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Biomedical subjects

D L Longo

Publications and source records attributed to D L Longo.

At least 253 records · Page 14Linked to original sources
PubMed1992

Recombinant human growth hormone promotes human lymphocyte engraftment in immunodeficient mice and results in an increased incidence of human Epstein Barr virus-induced B-cell lymphoma.

Recombinant human growth hormone (rhGH) previously has been demonstrated to promote human or mouse T-cell engraftment in immunodeficient mice. We then wanted to examine long-term effects of rhGH on human cell engraftment in these mice. Mice with severe combined immune deficiency (SCID) were given human peripheral blood lymphocytes or human bone marrow cells and daily injections of rhGH (20 micrograms ip every other day). Upon later assessment for engraftment by flow cytometric analysis, it was determined that rhGH strongly promoted human T-cell engraftment in the thymus and spleens of these mice. However, there was considerable variability in both the incidence and extent of engraftment which appears to be due to donor-to-donor variation. Additionally, rhGH promoted B lymphomagenesis in these mice since long-term treatment of these xenogeneic chimeras with rhGH resulted in the increased incidence of human Epstein-Barr virus (EBV)-infected B-cell lymphoma. Thus, while rhGH can be used to optimize human T-cell engraftment in SCID mice, it also increases the likelihood of B-cell lymphoma generation when the donor is EBV infected. The results suggest that the activation of human T cells by rhGH results in an increased ability of these cells to traffic to the peripheral lymphoid organs of the SCID mice and results in a lymphoid microenvironment conducive to the outgrowth of EBV-transformed B lymphocytes.

Animals↗
PubMed1992

Hodgkin's disease.

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Hodgkin Disease↗
PubMed1992

Regulation of intracellular actin polymerization by prenylated cellular proteins.

Posttranslational modification by covalent attachment of polyisoprene intermediates to a carboxyterminal CAAX-box motif is required for the biologic function of proteins such as p21ras, the supergene family of ras-related proteins, nuclear lamins, and subunits of heterotrimeric G-proteins. Cells grown in the presence of lovastatin, which inhibits HMG-CoA reductase and prevents synthesis of intermediates required for protein prenylation, develop a round, refractile morphology. Our data indicate that this is due to the selective loss of actin cables without gross changes in the microtubular lattice or intermediate filament structure. Microinjection of a competitive peptide inhibitor of protein prenyltransferases into the cytoplasm of cells induces an identical change in morphology with loss of actin cables. Mevalonate (MVA) reverses the lovastatin-induced morphologic change by inducing a rapid repolymerization of actin cables with coincident reversion to the flat morphology. Furthermore, microinjection of farnesyl-pyrophosphate or geranylgeranyl-pyrophosphate into lovastatin-treated cells also results in rapid morphologic reversion. The morphologic reversion induced by MVA requires the presence of serum, and is independent of extracellular calcium. The addition of cycloheximide to the growth medium prevents lovastatin-induced loss of actin cables, and causes morphologic reversion of lovastatin-treated cells by a mechanism that is independent of MVA. A1F4- induces morphologic reversion in a manner indistinguishable from MVA. These data indicate that prenylated protein(s) play a critical role in regulating the state of intracellular actin, and that GGPP can rescue the lovastatin-induced morphologic phenotype in the absence of upstream intermediates of cholesterol biosynthesis. We have begun to dissect the signaling events that mediate this pathway.

Actin Cytoskeleton↗
PubMed1992

CD5 expression in B-cell small lymphocytic malignancies. Correlations with clinical presentation and sites of disease.

The authors examined the relationship between CD5 antigen expression and a nodal or extranodal presentation for three subtypes of low-grade non-Hodgkin's lymphoma: small lymphocytic (23 cases), small lymphocytic with plasmacytoid differentiation (10 cases), and lymphocytic lymphoma of intermediate differentiation (IDL) (29 cases). Antigen expression was studied by the avidin-biotin complex immunoperoxidase technique in frozen sections and correlated with expression of other B- and T-cell markers. Lack of CD5 expression was significantly associated with extranodal presentation among the over-all study group (p less than 0.001), as well as for those with small lymphocytic lymphoma and IDL, but not for those presenting with small lymphocytic lymphomas with plasmacytoid differentiation (p less than 0.21). Eleven patients presented exclusively with extranodal disease involving lung and respiratory tract, skin and subcutaneous tissue, salivary gland, stomach, conjunctiva, and uterus. All such lesions were CD5 negative and had been classified as small lymphocytic (four cases), small lymphocytic-plasmacytoid (four cases), and IDL (three cases). Retrospective review of these 11 cases demonstrated common histologic features described as characteristic of lymphomas of mucosa-associated lymphoid tissue (MALT). Two additional patients presented with disseminated nodal disease and involvement of gastrointestinal tract and oropharynx; both were CD5 positive. These findings support the concept that at least two antigenically distinct B-cell subpopulations may be involved in pathogenesis of low-grade small lymphocytic malignancies.

