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J U Gutterman

Publications and source records attributed to J U Gutterman.

At least 145 records · Page 8Linked to original sources
PubMed1987

Therapy of chronic myelogenous leukemia with recombinant interferon-gamma.

Recently, we reported that recombinant interferon-alpha (rIFN-alpha) can induce hematologic remissions and cytogenetic improvement in newly diagnosed Philadelphia (Ph)-positive chronic myelogenous leukemia (CML) patients. Although IFN-gamma is a structurally distinct molecule, this agent suppresses in vitro hematopoietic progenitor cells in a fashion similar to that of IFN-alpha. Therefore, we initiated a study of rIFN-gamma at doses of 0.25 to 0.5 mg/m2/d intramuscularly in patients with Ph-positive benign-phase CML. Twenty-six of 30 patients entered in the study were evaluable. Six patients have achieved a complete hematologic response; four, a partial hematologic response. The median follow-up period of patients who are in complete remission is 7.5 months (range, 5 to 12 months). No relapses have occurred among the complete responders. So far, five patients have had cytogenetic improvement with emergence of 5% to 45% diploid cells in the bone marrow. Fever and flulike symptoms were the most common side effects, with partial tolerance often developing after about 1 week. The majority of patients tolerated therapy with minimal change in performance status. In conclusion, rIFN-gamma has demonstrated clinical activity in CML. On the basis of these observations and the in vitro synergistic growth-inhibitory effects of IFN-alpha and IFN-gamma, we have started trials of combination IFN therapy in CML patients.

Adult↗
PubMed1987

Alpha interferon production in patients with hairy cell leukemia: correlations with disease activity and remission status.

Nineteen patients with hairy cell leukemia (HCL) were studied for in vitro production of alpha interferon (IFN alpha). The patients were divided into three groups. The first group consisted of 8 patients with active disease, all of whom showed a severe deficiency in IFN alpha production (no detectable titers in 6 and less than 40 units/ml in the other 2) compared to normal controls (range: 320-10,500 units/ml; median: 2,560 units/ml). The second group consisted of 6 patients who achieved a partial remission (PR) after IFN alpha treatment. These 6 patients had normal numbers of mononuclear cells in the peripheral blood, but still had deficient IFN alpha production (titers of IFN alpha were below 10 units/ml in 5 of the 6 patients). The third group consisted of 5 patients in complete remission (3 after IFN alpha treatment and 1 each after splenectomy and infection). This group had IFN alpha production that was not significantly different from that of controls 35 years or older (median: 640 units/ml; range 60-2,560 units/ml for patients vs. 1,513 units/ml; range 320-5,120 units/ml for controls; p greater than 0.05). These data show a direct relationship between the activity of HCL and the capacity to produce IFN alpha in vitro. The data also suggest that deficiency of endogenous production of IFN alpha may be relevant to the induction and sustenance of remissions in this disease and that relapses may be partly associated with failure to fully restore endogenous IFN alpha production.

Adult↗
PubMed1987

Expression of c-abl in Philadelphia-positive acute myelogenous leukemia.

The identical cytogenetic marker, t(9;22)(q34;q11) (Philadelphia [Ph] translocation), is found in approximately 90%, 20%, and 2% of adult patients with chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), and acute myelogenous leukemia (AML), respectively. In CML, the molecular events resulting from the Ph translocation include a break within the bcr locus on chromosome 22, transfer of the c-abl protooncogene from chromosome 9 to 22, and formation of an aberrant 210-kD bcr-abl fusion protein (p210bcr-abl). Recently, the absence of bcr rearrangement and expression of a distinct aberrant 190-kd abl protein (p190c-abl) has been described in Ph-positive ALL, with the suggestion that the two abl variants may be pathogenetically associated with myeloid v lymphoid leukemogenesis. Here we report that the genomic configuration and translation product of Ph-positive AML can be similar to that of Ph-positive ALL: the break at 22q11 may occur outside the 5.8 kb bcr region and result in expression of a 190-kD abl protein lacking these bcr sequences. Phosphokinase enzymatic activity, a fundamental property of p210bcr-abl, was also associated with AML-derived p190c-abl. Our current observations indicate that p190c-abl can be found in cells of lymphoid or myeloid lineage and is therefore unlikely to play a specific role in the development of lymphoid leukemias. Formation of p190c-abl instead of p210bcr-abl appears to be a characteristic of the acute rather than the chronic Ph-positive leukemic state.

