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J U Gutterman

Publications and source records attributed to J U Gutterman.

At least 163 records · Page 9Linked to original sources
PubMed1986

Rearrangement in the breakpoint cluster region and the clinical course in Philadelphia-negative chronic myelogenous leukemia.

We have followed one patient with Philadelphia (Ph)-negative chronic myelogenous leukemia and identified an additional four patients from the literature who showed the rearrangement in the breakpoint cluster region (bcr) on chromosome 22 characteristic of Ph-positive chronic myelogenous leukemia. The clinical course of these five patients was similar to that of Ph-positive patients, with easily controlled leukocyte counts, a prolonged benign phase, and prolonged survival. Furthermore, we have shown, for the first time, that bcr rearrangement in Ph-negative chronic myelogenous leukemia can result in expression of the aberrant 210-kilodalton bcr-abl fusion protein, which has been strongly implicated in Ph-positive leukemogenesis. Research data pertaining to possible cytogenetic mechanisms leading to production of p210bcr-abl in the absence of the Ph chromosome are reviewed. Molecular analysis provides an important tool for classifying and predicting prognosis of some patients with Ph-negative chronic myelogenous leukemia.

Chromosomes, Human, Pair 11↗
PubMed1986

In vivo sensitivity and resistance of chronic myelogenous leukemia cells to alpha-interferon: correlation with receptor binding and induction of 2',5'-oligoadenylate synthetase.

Fourteen patients with chronic myelogenous leukemia were treated with partially pure leukocyte interferon (HuIFN alpha). The binding of recombinant leukocyte clone A IFN and the induction of 2',5'-oligoadenylate synthetase (2,5A) in peripheral blood cells were studied to determine whether they correlate with clinical response to IFN therapy. The mean pretherapy binding of radiolabeled recombinant leukocyte clone A IFN to peripheral blood cells was 0.053 +/- 0.02 (SE) fmol (53 +/- 20 amol)/10(6) cells and 0.049 +/- 0.015 fmol/10(6) cells in sensitive and resistant patients, respectively. Twenty-four h after the first HuIFN alpha dose, the binding of recombinant leukocyte clone A IFN decreased 3- to 8-fold in both sensitive and resistant patients. The activity of 2,5A synthetase was induced approximately 100-fold in sensitive patients from a pretherapy mean of 3 +/- 2 nmol/mg to a maximum of 317 +/- 184 nmol/mg during therapy. In contrast, 2,5A synthetase was induced from a pretherapy mean of 0.9 +/- 0.9 nmol/mg to only 6.7 +/- 4.9 nmol/mg in resistant patients. In two patients originally sensitive to HuIFN alpha who developed resistance to therapy, receptors were present in both sensitive and resistant disease stages and appeared to down regulate with therapy regardless of response. In these two patients, 2,5A synthetase was significantly induced with therapy in the sensitive stage but not in the resistant stage. This study shows that lack of clinical response to interferon therapy may coincide with failure to induce 2,5A synthetase activity. This suggests that resistance to alpha-interferon therapy may be mediated by events beyond receptor binding resulting in a failure to induce enzymes responsible for mediation of interferon antiproliferative effects.

2',5'-Oligoadenylate Synthetase↗
PubMed1986

Differential expression of p21ras gene products among histological subtypes of fresh primary human lung tumors.

Activation of the ras oncogene has been associated with a number of human tumors. In this study, expression of p21ras in different histological types of fresh primary bronchogenic carcinomas was examined. p21ras products were detected in all lung tissues that were analyzed. Only 1 of 23 tumors demonstrated aberrant migration of p21ras. In contrast, 10 tumors had substantially elevated levels of p21ras products with respect to the adjacent normal lung tissues and with respect to the other lung tumors. There was no correlation between increased ras protein expression and tobacco exposure of the patient or extent of disease at the time of diagnosis. However, 9 of 11 tumors with a squamous component as opposed to only 1 of 12 tumors belonging to other histological classifications demonstrated increased p21ras. These data suggest that, in bronchogenic carcinomas, mutations associated with structural abnormalities and aberrant migration of p21ras occur infrequently as compared to quantitative changes in p21ras. Furthermore, differential expression of c-ras products in primary human lung tumors correlates with pathological cell type, and may be a common event in squamous cell carcinomas, but not adenocarcinomas or small cell carcinomas of the lung.