Antigens, CD↗
PubMed1992

Non-Hodgkin's lymphomas arising in patients successfully treated for Hodgkin's disease. A clinical, histologic, and immunophenotypic study of 14 cases.

We report on 14 patients who developed Hodgkin's disease (HD), were successfully treated, and subsequently developed non-Hodgkin's lymphoma (NHL). The median interval between the diagnosis of HD and the diagnosis of NHL was 136 months (range 11-336). The clinical features of the patients with HD were similar to other patients with HD. Results of biopsies showed 12 nodular sclerosis and one mixed cellularity; one was not further classified. Immunophenotypic studies in nine cases showed that the Reed-Sternberg (RS) and Hodgkin's (H) cells were LeuM1+ LCA-. The patients were treated for HD in a nonuniform manner: two received radiation therapy, four received chemotherapy, and eight received both modalities. The NHLs were usually extranodal (79%) with frequent presentation as an abdominal mass. According to the Working Formulation, six lymphomas were small noncleaved cell (four non-Burkitt's, two Burkitt's), three were diffuse large cell, and two were follicular and diffuse large cell. Three neoplasms were not classified: two lymphomas with plasmacytoid differentiation were placed in the intermediate and low-grade categories, respectively, and one neoplasm was a plasmacytoma. All 14 neoplasms had an immunophenotype typical of NHL of B-cell lineage and were LeuM1-. Seven of the 12 patients treated with combination chemotherapy experienced a complete remission of their NHL. We conclude that the clinical, histologic, and immunophenotypic findings of the NHLs in these patients are analogous to those of NHLs that occur in immunosuppressed patients, suggesting that immunodeficiency plays a role in the pathogenesis of NHLs arising after HD.

Adolescent↗
PubMed1992

Kappa B site-dependent activation of the interleukin-2 receptor alpha-chain gene promoter by human c-Rel.

The cis-acting control elements of the interleukin-2 receptor alpha-chain (IL-2R alpha) gene contain a potent kappa B-like enhancer whose activity can be induced by various mitogenic stimuli. Recent cloning of the p50 and p65 subunits of the kappa B-binding protein NF-kappa B complex revealed a striking sequence homology of these proteins with the c-rel proto-oncogene product (c-Rel). On the basis of this homology, we examined the potential role of c-Rel in controlling IL-2R alpha transcription. We now demonstrate that the recombinant human c-Rel protein binds to the kappa B element in the IL-2R alpha promoter and results in alteration of the DNA structure in the adjacent downstream regulatory elements containing the CArG box and the GC box. We found that human c-Rel can activate transcription from the IL-2R alpha promoter, but not the kappa B-containing human immunodeficiency virus type 1 promoter, upon cotransfection into Jurkat T cells. Furthermore, truncation of the carboxyl terminus of c-Rel results in a c-Rel mutant (RelNA) that (i) localizes exclusively in the nucleus and (ii) acts in synergy with wild-type c-Rel in activating transcription from the kappa B site of the IL-2R alpha promoter. Finally, induction of surface IL-2R alpha expression coincides with the induced levels of endogenous c-Rel and induced c-Rel binding to the IL-2R alpha kappa B site. Our study identified c-Rel as one component of the Rel/NF-kappa B-family proteins involved in the kappa B-dependent activation of IL-2R alpha gene expression. Furthermore, our results suggest that a Re1NA-like cellular factor (e.g., NF-kappa B p50 or p49 subunit) acts in synergy with c-Re1 during T-cell activation.

Base Sequence↗
PubMed1992

Phase I and II study of high-dose ifosfamide, carboplatin, and etoposide with autologous bone marrow rescue in lymphomas and solid tumors.