Cell Line↗
PubMed1987

Mid-term observations on the efficacy of alpha-interferon in hairy cell leukemia and status of the interferon system of patients in remission.

We summarize our experience using alpha-interferon (IFN-alpha) in the treatment of 93 patients with hairy cell leukemia. Both partially purified interferon and recombinant IFN-alpha produced over 85% response rate. Equal efficacy at 12 months of treatment was found for both types of IFN-alpha. However, continuation of treatment up to 24 months with partially purified IFN-alpha resulted in an increased number of complete remissions. An increase in the number of bone marrow's hairy cells occurred in 70-80% of the patients in whom a treatment was discontinued. Only 20% of the patients required reinitiation of treatment, and in all, reinduction of remission was readily obtained. Toxicity to IFN-alpha in patients with hairy cell leukemia was minimal. IFN-alpha production by patients in remission was studied. Only those patients in complete remission showed adequate IFN-alpha production. The role of endogenous IFN-alpha in the induction and sustenance of remission in hairy cell leukemia is discussed.

Humans↗
PubMed1987

Proto-oncogene expression in human normal bone marrow.

We and other investigators have previously reported our findings on oncogene expression in human leukemia in an attempt to study the possible involvement of these genes in the leukemic state. An important shortcoming of these studies has been the lack of information on the expression of these genes in normal hematopoietic cells. To address this question we analyzed both the transcript size and level of expression of six oncogenes in fresh hematopoietic cells obtained from hematologically normal individuals and compared the results to those found in fresh samples obtained from patients with various forms of leukemia (acute myelogenous leukemia, acute lymphocytic leukemia, and chronic myelogenous leukemia). We found low level expression of c-myc, c-myb, c-fes, and c-raf in normal bone marrow in sharp contrast to the high levels of expression found in some forms of leukemia. C-fos was highly expressed in both normal bone marrow and certain leukemias. We were unable to detect c-sis expression in our normal samples. With the exception of c-fes, there was no variation in transcript size when comparing normal and leukemic samples. Having defined the transcript sizes and levels of expression for these proto-oncogenes in normal hematopoietic cells, we know that aberrant transcript size for the genes we have studied is not a common event in leukemias. The levels of expression, however, vary widely between normal hematopoietic cells and leukemia as well as between different types of leukemia.

Actins↗
PubMed1986

c-K-ras codon 12 GGT-CGT point mutation. An infrequent event in human lung cancer.

Hu-c-ras represent a family of oncogenes which are capable of inducing malignant transformation in the NIH/3T3 mouse cell line. Associated with this transformation are specific point mutations observed in the 12th and 61st codon of c-K-ras and N-ras and c-Ha-ras, respectively. These base changes generate, in some instances, a new restriction enzyme cleavage site and a restriction fragment length polymorphism (RFLP). One such RFLP has recently been reported for the mutation GGT-CGT at codon 12 of c-K-ras. Our data suggest that this point mutation is rarely present in human lung cancer and therefore is not likely to play a major role in cancer development.

Cell Transformation, Neoplastic↗
PubMed1986

Recombinant gamma interferon induces hypertriglyceridemia and inhibits post-heparin lipase activity in cancer patients.