Adenocarcinoma↗
PubMed1986

Activation or suppression of the tumoricidal properties of monocytes from cancer patients following treatment with human recombinant gamma-interferon.

The purpose of these studies was to examine the antitumor properties of blood monocytes from patients undergoing phase I trials with recombinant human gamma-interferon (rIFN-gamma). Thirty-one patients with different malignancies were divided into three major treatment groups. The first group of patients received rIFN-gamma by a 6-h i.v. infusion. Activation of blood monocytes was dependent upon the dose of rIFN-gamma administered. The second group of patients received IFN-gamma by a continuous 24-h i.v. infusion. In general, this treatment did not produce antitumor activity in blood monocytes. The third group of patients received daily i.m. injections of rIFN-gamma. Daily i.m. administrations of 0.25-0.5 mg rIFN-gamma/m2/day produced significant activation of antitumor properties in the patients' monocytes, whereas the daily i.m. administrations of 1 mg IFN-gamma/m2/day did not. In fact, the blood monocytes from these patients did not even respond to optimal activating stimuli in vitro. We conclude that the systemic administration of appropriate amounts of IFN-gamma can activate blood monocytes of cancer patients to become tumor cytotoxic. High doses of the same biological should be avoided since it can actually suppress the desired effect. For biologicals with immunostimulatory activity the concept that "more drug is better" may not be operative.

Cytotoxicity, Immunologic↗
PubMed1986

Phase I study of i.v. administered recombinant gamma interferon in cancer patients.

We report a phase I study of the biological effects, tolerance, and pharmacokinetics of 6- and 24-hour iv infusions of recombinant interferon-gamma (rIFN-gamma) in cancer patients. Twenty-one patients received the 6-hour iv infusion regimen at doses ranging from 0.016 to 0.65 mg/m2/day. Forty-one patients received the 24-hour iv infusion regimen at doses ranging from 0.01 to 0.05 mg/m2/day. Fever and flu-like symptoms were the most common side effects and were seen at all dose levels. The maximum tolerated dose was 0.16 mg/m2 for the 6-hour regimen and 0.01 mg/m2/day for the 24-hour regimen. A dose-dependent granulocytopenia was observed at doses greater than or equal to 0.05 mg/m2/day. A marked increase in beta2 microglobulin occurred by Day 5 of treatment in almost all patients, regardless of the dose level. Consistent serum levels of rIFN-gamma were achieved only at doses of 0.325 mg/m2/day of the 6-hour infusion. The mean serum concentrations at this dose ranged from 18 to 83 units/ml as measured by bioassay (0.64-2.4 ng/ml by enzyme-linked immunoassay). Antibody against rIFN-gamma did not develop in any patient. During the short period of evaluation of this study, one patient with renal cell carcinoma achieved a partial response, and three patients with renal cell (two) and lung carcinoma (one), respectively, achieved minor responses. This study will form the framework for phase II efficacy trials of iv rIFN-gamma.

Adult↗
PubMed1986

Treatment of hairy cell leukemia with recombinant alpha-interferon.

Thirty patients with hairy cell leukemia were treated with recombinant interferon alpha-A (rIFN alpha A; Roferon-A); seven were previously untreated. Nine complete and 17 partial remissions were documented by bone marrow core biopsies. All patients' peripheral blood hematologic indexes either improved or normalized. Twelve of 13 patients with retroperitoneal or mediastinal adenopathy obtained remissions of tumor masses. All seven patients with splenomegaly showed prompt reduction in the size of the spleen to normal size. The incidence of complete remissions was significantly higher (P = .02) in previously untreated patients (5 of 7) than in those in whom splenectomy had been performed (4 of 23), a result presumed to be related to the pretreatment tumor burden. rIFN alpha A was well tolerated; mild fatigue was the most frequent complaint. In most patients, tumor remissions resulted in an improved quality of life: they eliminated the need for transfusing blood products and reduced the incidence of infections, and immune deficits were apparently restored in some of the patients. We conclude that rIFN alpha A is an effective therapy for all stages of hairy cell leukemia including previously untreated or newly diagnosed patients.

Adult↗
PubMed1986

Treatment of multiple myeloma with recombinant alpha-interferon.

