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Biomedical subjects

J Gutterman

Publications and source records attributed to J Gutterman.

At least 37 records · Page 2Linked to original sources
PubMed1988

Suppression of c-myc and c-myb expression in myeloid cell lines treated with recombinant tumor necrosis factor-alpha.

Proto-oncogenes are thought to be involved in cellular differentiation and proliferation. Tumor necrosis factors (TNFs) are specific cytokines that have cytostatic and cytotoxic effects in vitro against a wide range of human tumor cells. We have previously demonstrated that recombinant TNFs (rTNFs) have an antiproliferative effect on certain human leukemic cell lines (HL-60, KBM3, KBM5) and no effect on others (K562). To study the possible role of the c-myc and c-myb oncogenes in this antiproliferative effect of TNF, we examined their expression in cell lines HL-60, KBM3, KBM5, and K562 before and after incubation with rTNF-alpha. Expression of c-myc and c-myb was elevated in all cell lines prior to incubation with rTNF-alpha. In the sensitive cell lines HL-60, KBM5, and KBM3 expression of c-myc and c-myb decreased rapidly 8-, 16-, and 4-fold, respectively, by 24 hr. K562 cells, insensitive to rTNF-alpha, exhibited no change in c-myc or c-myb expression over 24 hr. These studies demonstrated that down-regulation of c-myc and c-myb expression were associated with antiproliferative effects of rTNF-alpha on these cell lines.

Cell Line↗
PubMed1988

Analysis of breakpoints within the bcr gene and their correlation with the clinical course of Philadelphia-positive chronic myelogenous leukemia.

Chronic myelogenous leukemia (CML) is characterized by a reciprocal translocation between chromosomes 9 and 22. The breakpoints on chromosome 22 are clustered within a 5.8-kilobase (kb) DNA fragment known as the breakpoint cluster region (bcr), which encodes part of a functionally active gene. We analyzed the bcr in DNAs from 108 consecutive, unselected Philadelphia chromosome-positive CML patients by Southern blot and determined five restriction enzyme fragments within which breaks occur on chromosome 22. The exact sublocalization was determined in the DNA of 100 patients. It was found to be within the 5.8-kb in 99 patients and outside the bcr in only one. Within the bcr, most of the breakpoints occurred in fragments 1, 2, and 3. Overall, laboratory and clinical features of CML did not correlate with specific breakpoint fragments, but chronic-phase duration was longer in patients with a breakpoint in fragment 2 of the bcr. Large 3' bcr deletions were found in nine patients but did not influence clinical outcome. DNA from one of six patients analyzed both during chronic phase and blastic crisis showed an additional aberrant fragment, which suggested that a second abnormal clone developed in blastic crisis.

Blast Crisis↗
PubMed1987

Analysis of the epidermal growth factor receptor gene in fresh human head and neck tumors.

Seventeen fresh uncultured tumors obtained from biopsies of patients with various forms of head and neck cancer and two squamous cell carcinoma cell lines were analyzed for RNA expression and structural alterations of the epidermal growth factor reception gene. We used cDNA probes for the external and the internal domains of the gene. Enhanced mRNA expression was found only in one squamous cell carcinoma cell line, which is known to have high levels of epidermal growth factor receptor. No amplification or structural rearrangement of the epidermal growth factor receptor gene was found.

Adenocarcinoma↗
PubMed1987

Phase I study of recombinant tumor necrosis factor in cancer patients.

Tumor necrosis factor is a cytokine derived from activated macrophages. This agent is cytostatic and cytolytic against transformed human cell lines in vitro and has in vivo activity against a variety of murine tumors. We report a clinical study of the pharmacokinetics, toxicity, and biological activity of i.v. and i.m. administered recombinant human tumor necrosis factor (rTNF). Twenty patients with metastatic cancer were given rTNF in doses ranging from 1 to 200 micrograms/m2 by alternating i.m. and i.v. bolus injections with a minimal intervening period of 72 h. Each patient received a maximum of eight treatments given twice weekly over a 4-week period. With i.v. bolus administration, serum concentrations of rTNF were detected by enzyme-linked immunosorbent assay at doses of 25 micrograms/m2 or greater. The clearance of rTNF in the serum was described by a monoexponential equation with a half-life calculated to be 14-18 min. After i.m. administration, serum concentrations of rTNF were consistently detected by enzyme-linked immunosorbent assay at doses of 150 micrograms/m2 or greater. Peak concentrations were observed within 2 h and rTNF was occasionally detected, at the lower limit of sensitivity of the assay, at 24 h postinjection. rTNF was well tolerated clinically in this dose range, and there was evidence of antitumor effect.

Adult↗
PubMed1987

Clinical and laboratory changes induced by alpha interferon in chronic lymphocytic leukemia--a pilot study.