PURPOSE: High-dose chemotherapy produces durable disease-free remissions in a minority of patients with resistant lymphomas and solid tumors. In an attempt to improve on the available regimens, ifosfamide, carboplatin, and etoposide (ICE) were selected for a new high-dose regimen because of their favorable spectrum of nonhematopoietic toxicity and evidence of synergy in in vitro systems. PATIENTS AND METHODS: Forty-one patients with drug-resistant Hodgkin's and non-Hodgkin's lymphomas, and breast and testicular cancers were entered onto a phase I and II trial of a single course of ICE with autologous bone marrow rescue. Before transplantation, all patients received combination chemotherapy until maximal tumor response was achieved. RESULTS: Patients received total doses of ifosfamide from 10 to 18 g/m2, carboplatin from 0.9 to 1.98 g/m2, and etoposide from 0.6 to 1.5 g/m2 administered during a 4-day period, with a maximum-tolerated dose (MTD) of ifosfamide 16 g/m2, carboplatin 1.8 g/m2, and etoposide 1.5 g/m2. The dose-limiting toxicities included irreversible renal, cardiac, and CNS dysfunction. There were three toxic deaths (7%), and all occurred above the MTD. Thirteen patients who were treated at the MTD tolerated the regimen well; reversible renal dysfunction and grade 2 mucositis commonly were observed. Of 23 heavily pretreated patients with persistent disease at the time of transplant, 10 (43%) achieved complete remissions (CRs) and 11 (48%) achieved partial remissions (PRs). Hodgkin's and non-Hodgkin's lymphoma patients who were treated at or below the MTD had a median potential follow-up of 11.9 months, and 12-month progression-free survivals of 62% and 48%, respectively. CONCLUSION: High-dose ICE with bone marrow rescue was well tolerated with a high response rate, and should be considered for further testing.

Adult↗
PubMed1992

Conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin's disease after combination chemotherapy: the low probability for cure.

PURPOSE: The study was undertaken to evaluate clinical prognostic factors, probability of response to therapy, duration of response, and overall survival of patients with Hodgkin's disease relapsing from a chemotherapy-induced complete remission. PATIENTS AND METHODS: Study population comprised 107 patients with Hodgkin's disease treated with combination chemotherapy at the National Cancer Institute who relapsed after achieving a complete remission. RESULTS: Half of the relapses occurred within the first year of achieving complete remission; among patients in remission 5 years or longer, only 4% relapsed. The overall survival of the relapsed patients is projected to be 17% at 20 years, calculated from the date of relapse. Primary treatment regimen, presence of B symptoms, stage, sex, liver involvement, pleural involvement, marrow involvement, and histologic subtype did not affect the survival of relapsed patients. Only age at diagnosis (older or younger than 30 years) and length of initial remission (shorter or longer than 1 year) made a significant impact on survival. Patients whose initial remission was longer than 1 year had significantly higher complete response rates to salvage therapy, significantly more durable second remissions, and significantly longer survival than patients whose initial remission was shorter than 1 year. Survival beyond 11 years from relapse of patients with long initial remissions was 24%; for those with short initial remissions, 11% (P2 = .027). Despite the fact that with salvage therapy, patients with long initial remission had an 85% complete response rate to mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) with a disease-free survival of 45% at 20 years, acute leukemia and other treatment-related complications combined to lower the survival rate of this more favorable subset. CONCLUSIONS: These data with conventional-dose salvage therapy provide results for comparison with novel salvage approaches including myeloablative therapy with autologous marrow or peripheral-blood stem-cell support.

Adolescent↗
PubMed1992

Recent National Cancer Institute lymphoma trials of etoposide-containing combination chemotherapy.

Short-course prednisone/doxorubicin/cyclophospha- mide/etoposide-cytarabine/bleomycin/vincristine/methotrexate (ProMACE-CytaBOM) contains the same drugs as standard ProMACE-CytaBOM but is delivered weekly for 16 weeks rather than 2 weeks out of 3 for 18 weeks. This results in a significant increase in dose intensity, ranging from 27% to 65% for all drugs. A total of 46 patients have been treated with short-course ProMACE-CytaBOM. The overall complete response rate of 91% and relapse rate of 17% compares favorably with results obtained using standard ProMACE-CytaBOM (86% and 27%, respectively). Toxicity was slightly greater with short-course therapy, but in general the regimen was well tolerated. Further dose intensification is possible in eligible patients by dose escalating myelotoxic drugs. A second strategy for augmenting the dose intensity is to deliver the drugs by continuous intravenous infusion. Infusional chemotherapy with doxorubicin/etoposide/vincristine/oral prednisone/bolus cyclophosphamide (EPOCH) results in significant antitumor activity in heavily pretreated patients with chemotherapy-resistant Hodgkin's disease and non-Hodgkin's lymphomas. Complete responses or partial responses were seen in 91% of 21 evaluable patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Lymphomas.