Thirty-two patients with multiple myeloma were treated with recombinant alpha-interferon clone A (rIFN alpha A) daily by intramuscular injection with an initial dose of 12 X 10(6) U/m2. Of 27 patients evaluable for response, tumor responses were obtained in seven of 14 previously untreated patients (50%) and two of 13 who had relapsed or failed prior chemotherapy (15%). In all patients who had tumor response, there was restoration from subnormal levels of serum immunoglobulins, an effect infrequently observed with chemotherapy. The median duration of tumor responses exceeded 14 months (range, 6 to 20). Moderate-to-severe fatigue was the predominant side effect and necessitated dose reductions in all patients. We conclude that treatment of early stages of multiple myeloma with rIFN alpha A is beneficial because of the substantial response rate and the improvement in the synthesis of serum immunoglobulins. rIFN alpha A has a potential role in combination with other agents in the treatment of multiple myeloma.

Female↗
PubMed1985

Human interferon alpha in malignant lymphoma and Hodgkin's disease. Results of the American Cancer Society trial.

Forty-nine patients with non-Hodgkin's lymphoma or Hodgkin's disease were entered into a multi-institutional phase II trial to evaluate the antitumor activity of human interferon alpha, prepared from buffy coats. Interferon alpha was administered intramuscularly in doses of 1 X 10(6) u, 3 X 10(6) u or 9 X 10(6) u daily for 30 days. Objective partial responses were seen in 3 of 18 patients with nodular lymphoma, all at the 9 X 10(6) u dose. Interferon alpha was not observed to be of therapeutic benefit in the other subtypes of non-Hodgkin's lymphoma or Hodgkin's disease. The major toxicities consisted of fatigue, fever, myalgias and weight loss. Serum interferon levels obtained 3 to 4 hours after injection varied widely, even among patients treated at the same dose level. Despite the relatively low doses of interferon used and the brief period of administration, this study extends the earlier observations of the antitumor effect of interferon in nodular lymphoma. These results are discussed in relation to the cumulative experience in human lymphoma using alpha interferons induced in human leukocytes and those produced in bacteria by recombinant DNA techniques.

Adolescent↗
PubMed1985

Immune thrombocytopenia following alpha-interferon therapy in patients with cancer.

Immune thrombocytopenia occurred in five patients with cancer receiving alpha-interferon. The median pretreatment platelet count was 217,000/cu mm, which fell to a median of 12,000/cu mm after a median of 25 days of interferon therapy. All had normal numbers of megakaryocytes, with dysplasia noted in three; all four who were tested had platelet-associated immunoglobulin. All had normalization of platelet counts with prednisone therapy. Four tolerated re-treatment with interferon, two with concurrent prednisone administration and two others following splenectomy. Immune thrombocytopenia should be considered in patients who become thrombocytopenic during interferon therapy.

Adult↗
PubMed1985

Down-regulation of peripheral blood cell interferon receptors in chronic myelogenous leukemia patients undergoing human interferon (HuIFN alpha) therapy.

Our interest in studying interferon (IFN) receptor activity in peripheral blood cells (PBCs) from patients with chronic myelogenous leukemia (CML) receiving therapeutic doses of partially purified leukocyte IFN (IFN alpha) stems from a need for more adequate monitoring of IFN therapy. The binding of 35S-labelled recombinant DNA-derived leukocyte clone A IFN (35S-rIFN alpha A) to PBCs from 8 patients with CML was determined before and during IFN alpha treatment. The patients' mean pretherapy binding level (0.049 femtomoles of bound 35S-rIFN alpha A) was in the range of values obtained from 4 normal donors (mean of 0.054 femtomoles bound). Within 24 hr of the first IFN alpha dose, the mean femtomoles bound decreased 10-fold and remained low during the course of IFN alpha treatment. In I/I patient, we demonstrated that this decreased binding was due to a loss in number of IFN receptors. The apparent number of receptors after 5 doses of IFN alpha decreased from approximately 600 receptors per cell at pretherapy to approximately 75 receptors per cell, with no difference in the dissociation constants (1.13 X 10(-10)M, 0.968 X 10(-10)M, before and during treatment, respectively). In 4/4 patients, we demonstrated indirectly that the decreased binding was not due to receptor saturation as a result of residual circulating IFN alpha. In 3/3 patients, we demonstrated a gradual recovery of binding capacity after incubating the patients' PBCs at 37 degrees C. Within 2-7 days in vivo recovery of binding, comparable to pretherapy levels, was observed in 3/3 patients whose IFN alpha therapy was discontinued. Combining all these data, we conclude that in both responding and nonresponding patients with CML, IFN alpha exposure induces decreased binding of labelled IFN when a single recombinant DNA-derived IFN species is used. We feel the supporting data indicate that the decreased binding capacity may be due to receptor down-regulation. In the limited number of patients studied thus far, there was no correlation between clinical hematologic response and occurrence of down-regulation, however, down-regulation of cell surface receptors may be required to sustain a biological effect. Further studies of both the kinetics of down-regulation and activation of key enzyme systems are required to fully evaluate the relevance of these findings.