Ten chronic lymphocytic leukemia patients were treated with partially pure alpha interferon (IFN-alpha) at doses ranging from 3-9 X 10(6) units administered intramuscularly daily. Of these patients, three patients with disease stages 0, 1, and 3 (and prolymphocytic leukemia), respectively, responded with partial remissions lasting from 10 to 24+ months; four additional patients had minor responses. Among those responding, modulation of B cell chronic lymphocytic leukemia, surface immunoglobulins, and surface antigens were observed in four patients. These changes included a decline in the proportion of B cells bearing surface immunoglobulin without change in the number of the B cells. Likewise, a decline in the proportion of B cells bearing T-1 antigen was observed in three patients. Increase in the percentage of T cells, primarily the T helper cells, was seen in two of the responding patients. Specific binding of alpha interferon was demonstrated prior to therapy in CLL cells of all patients. This binding declined rapidly following treatment with IFN-alpha. Induction of the enzyme 2'5' oligoisoadenylate synthetase was examined in CLL patients prior to and during therapy with IFN-alpha. Variable levels of the enzyme were induced in all patients on therapy; however, only minimal induction was observed in two of three patients failing therapy.

2',5'-Oligoadenylate Synthetase↗
PubMed1987

Molecular characteristics of chronic myelogenous leukemia in blast crisis.

We have studied the expression of c-abl and c-myc in leukemic cells of patients in all clinical phases of chronic myelogenous leukemia. We demonstrate that an aberrant 8-Kb c-abl related transcript is present in the RNA of the leukemic cell from all patients with Ph+ CML and that the loss of both normal chromosome #9 is associated with the loss of the normal c-abl related transcripts. This represents direct evidence that the normal c-abl related transcripts derive from the normal c-abl gene locus on the normal chromosome #9, while the aberrant c-abl related transcript in Ph+ CML derives from the hybrid bcr-abl gene formed as a result of the t(9;22). We further demonstrate that trisomy 8 in some instances is associated with enhanced expression of the c-myc oncogene.

Blast Crisis↗
PubMed1987

Intensive combination chemotherapy and interferons in the management of chronic myelogenous leukemia.

Compared to single-agent therapy with hydroxyurea or myleran (155 patients), intensive chemotherapy with vincristine, cytosine arabinoside, prednisone and cyclophosphamide (60 patients) or anthracyclines (37 patients) showed significant survival improvement overall (p less than 0.01) and among intermediate- and high-risk patients. Of 51 patients treated with human leukocyte alpha interferon (IFN-alpha), 36 (71%) had complete hematologic remission (CHR); 20 patients (39%) showed Ph suppression which was persistent in 13 for greater than 21 months. Survival was better in patients obtaining remission with IFN-alpha. Recombinant gamma interferon (IFN-gamma) was also active in chronic myelogenous leukemia. Therapy with combined IFN-alpha + IFN-gamma has been initiated. Compared to the expected survival, the observed survival is favorable for IFN-alpha and the combined chemotherapy and IFN-alpha programs. Future therapeutic trials will incorporate initial IFN therapy followed by cyclic intensive chemotherapy at 6-month intervals and IFN maintenance between chemotherapy cycles.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Hematologic response of four patients with smoldering acute myelogenous leukemia to partially pure gamma interferon.

In vitro and in vivo studies were conducted to obtain basic information on the activity of gamma interferon (IFN-gamma) in acute myelogenous leukemia (AML). In a selected case of AML, recombinant IFN-gamma, but not IFN-alpha, induced differentiation of primary leukemic blasts in vitro. Similarly, IFN-gamma inhibited leukemic colony formation in vitro. This contrasted with IFN-alpha which was inactive. In one case of AML (M2), partially purified IFN-gamma given intravenously caused a shift of the WBC profile from immature blasts to maturing myeloid cells and neutrophil granulocytes. Intravenous IFN-gamma treatment of another patient who had AML as a second malignancy resulted in a complete hematologic remission, normalization of marrow granulocyte-macrophage colony-forming cell in vitro growth, and conversion of marrow cytogenetics from 95% hyperdiploid clone with complex abnormalities into 100% diploid. The results indicate a potential use of IFN-gamma in the treatment of selected patients with AML and the possibility of in vitro pretreatment evaluation of these patients' leukemic response to IFNs.

Adult↗
PubMed1987

Molecular analysis of interferon-induced suppression of Philadelphia chromosome in patients with chronic myeloid leukemia.