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Hodgkin Disease↗
PubMed1992

Relationships between cdc2 kinase, DNA cross-linking, and cell cycle perturbations induced by nitrogen mustard.

M phase-promoting factor (MPF) consists of a p34cdc2 (cdc2) kinase and cyclin B complex which in its active form promotes G2 to M transition. The role of MPF in G2 arrest following DNA damage, however, has remained largely uncharacterized. We have investigated whether nitrogen mustard (HN2) interfered with either the formation of MPF or its activation. For this purpose, we measured cdc2 kinase activity relative to cdc2 and cyclin B protein turnover and the phosphorylation status of cdc2. Studies were performed in two exceptional human lymphoma cell lines, which differed in HN2 sensitivity by 5-fold (CA46, 50% growth-inhibitory dose = 1.0 microM; JLP119, 50% growth-inhibitory dose = 0.2 microM) but exhibited virtually identical DNA interstrand and DNA-protein cross-link exposure. Following HN2 treatment, CA46 cells ceased to enter mitosis and exhibited a marked delay in G2 phase. Failure to enter mitosis paralleled inhibition of cdc2 kinase. Inhibition was not due to decreased levels of cdc2 or cyclin B protein; rather, G2 arrest correlated with the accumulation of both tyrosine-phosphorylated cdc2 and cyclin B. These findings implied that G2 arrest resulted from a down-regulation of the processes that activate MPF. We also found that JLP119 cells, within a few hours of mitosis at the time of drug treatment, evaded checkpoint control and continued cell division unabated by DNA damage. Furthermore, despite similar DNA cross-link exposure, JLP119 cells within the window of checkpoint control were more susceptible to S phase delay than CA46 cells. Altered cell cycle responses correlated with the greater susceptibility of JLP119 cells to the cytotoxic effects of HN2.

CDC2 Protein Kinase↗
PubMed1991

Antineoplastic dolastatins: potent inhibitors of hematopoietic progenitor cells.

Dolastatins 10 and 15, isolated from the shell-less marine mollusk Dolabella auricularia, are potent antineoplastic agents with unknown myelotoxic effects in vivo. The goal of this study was to determine whether the dolastatins inhibit the proliferation of normal hematopoietic progenitor cells. Assays to test inhibition of colony formation and of cell proliferation were performed in vitro with bone marrow cell preparations enriched for progenitor cells and with progenitor cell lines, respectively, using varying drug concentrations and exposure times. Dolastatins 10 and 15 both inhibited human and murine bone marrow cell colony formation in a concentration-dependent manner, with the concentration required for half maximal inhibition ranging from 0.1 to 1 pg/mL for dolastatin 10 and from 10 to 100 pg/mL for dolastatin 15. These concentrations are 25-fold to 100-fold lower than the concentration required for antineoplastic activity. Complete inhibition of human bone marrow cell colony formation was observed at concentrations of 10-100 pg/mL for dolastatin 10 and 1000-10,000 pg/mL for dolastatin 15. Committed progenitor cells and multipotential progenitor cells were similarly inhibited. The magnitude of inhibition of human hematopoietic cell colony formation was dependent on pre-exposure time to dolastatins 10 and 15, with a reversible effect up to 8 hours and with a 24-hour preincubation resulting in maximal (100%) and irreversible inhibition. Dolastatin 10 at a concentration of 10-100 pg/mL limited the proliferation of six human and four murine hematopoietic progenitor cell lines, as measured by tritiated thymidine incorporation, to between 34% and 83% of that occurring in the absence of the drug. These results indicate that the dolastatins are potent inhibitors of normal hematopoietic progenitor cell proliferation.

Animals↗
PubMed1991

Effects of recombinant transforming growth factor-beta 1 on hematologic recovery after treatment of mice with 5-fluorouracil.