Blood Cells↗
PubMed1985

Phase I clinical trial of intralesional or intraventricular leukocyte interferon for intracranial malignancies.

Eight patients were treated with leukocyte interferon for a variety of neurological malignancies that had failed or recurred after conventional therapy. Three patients with malignant astrocytoma received intratumoral interferon in dosages up to 9 million units 3X/week, with total dosages of up to 160 million units. Interferon was administered intraventricularly in 4 patients with leptomeningeal metastases and one patient with multiple brain metastases. Dosages increased from 1 to 10 million units 3X/week, and total dosages of up to 113 million units were given intraventricularly. Acute side effects of fever, nausea, vomiting, and headache occurred almost exclusively with intraventricular injections, and these subsided after the initial injection. Fatigue, loss of appetite, weight loss, and hematologic toxicity developed a few weeks after onset of treatment, independent of the dose given. A modest tumor regression was seen on CT scans of one patient with a malignant astrocytoma, who was treated with interferon for 8 months. In all 4 patients with leptomeningeal metastases, the CSF became free of malignant cells for 6 to 10 weeks, while clinical improvement was less dramatic.

Adult↗
PubMed1985

Expression of p21ras in fresh primary and metastatic human colorectal tumors.

Activation of the cellular oncogene ras has been implicated in many types of human malignancies. In this study, the relative levels of p21 protein product of ras (p21ras) in primary and metastatic colon tumors were compared to those in adjacent normal tissues. Nine of the 17 primary tumors had substantially elevated levels of p21ras with respect to adjacent normal tissues. Eight of these tumors were from Dukes' B and C stages. Four of the five tumors classified as "D" stage (in which distant metastases are present) did not show elevated levels of p21ras. In metastases from primary colon tumors, nine of nine were considerably reduced in p21ras expression regardless of the site of metastasis. These data suggest that elevation of p21ras may be a common event in early stages of colon tumors, and tumor progression may lead to a more autonomous population of cells in which other growth factors supplant the role of this protein.

Adult↗
PubMed1985

Leukocyte interferon conjugated to beta-D-galactosidase for receptor studies: a preliminary report.

In this report, we describe a simple procedure for labeling leukocyte interferon (IFN) with the enzyme beta-D-galactosidase (beta-gal), through a low-molecular-weight linking agent. The labeling procedure did not appear to alter the properties of the enzyme, the antiviral activity of the recombinant DNA-derived human clone A leukocyte IFN (rIFN alpha A), or the ability of the IFN to bind to Daudi cells. The binding of the putative IFN-enzyme complex to Daudi cells could be blocked by excess unlabeled IFN or by monoclonal antibody to IFN receptors. Our preliminary results indicate that enzyme labeling of IFN can result in a biologically active agent that has potential for use in the quantitation of circulating IFN and specific receptor proteins. In addition, this labeling procedure may be potentially useful with other immunomodulatory proteins.

Antibodies, Monoclonal↗
PubMed1985

Suppression of clonal evolution in two chronic myelogenous leukaemia patients treated with leucocyte interferon.

Two patients with Philadelphia chromosome-positive (Ph1+) chronic myelogenous leukaemia (CML) were treated with human leucocyte interferon (HuIFN-alpha). Karyotypic changes in addition to the Ph1 chromosome developed in these patients before the start of HuIFN-alpha treatment. In one patient the administration of HuIFN-alpha resulted in clinical haematological remission and stable suppression of the secondary Ph1 clone. The second patient was in myeloid blastic crisis when given HuIFN-alpha. While she was receiving HuIFN-alpha, suppression of the blast cell population in the bone marrow occurred. The subsequent cytogenetic changes included a near-complete suppression of a secondary Ph 1 clone of cells carrying a deletion in the short arm of chromosome 7 and partial population of the bone marrow with primary Ph1 clone. These observations suggest a potential role for interferons in altering the progressive course of CML.