Treatment with recombinant human interferon alpha-A (Roferon-A) is associated with stable suppression of the population of cells that display the Philadelphia (Ph1) chromosome in some patients with chronic myelogenous leukemia (CML) as defined by cytogenetic analysis. Southern blot analyses employing a 3' breakpoint cluster region (bcr) probe (Pr-1) were performed to confirm a complete suppression of the Ph1+ chromosome-positive clone of cells at the DNA level. The complete disappearance of rearranged restriction fragments of the bcr gene, which were a characteristic of the disease prior to Roferon-A therapy, was accompanied by the restoration of normal bone marrow and achievement of durable ongoing complete remission for 9 and 6 months, respectively, in two patients with Philadelphia-positive (Ph1+) CML. Molecular analysis is a valuable probe for monitoring the clinical course of disease in patients with Ph1+ CML.

Adult↗
PubMed1987

Diversity of the effect of recombinant tumor necrosis factors alpha and beta on human myelogenous leukemia cell lines.

In vitro characteristics of response to recombinant tumor necrosis factors alpha (rTNF-alpha) and beta (rTNF-beta) were studied in six human myelogenous leukemia cell lines. Heterogeneity of the response to rTNF was observed, and one line (K562) was resistant. No enhancement of cell growth was noted in any cell line. The dose-response curves for rTNF-alpha were characteristically sigmoid, the maximum inhibitory effect occurring between 25 and 200 ng/mL. Nonresponsiveness within this range indicated resistance that could not be overcome, even with very high doses of rTNF alpha. A similar response of sensitive and resistant lines occurred after exposure to rTNF-beta. The clonogenic cells were more sensitive than the overall population to the action of rTNF alpha, and prolonged exposure was necessary for manifestation of the effect. Concomitant exposure to recombinant interferon-alpha (rIFN-alpha) increased the response of two cell lines to rTNF-alpha, but no clear synergistic action could be demonstrated. The addition of rIFN-gamma was without effect. Variations in the rTNF-alpha-induced proliferative response could not be explained by differences in the number of binding sites per cell or their affinity for rTNF-alpha. That the clonogenic cells showed a higher sensitivity than the whole population might indicate a preferential effect on more primitive, actively proliferating cells with high growth potential.

Cell Division↗
PubMed1987

Biologic therapy of chronic myelogenous leukemia.

In a study using human IFN-alpha, 36 of 51 patients with chronic phase CML achieved a complete hematologic remission. More significantly, 20 patients showed suppression of Ph-positive metaphases with reappearance of cells with normal karyotype. To date, the authors have treated 44 chronic phase CML patients with recombinant IFN-alpha as their frontline biologic therapy with similar hematologic and cytogenetic responses. Gamma interferon is active against CML but less so than IFN-alpha. Chemotherapy followed by IFN-alpha also shows promise. Interferons have produced only limited responses in terminal phase CML patients.

Blast Crisis↗
PubMed1987

Clinical investigation of human alpha interferon in chronic myelogenous leukemia.

Fifty-one patients with previously untreated or minimally treated chronic myelogenous leukemia in chronic phase received human alpha interferon 3 to 9 X 10(6) units intramuscularly (IM) daily until complete hematologic remission, then at doses ranging from 3 X 10(6) units every other day to 9 X 10(6) units daily. Forty-one (80%) patients achieved a hematologic response, 36 (71%) of them attaining a complete hematologic remission with normal peripheral WBC and differential counts. Responding patients showed continuous but slow normalization of several other blood and marrow parameters including platelet counts, serum lactic dehydrogenase and B12 levels, and marrow cellularity and maturation index. Suppression of the Philadelphia chromosome on serial cytogenetic studies of marrow metaphases was documented in 20 of the 36 patients who achieved complete hematologic remission (56%; 39% of total group), eight of whom (22%) had a decrease of the Philadelphia chromosome-positive metaphases to less than 35%. These changes were persistent for 6 months or longer in 18 patients, seven of whom had continuous suppression of the Philadelphia chromosome to less than 90% for a median of 30+ months (range 21+ to 39+ months). After a median follow-up period of 37 months, 25 patients remain in continued disease control with interferon therapy. The projected 3-year survival rate is 76%, with a yearly death rate of 6%, 9%, and 9% in the first 3 years. Response, Philadelphia chromosome suppression, and survival were significantly better among patients in the low-risk category compared to intermediate- and high-risk categories, as defined by a multivariate analysis-derived prognostic model. The projected 3-year survival rate was 94% for patients who achieved a complete hematologic remission on interferon therapy and 45% for those who did not. Thirteen patients have developed blastic crisis, six with lymphoid and three with undifferentiated morphology. We conclude that human leukocyte alpha interferon effectively controls chronic myeloid leukemia and allows reappearance of diploid hemopoietic cells in some patients.

Aged↗
PubMed1986

Rearrangement and enhanced expression of c-myc oncogene in fresh tumor cells obtained from a patient with acute lymphoblastic leukemia.