Transforming growth factor beta 1 (TGF-beta 1) has been shown to inhibit bone marrow colony formation after in vitro treatment as well as after in vivo administration to normal mice. These data suggest that TGF-beta might either protect, or further depress, progenitor cell levels in mice exposed to a cell cycle-active drug such as 5-fluorouracil (5FU). rTGF-beta 1 was administered repeatedly by either the i.v. or i.p. routes to mice during the hyperproliferative state of the bone marrow that occurs 7 to 9 days after the i.v. administration of 150 mg/kg 5FU. The formation of both multilineage and the more differentiated (CFU-c) colonies was inhibited by 20 to 40%/culture, and 66 to 93%/mouse. When multiple doses of rTGF-beta 1 were administered systemically immediately before the injection of 5FU, the resulting rebound in the number of CFU-c and multilineage colonies containing granulocyte, erythroid, megakaryocyte, and macrophage lineage colonies per culture was markedly inhibited by 30 to 77%, whereas the total number of CFU per mouse was inhibited up to 93%. This effect was maximal when rTGF-beta 1 was administered at daily doses of greater than or equal to 5 micrograms/mouse for at least 3 days. This inhibition of the recovery of the bone marrow from 5FU treatment induced by rTGF-beta 1 was a delayed transient response because by day 16 the progenitor cell numbers and bone marrow cellularity were identical to the 5FU-treated marrow controls.

Animals↗
PubMed1991

Selection of antigen-specific, idiotype-positive B cells in transgenic mice expressing a rearranged M167-mu heavy chain gene.

Flow cytometric analysis of antigen-specific, idiotype-positive (id+), B cell development in transgenic mice expressing a rearranged M167-mu gene shows that large numbers of phosphocholine (PC)-specific, M167-id+ B cells develop in the spleen and bone marrow of these mice. Random rearrangement of endogenous V kappa genes, in the absence of a subsequent receptor-driven selection, should give rise to equal numbers of T15- and M167-id+ B cells. The observed 100-500-fold amplification of M167-id+ B cells expressing an endogenous encoded V kappa 24]kappa 5 light chain in association with the M167 VH1-id transgene product appears to be an antigen driven, receptor-mediated process, since no amplification of non-PC-binding M167 VH1/V kappa 22, T15-id+ B cells occurs in these mu-only transgenic mice. The selection and amplification of antigen-specific, M167-id+ B cells requires surface expression of the mu transgene product; thus, no enhancement of M167-id+ B cells occurs in the M167 mu delta mem-transgenic mice, which cannot insert the mu transgene product into the B cell membrane. Surprisingly, no selection of PC-specific B cells occurs in M167-kappa-transgenic mice although large numbers of B cells expressing a crossreactive M167-id are present in the spleen and bone marrow of these mice. The failure to develop detectable numbers of M167-id+, PC-specific B cells in M167-kappa-transgenic mice may be due to a very low frequency of M167-VH-region formation during endogenous rearrangement of VH1 to D-JH segments. The somatic generation of the M167 version of a rearranged VH1 gene may occur in less than one of every 10(5) bone marrow B cells, and a 500-fold amplification of this M167-Id+ B cell would not be detectable by flow cytometry even though the anti-PC antibody produced by these B cells is detectable in the serum of M167-kappa-transgenic mice after immunization with PC.

Animals↗
PubMed1991

Prolonged, continuous treatment of hairy cell leukemia patients with recombinant interferon-alpha 2a.

Interferons are not curative in hairy cell leukemia (HCL), and retreatment is necessary in most patients whose therapy is stopped. In an attempt to maintain or improve responses, we administered recombinant interferon-alpha 2a (rIFN-alpha 2a) continuously to patients with HCL who initially responded to this therapy. Of 53 evaluable patients enrolled in this study, 32 have received rIFN-alpha 2a continuously for a median of 5 years. Patients received 3 million units of rIFN-alpha 2a subcutaneously (SC) daily for 6 months, followed, in responding patients, by the same dose three times weekly. Twenty-one patients (40%) discontinued IFN after a median of 29 months, seven of whom developed resistant disease in association with anti-IFN antibodies. Treatment produced high response rates: complete response plus partial response (CR + PR) = 40 of 53 (76%), CR + PR + minor response (MR) = 43 of 53 (82%), with no differences in response rates between patients with and without splenectomy. Sixteen patients who had MR at 18 months had PR with prolonged treatment, nine of whom had a significant further reduction in the hairy cell infiltrate in the bone marrow (BM). The median granulocyte and platelet counts have continued to increase and the median serum soluble interleukin-2 receptor (sIL-2R) level has continued to decrease with prolonged treatment. Two patients developed erythrocytosis that may be treatment related, but no other new toxicities were noted with prolonged treatment. We conclude that prolonged, continuous rIFN-alpha 2a treatment has acceptable toxicity, is not associated with late development of IFN resistance, and results in continued hematologic improvement with time on treatment.

Adult↗