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Biomedical subjects

B Clarkson

Publications and source records attributed to B Clarkson.

At least 91 records · Page 5Linked to original sources
PubMed1984

Activation of a translocated c-myc gene: role of structural alterations in the upstream region.

The translocated c-myc gene in AW-Ramos, a Burkitt lymphoma cell line carrying the 8;14 translocation, is expressed at 2- to 5-fold higher levels than c-myc in lymphoblastoid cell lines. The translocation event has joined c-myc to the IgM switch region. As a consequence, a recently identified immunoglobulin transcriptional enhancer element is not linked to the translocated c-myc gene. Chromosomal recombination occurs approximately equal to 340 nucleotides upstream of the c-myc 5' cap site, leaving all three c-myc exons intact. The nucleotide sequences of the two coding exons in the translocated c-myc gene are identical to those of the normal c-myc gene. Nucleotide sequence analyses of the first, noncoding c-myc exon and of the region between this exon and the chromosomal recombination point reveal two single-base differences from normal c-myc. Our data indicate that altered expression rather than an altered gene product is responsible for c-myc activation in AW-Ramos cells and that this is a result of either loss of regulatory sequences located greater than 340 nucleotides upstream of c-myc or disruption of normal c-myc regulation by one or both base substitutions. Alternatively, unidentified enhancer-like sequences in the Ig locus may alter the expression of c-myc.

Base Sequence↗
PubMed1984

Primary therapy of acute promyelocytic leukemia: results of amsacrine- and daunorubicin-based therapy.

Remission rates for patients with acute promyelocytic leukemia (APL) have improved with the use of anthracyclines and proper management of disseminated intravascular coagulopathy. In a prospective randomized trial of chemotherapy in patients with acute nonlymphoblastic leukemia, there were 16 patients with APL. All 7 of the patients receiving the amsacrine-containing regimen and 5 of 9 receiving the daunorubicin-containing regimen achieved a remission. All patients, except 2 of the 3 who underwent bone marrow transplantation, remain alive and in remission from 1+ to 25+ mo. Amsacrine is an effective replacement for daunorubicin in the treatment of APL, and its use does not compromise the favorable remission duration characteristic of APL.

Adult↗
PubMed1983

Philadelphia chromosome and terminal transferase-positive acute leukemia: similarity of terminal phase of chronic myelogenous leukemia and de novo acute presentation.

Twenty-eight patients with Philadelphia chromosome (Ph1)--positive and terminal transferase (TdT)--positive acute leukemia (AL) were treated with intensive chemotherapy used for adult acute lymphoblastic leukemia (L-10 and L-10M protocols). Fifteen patients had a documented chronic phase of Ph1-positive chronic myelogenous leukemia preceding the acute transformation (TdT + BLCML) while the remaining 13 patients did not (TdT + Ph1 + AL). An overall complete remission (CR) rate of 71% was obtained with a median survival of 13 months in the responders. Clinical presentation, laboratory data, cytogenetics, response to treatment, and survivals of the two groups of patients are compared. These results appear to be similar, suggesting a common or closely related origin. Since the overall survival of those receiving chemotherapy maintenance is poor, three patients underwent allogeneic bone marrow transplantation (BMT) from histocompatibility leukocyte antigen--matched siblings after they achieved CR. One of them is a long-term survivor (35 + months) with a Ph1-negative bone marrow. New techniques such as BMT should be considered in young patients with a histocompatibility leukocyte antigen--compatible sibling once a CR has been achieved.

Acute Disease↗
PubMed1983

Prognostic significance of receptors for the third component of complement an heavy chain phenotype in diffuse B-cell lymphomas.

As part of a larger study to determine the prognostic significance of cell marker phenotype in diffuse lymphomas, 51 patients with monoclonal B-cell lymphoma were further characterized by receptors for C3 (EAC rosettes) as well as heavy and light chain phenotypes. Patients with greater than 10% EAC rosette-forming cells were found to have a statistically significant longer survival than those with less than 10% EAC rosettes (p = 0.005). A similar trend in survival duration was found for patients whose cells expressed mu heavy chain on their surfaces when compared to those with gamma heavy chain on their cell surfaces (p = 0.05). No difference was observed for light chain phenotype. No correlation was observed between these prognostic groups and any of the three most frequently used histologic classifications (i.e., Rappaport, Lukes, Kiel).

Adult↗
PubMed1983

Proliferative potential of subpopulations of granulocyte-macrophage progenitor cells in normal subjects and chronic myelogenous leukemia patients.