Animals suffering from malignancy or chronic infection develop characteristic metabolic abnormalities, including a well-defined hypertriglyceridemic state. These abnormalities have been attributed to release of one or more mediators from activated macrophages. We report that cancer patients receiving RIFN-gamma, a potent macrophage activator, at doses of greater than or equal to 0.25 mg/m2/d i.m. show marked increases in triglyceride but not in cholesterol levels (pretreatment triglyceride level of 180 +/- 190 mg/dl [mean +/- SD] vs. a day-14 level of 370 +/- 242 mg/dl, n = 23, p less than 0.001 by the paired t test). This hypertriglyceridemia was characterized by an increase in very low-density lipoproteins and a decrease in plasma post-heparin lipase activity, consistent with defective triglyceride clearance (mean pretreatment lipase level of 2.1 mumol/ml/h vs. a day-14 level of 1.2 mumol/ml/h, n = 6, p = 0.02 by the paired t test). rIFN-gamma did not directly inhibit lipoprotein lipase enzymatic activity in vitro. Other possible mechanisms of action, such as suppression of lipase by an rIFN-gamma-induced mediator released from activated macrophages, or a direct effect of interferon on lipase biosynthesis, require further investigation. Our observations provide evidence that factors produced by the immune system can regulate lipid metabolism in man.

Adult↗
PubMed1986

Psoriasis and alpha-interferon.

Two patients with metastatic renal carcinoma who were treated with recombinant-DNA-derived alpha-interferon (rIFN alpha) had exacerbation of concomitant psoriasis, and another patient experienced onset of psoriasis during treatment with rIFN alpha. This suggests that interferons may participate in the pathophysiology of psoriasis.

Acute Disease↗
PubMed1986

Hematologic remission and cytogenetic improvement induced by recombinant human interferon alpha A in chronic myelogenous leukemia.

We treated 17 patients who had Philadelphia-chromosome-positive chronic myelogenous leukemia (4 of whom had not received therapy and 13 of whom had been treated with hydroxyurea or busulfan for less than six months) with recombinant human interferon alpha A (Roferon-A). The interferon was given as 5 X 10(6) units per square meter of body-surface area per day intramuscularly during induction therapy. Fourteen patients responded to the treatment, of whom 13 had a hematologic remission and 1 had a partial hematologic remission. The median number of white cells in those patients declined from 60.9 X 10(3) to 3.4 X 10(3) per microliter, and the median number of platelets decreased from 476 X 10(3) to 231 X 10(3) per microliter. Among the five responding patients who had splenomegaly before treatment, the spleen size returned to normal in four and decreased by 75 percent in one, although it remained enlarged. Bone marrow cellularity declined from a median of 92.5 percent to a median of 57.5 percent. In six of the patients with hematologic remission, complete suppression of Philadelphia cells was observed on at least one examination. Of the 14 patients who responded, 11 have received the interferon therapy for 9 to 15 months. One patient relapsed during the treatment, and the treatment has been temporarily interrupted in two patients because of toxicity. These data are preliminary and will need further confirmation, but they suggest that recombinant human interferon alpha A is effective in inducing hematologic remission in most patients with benign-phase chronic myelogenous leukemia and in suppressing the Philadelphia chromosome in some of these patients.

Adolescent↗
PubMed1986

Treatment of hairy cell leukemia with alpha interferons.

A review of clinical research with alpha interferons in the treatment of hairy cell leukemia is presented. The results of several studies have shown that alpha interferons effectively reduce leukemic infiltrates in the bone marrow and other organs, with attendant resolution of cytopenias. Alpha interferons have shown efficacy in the treatment of patients in all clinical stages of the disease, including those previously untreated, and may become the treatment choice for hairy cell leukemia. Hairy cell leukemia will also provide a useful human clinical model in which some of the fundamental mechanisms of interferon activity can be studied.

Dose-Response Relationship, Drug↗
PubMed1986

Expression of epidermal growth factor receptor and associated glycoprotein on cultured human brain tumor cells.

The expression of epidermal growth factor (EGF-R) in normal glial and glioma cells grown in culture was examined by using several independent assays. Immunoprecipitation with the monoclonal antibody R1 of extracts from metabolically labeled glial and glioma cells revealed a protein of Mr approximately 170,000, with a migration in sodium dodecyl sulfate-polyacrylamide gels identical to the EGR-R of A431 epidermal carcinoma cells. Furthermore, in the majority of glioma extracts, a protein of Mr approximately 190,000 was specifically immunoprecipitated by this antibody. Similar results were obtained by immunoblotting with a second antibody directed against a synthetic peptide in the sequence of the v-erb-B oncogene. In cell lines expressing both proteins, each was specifically phosphorylated on tyrosine in immune complex kinase assays. The majority of glioma cells bound between 40,000 to 80,000 125I-labeled epidermal growth factor molecules per cell. These results suggest that the expression of EGF-R is common in cultured human glioma cells. In addition, a structurally related protein, is expressed in some of these cells.

