (115.8 pg/2.4 x 10(7) cells; range, 0 to 2,000 pg/2.4 x 10(7) cells) than the median level in 25 control samples (10.8 pg/2.4 x 10(7) cells; range, 0 to 95.5 pg/2.4 x 10(7) cells) (P < .01). IL-1 beta was bioactive, as demonstrated with a bioassay based on cytotoxicity to a melanoma cell line (A375). For survival analysis, elevated IL-1 beta levels were defined as those exceeding the mean + 2 SD of normal levels (83 pg/2.4 x 10(7) cells). The survival of the 44 patients with elevated IL-1 beta levels was significantly shorter than that of those who had low IL-1 beta levels (median, 44 v 58 months; P = .049 by Wilcoxon-Gehan method). An association between IL-1 beta and CML prognostic criteria shows that IL-1 beta levels were significantly higher in patients in accelerated/blastic crisis phases of the disease (364.0 pg/2.4 x 10(7) cells) compared with patients in chronic phase (102.0 pg/2.4 x 10(7) cells) (P < .01), and that high IL-1 beta levels correlated with increased blasts in the marrow and peripheral blood (P < .01). In contrast, while IL-1RA levels did not differ between chronic-phase CML patients (median, 471.7 pg/2.4 x 10(5)) and healthy volunteers (median, 454.4 pg/2.4 x 10(5)), patients with accelerated/blast crisis disease had significantly lower levels of IL-1RA (median, 218.7 pg/2.4 x 10(5); P = .03). Finally, although IL-1 beta has been previously shown to increase IL-1RA levels, there was no correlation between IL-1 beta and IL-1RA levels in our CML patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Bone Marrow↗