Adult↗
PubMed1985

Antitumor activity of recombinant-derived interferon alpha in metastatic renal cell carcinoma.

Fifty-six patients with metastatic renal cell carcinoma (RCC) were treated with recombinant DNA-derived interferon alpha (rIFN alpha A). The first 30 patients were randomized between doses of 2 X 10(6) U/m2 and 20 X 10(6) U/m2 intramuscularly daily. No complete (CR) or partial (PR) remissions were achieved in 15 patients receiving the low dose. In contrast, 27% of those receiving the high dose achieved CR or PR. Subsequently, 26 additional patients were given the high dose and achieved a 31% response rate. Remissions lasted from 1 to more than 12 months (median, 3 months). Responses occurred predominantly in lung parenchyma or mediastinal node metastases. Toxicity of the high dose required dose reduction in 50% of the patients. Neutralizing antibodies to rIFN alpha A developed in seven of 12 responsive (58%) and nine of 29 (31%) nonresponsive patients (P = greater than .5). The median duration of remission among the antibody-positive and antibody-negative patients were 2 and 10 months, respectively (P = .009). The clinical significance of the antibodies to rIFN alpha A remains unclear, but the coincidence between the detection of antibodies and the early relapse of the disease in some responsive patients suggests that these antibodies may abrogate the biologic activity of rIFN alpha A. This effect, however, was not associated with adverse clinical sequelae.

Adult↗
PubMed1985

Treatment of acquired immunodeficiency syndrome--related Kaposi's sarcoma with lymphoblastoid interferon.

Twelve homosexual patients with Kaposi's sarcoma associated with the acquired immune deficiency syndrome (AIDS) were treated with a preparation of purified human lymphoblastoid interferon (Wellferon [Burroughs Wellcome, Research Triangle Park, NC]). They were given a dose of 20 X 10(6) U/m2 intramuscularly daily for approximately two months. Responders continued their treatment on a maintenance schedule of 20 X 10(6) U/m2 three times a week. Four patients experienced complete remissions, and four experienced partial remissions that resulted in a total response rate of 67%. The median duration of treatment was 14 weeks (7 to 28+ weeks), and the median response duration was 28+ weeks (19 to 29+ weeks). Of the four patients in complete remission, one relapsed at 25 weeks and one at 26 weeks; the other two remained in complete remission at 28 and 29+ weeks. The clinical toxicity consisted of chills, fever, fatigue, and asthenia. Hematologic toxicity was similar to that previously described for other preparations of alpha-interferon and consisted of moderate leukopenia and thrombocytopenia. Asthenia, a condition present in all 12 patients, was severe in 50%. A minimal tumor burden, the absence of circulating interferon before treatment, and a performance status of greater than or equal to 90% on the Karnofsky scale were related to an improved response rate. Measurement of immunologic parameters showed significant declines in the already impaired T cell levels, lymphocyte blastogenic response to concanavalin A, monocyte-mediated antibody-dependent cellular cytotoxicity, and monocyte-adherence. Activation of natural killer cells was not noted, and no life-threatening infections occurred during treatment. These data suggest that human lymphoblastoid interferon is an active agent in the treatment of Kaposi's sarcoma, and its use warrants further study in a larger number of patients.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Phase II study of interferon alpha in metastatic renal-cell carcinoma: a progress report.

Partially purified interferon alpha (IFN alpha) was administered to 50 patients with metastatic renal-cell carcinoma (RCC) studied for more than two years. Complete or partial remissions were observed in 26% of the patients. Duration of remissions range from two to 16 months (median, six months). No distinct prognostic factors were clearly identified in the responsive patients, but responses occurred more frequently in men with optimal performance status who had undergone nephrectomy and in whom the metastatic disease was confined to the lungs, pleura, or mediastinum. Leukopenia and granulocytopenia were useful markers of biological activity but did not predict tumor response. Side effects and toxicity at the dosage used (3 X 10(6) units intramuscularly daily) were well-tolerated and consisted predominantly of fatigue and asthenia. We concluded that IFN alpha is useful for palliating metastatic RCC, but no impact on survival was demonstrated. Further studies are required to determine the optimal dose, routes of administration, and treatment schedules.

Adult↗