Brain Neoplasms↗
PubMed1986

Activation of 2',5'-oligoadenylate synthetase and B-2 microglobulin in cancer patients treated with partially pure gamma interferon: dependence of biological effect on administration route.

Partially pure immune (gamma) interferon (IFN-gamma) was administered to patients intramuscularly (IM), by rapid IV bolus, and by 6-h continuous infusion as part of a phase I clinical trial. The activity of 2',5'-oligoadenylate synthetase (2,5 A) in peripheral blood cells and the concentration of beta-2 microglobulin (B-2M) in serum were monitored as indicators of interferon biological activity in vivo. Five patients received IFN-gamma by the IM route in doses ranging from 6.5 X 10(5) to 9.6 X 10(6) antiviral units daily. There was little induction either of serum B-2M or of 2,5A in peripheral blood cells. Eight patients received IFN-gamma by rapid (5 min) IV bolus infusion in doses ranging from 6.5 X 10(5) to 54 X 10(6) antiviral units daily. As with IM administration, there was little significant induction of 2,5A synthetase, but the concentration of B-2M was increased above pretherapy values in most patients. Eleven patients received IFN-gamma by 6-h infusion daily for 10 days at a dosage of 27 X 10(6) units/day. In contrast to IM and IV bolus administration, 6-h infusion of IFN-gamma resulted in significant induction of both B-2M serum concentration and of 2,5A activity in all patients. The induction of 2,5A was highest on days 2 and 4 of therapy and decreased to pretherapy values by day 7. During the second 10-day course of the infusion study 2,5A activity was not induced until day 7 of therapy, and it decreased rapidly thereafter. These studies show clearly that consistent biological activity such as B-2M activation and specific intracellular biochemical events such as 2,5A induction may be optimally obtained by the administration of IFN-gamma by continuous IV infusion.

2',5'-Oligoadenylate Synthetase↗
PubMed1986

The c-abl, bcr and C lambda genes are amplified in a cell line but not in the uncultured cells from a patient with chronic myelogenous leukemia.

Structural alterations of the oncogenes in human tumors are reported to result from a variety of mechanisms: point mutations, chromosomal translocations and gene amplifications. In over 90% of the cases of chronic myelogenous leukemia (CML), the c-abl oncogene is translocated from chromosome 9 to chromosome 22, and forms in part the Philadelphia (Ph1) chromosome. We have molecularly analysed a double Ph1-positive (Ph1+) cell line, KBM-5 that was established from a patient with CML in the blast-transformed phase (CML-BP). We report that the c-abl, bcr, and C lambda genes are amplified approximately eight-fold in the cell line but not in the fresh uncultured cells from which KBM-5 was derived.

Cell Line↗
PubMed1986

Trisomy 12 correlates with elevated expression of p21 ras in a human adenosquamous carcinoma of the lung.

Reported herein is the first case in which a specific chromosomal abnormality, namely trisomy 12, was observed in primary cultures of a human adenosquamous carcinoma of the lung. Because the c-K-ras had been shown to localize on chromosome 12, the relationship between trisomy and oncogene expression was examined in this tumor by concurrently assaying for the levels of ras oncogene protein product, p21, in both the tumor and adjacent normal tissues. An approximately tenfold increase in the level of p21 ras was observed in the tumor, compared with the adjacent normal tissue. The present finding suggests a possible relationship between chromosomal trisomy and oncogene activation.

Adenocarcinoma↗
PubMed1986

Phase I study of a combination of recombinant interferon-alpha and recombinant interferon-gamma in cancer patients.