Both enhanced and altered expressions of cellular oncogenes have recently been implicated in specific forms of human malignancy (for review: [2, 8]). The fact that certain human tumors have characteristic chromosomal translocations has led to the hypothesis that specific cellular oncogenes may be 'activated' in these genetic recombinations. In a number of human undifferentiated B-cell lymphoma (UBL) cell lines carrying the t(8:14) translocation it has been shown that the human c-myc gene is located on the region of chromosome 8 (8q24), which is translocated to the immunoglobulin heavy-chain (IHC) locus on chromosome 14 [7, 24]. We report here the molecular cloning of the recombination site between c-myc and IHC in fresh uncultured cells obtained from a patient with rapidly progressive and fatal acute lymphoblastic leukemia. The translocation was associated with an enhanced c-myc expression in the tumor cells of this patient.

Base Sequence↗
PubMed1986

Difluoromethylornithine and leukocyte interferon: a phase I study in cancer patients.

Difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, and human leukocyte interferon (IFN-alpha) have synergistic anti-tumor activities in vivo in B 16 melanoma and in vitro against several human cancer cell lines. We have, therefore, carried out a phase I combination study with DFMO plus alpha interferon in the following manner: DFMO was maintained at a steady dose for the first four levels, 1.5 g/m2 every 6 hr. IFN-alpha was given in 100% increments ranging from 0.4 X 10(6)U/m2 to 3.2 X 10(6)U/m2 i.m. daily. At the fifth dose level both IFN-alpha and DFMO were raised by 100 and 50% respectively. From levels one through four the combination was well tolerated with no dose interruptions required because of G.I. toxicity or myelosuppression. However, at dose level 5, one-third of the patients required dose cessation and decrease due to nausea, vomiting and diarrhea. We conclude that for phase II studies the maximal tolerated dose is 3.2 million units of IFN-alpha/m2 and 1.5 g/m2 of DFMO every 6 hr. Of 12 patients with metastatic melanoma, 2 had partial remissions lasting 58+ and 36+ weeks. Two additional patients had minor responses lasting 29 and 32+ weeks. Minor responses were observed in a patient with colon carcinoma and a patient with renal carcinoma. The clinical activity of the combination is currently being pursued in a phase II study among patients with metastatic malignant melanoma.

Adult↗
PubMed1986

Chronic myelogenous leukaemia: haematological remissions with alpha interferon.

Twenty-seven consecutive patients with previously untreated, or minimally treated benign phase Philadelphia-chromosome-positive, chronic myelogenous leukaemia (CML) were treated with partially purified human leucocyte (alpha) interferon; 24 of the 27 patients responded to therapy achieving either haematological remission (20 patients) or partial haematological remission (four patients). In the responding patients the peripheral white blood cells declined from a median of 89.6 X 10 X 10(9)/l to 4.5 X 10 X 10(9)/l. The serum lactate dehydrogenase declined from a mean of 8.36 Katal/l (492 mu/ml) to 2.8 Katal/l (165 mu/ml), and the vitamin B12 levels declined from 1492 pg/ml to 838 pg/ml. Fifteen patients had splenomegaly. The spleen size normalized in four and decreased by a median of 30% in 10 additional patients. The bone marrow cellularity fell from a median of 100% to a median of 62%. In seven of the 24 responding patients, followed for greater than or equal to 6 months, the percentage of Ph1-positive cells in the bone marrow declined to a median of 70% (range 5-75%). Alpha interferon was found to be an effective therapeutic agent for controlling the myeloid proliferation in CML, and in partially restoring the nonclonal haematopoietic cells in some of the patients.

Adult↗
PubMed1986

C-sis and C-abl expression in chronic myelogenous leukemia and other hematologic malignancies.

Cellular oncogenes have been localized at the breakpoints of characteristic chromosomal rearrangements occurring in certain hematologic malignancies. This has been reported to result in aberrant expression of the involved oncogenes. Over 90% of chronic myelogenous leukemia (CML) is characterized by a reciprocal translocation that brings c-abl from chromosome 9 to chromosome 22, and c-sis from chromosome 22 to chromosome 9. To investigate the possible role of these two oncogenes in the leukemic process, we studied their expression in a number of fresh samples obtained from patients with various forms of leukemia, by Northern blot analysis using c-onc probes. Seven of 24 samples obtained from patients with either CML or chronic myelomonocytic leukemia expressed a normal 4.0-kilobase (kb) c-sis transcript. C-sis expression was found only in the accelerated/blast phases but not in the chronic phase of CML. All of the CML Philadelphia chromosome-positive (Ph1+) samples expressed an aberrant 8-kb c-abl transcript. The expression of c-sis in

Humans↗