Combinations of interferon-alpha and interferon-gamma demonstrate synergistic antiviral and anti-proliferative activity in vitro. Therefore, we initiated a clinical study of combination interferon therapy in humans. Eighteen patients with metastatic solid tumors received daily intramuscular (IM) injections of recombinant interferon-alpha-A (IFN alfa-2a, Roferon-A; Hoffman-LaRoche, Nutley, NJ) and recombinant IFN-gamma (rIFN-gamma) for 6 weeks. The dose levels were 0.5, 1.0, 2.0, and 5.0 X 10(6) U/m2/d of each interferon. A minimum of two patients were entered sequentially at each dose level. Fever, chills, fatigue, and a greater than or equal to 50% drop in granulocyte counts were observed at all doses. Severity of symptoms corresponded to increasing dose levels. In contrast to the tachyphylaxis to these symptoms that usually develops in patients treated with the individual interferons, many patients on this study experienced persistent fever and worsening fatigue over 6 weeks. The maximum tolerated dose was 1 X 10(6) U/m2/d of each interferon. One patient with renal-cell carcinoma achieved a partial remission (duration, 3 months). Enzyme-linked immunoassay analysis in all four patients for whom complete data were available revealed that peak blood levels of IFN alfa-2a on day 22 were about tenfold higher than on day 1. Because of the possibility of cumulative toxicity, the recommended starting dose for further studies is 0.5 X 10(6) U/m2/d of each interferon, with escalation to 1.0 X 10(6) U/m2/d after 1 month if tolerance is acceptable. Phase II investigations to explore the antitumor efficacy of this regimen are planned.

Adult↗
PubMed1986

Clinical toxicity of interferons in cancer patients: a review.

All major types of human interferons (IFNs) have been purified and clinically administered as antitumor agents. We summarize here experience to date with toxicity of IFNs in cancer patients. The acute syndrome consists of fever, chills, myalgias, arthralgias, and headache, with some variation according to type of IFN, route of administration, schedule, and dose. Fatigue, perhaps reflecting CNS toxicity, is the most prevalent nonacute symptom. At high doses, IFNs are neurotoxic; the abnormalities seen by EEG resemble those in diffuse encephalitis. Hematologic toxicity consists mainly of leukopenia, but anemia and thrombocytopenia occur in some patients. Nausea, vomiting, and diarrhea are the main gastrointestinal symptoms. Elevation of serum transaminases seems to reflect liver toxicity. Renal function is well preserved, except for rare instances of acute renal failure. Cardiac toxicity remains questionable, although heart failure and arrhythmias have been associated with the administration of IFNs. Most, if not all, of these effects are reversible or can be ameliorated. With IFN alpha, the type most widely used in clinical studies, doses of 1 million to 9 million units (MU) are generally well tolerated, but doses greater than or equal to 18 MU yield moderate to severe toxicity. Doses greater than or equal to 36 MU can induce severe toxicity and significantly alter the performance status of the patient.

Antibody Formation↗
PubMed1986

Phase I study of multiple dose intramuscularly administered recombinant gamma interferon.

We report the results of a phase I study of the tolerance and biologic activity of intramuscularly (IM)-administered recombinant interferon-gamma (rIFN-gamma). Forty-four patients with metastatic cancer were given rIFN-gamma at doses ranging from 0.01 to 2.5 mg/m2/d for 42 days. The most common side effects were fever, flulike symptoms, night sweats, and granulocytopenia. The maximum tolerated dose was 0.5 mg/m2/d. Administration of rIFN-gamma resulted in modulation of immune system functions, including induction of major histocompatibility complex-associated antigens on blood leukocytes, an increase in blood surface immunoglobulin-bearing B cell and natural killer (NK) cell number, and NK cell cytotoxicity. Serum lysozyme, determined as an estimate of tissue macrophage activity, also increased. Serum assays for anti-interferon antibodies were negative in all patients. Five of eight evaluable patients with lymphoproliferative disorders showed objective evidence of tumor regression consisting of partial responses (two patients), and minor responses (three patients). These data suggest that further phase II studies of IM-administered rIFN-gamma are indicated.

Agranulocytosis↗