The studies described compare the subpopulations of granulocyte-macrophage progenitor cells present in normal marrow with those derived from the marrow of patients with Ph1-positive chronic myelogenous leukemia (CML). The subpopulations were separated on the basis of size by velocity sedimentation and measured for their proliferative capacity by the colony formation technique. A pattern of development of colonies in the individual fractions was obtained by assaying the absolute number of colonies present at time intervals from 3 to 21 days. The number of colonies present at 3 days was taken as 100%, and the percentage of increase or decrease from this value was determined on subsequent days. In the fractions containing the most rapidly sedimenting large cells, the pattern of development of colonies derived from normal and CML marrow was similar. The CML colony-forming units in culture (CFU-C) began to show a deviation from the normal CFU-C pattern of development in the fractions containing CFU-C intermediate in size, and this deviation became progressively more pronounced in the slowest sedimenting small cell fractions. In these latter fractions, the CFU-C derived from CML marrow decreased in number at a rate similar to those arising from the more rapidly sedimenting fractions. This is in contrast to CFU-C derived from normal marrow, which increased in number in the more slowly sedimenting fractions and in the intermediate fractions, remained constant in number, or decreased at a rate slower than those arising from the more rapidly sedimenting fractions. The most likely explanation for these findings is accelerated maturation of the early small granulocyte-macrophage progenitor cells in CML so that these cells show the same limited proliferative capacity as do the later larger progenitor cells.

Cell Division↗
PubMed1983

Phase I clinical trial of 13-cis-retinoic acid in myelodysplastic syndromes.

13-cis-Retinoic acid (13-cRA) induces maturation and differentiation of neoplastic myeloid cell lines in vitro. We conducted a phase I clinical trial of 13-cRA in patients with myelodysplastic syndromes (MDS), using a single daily oral dose schedule. Seventeen patients with MDS and one each with acute nonlymphoblastic leukemia and chronic myelogenous leukemia in blast crisis were treated with 13-cRA at doses ranging from 20 to 125 mg/m2/day. Hepatotoxicity was dose-limiting and was manifested by hyperbilirubinemia and increased SGOT levels. This effect was seen only at the highest dose level of 125 mg/m2/day and was completely reversible upon cessation of the drug. Other toxic effects were mild, and included cheilosis, hyperkeratosis, stomatitis, and elevation of serum triglyceride levels. Fifteen patients with MDS were evaluable for therapeutic response. Five patients showed improvement in hematologic parameters. These responses included normalization of bone marrow blast count and increases in leukocyte count, platelet count, and/or hemoglobin concentration. Responses were generally not seen until at least 3 weeks of therapy were completed. We conclude that further study of 13-cRA in myelodysplastic syndromes is warranted and recommend that future studies utilize a starting dose of 100 mg/m2.

Administration, Oral↗
PubMed1982

Effects of Hoechst 33342 on survival and growth of two tumor cell lines and on hematopoietically normal bone marrow cells.

Our objective in this investigation was to determine whether Hoechst 33342, which is widely recognized as a DNA specific fluorochrome for living cells, is in fact nontoxic and kinetically nonperturbing at dye concentrations required to achieve acceptable DNA distributions. Three cell types were tested: HeLa S-3; SK-DHL2, a human lymphoma cell line; and hematopoietically normal human bone marrow cells. In the third system, only the cloning efficiencies were determined. Results differed considerably for the different cell types. While HeLa cells yielded excellent DNA distributions and were almost completely resistant to the cytotoxic and cytokinetic effects of the dye, SK-DHL2 cells were highly sensitive to the fluorochrome even at dye concentrations which produced very poor DNA distributions. Human bone marrow cells were intermediate in their stainability and toxicity response, and acceptable DNA distributions could be obtained at the nontoxic dye concentration of 2.5 muM. Clearly, different cell types differ considerably with respect to their cytotoxic and kinetic responses to Hoechst 33342. In some cases it may not be possible to ensure adequate staining of the cells for flow cytometry without significantly altering their viability and/or proliferative behavior.

Benzimidazoles↗
PubMed1982

Combination chemotherapy of advanced chronic lymphocytic leukemia: the M-2 protocol (vincristine, BCNU, cyclophosphamide, melphalan, and prednisone).

The M-2 protocol (vincristine, cyclophosphamide, BCNU, melphalan, and prednisone) was administered monthly to 63 evaluable patients with advanced chronic lymphocytic leukemia. Complete remission (absence of all clinical and bone marrow evidence of leukemia) and partial response (greater than 50% decrease in organ enlargement and reduction of WBC count to below 15,000 x 10(6)/liter) were achieved in 17% and 44%, respectively, for a total response rate of 61%. The median survivals from therapy of patients achieving a CR, RR, or no response were 73+, 40, and 14 mo respectively. The median survival time from onset of treatment for stages II, III, and IV disease were 47, 20 and 19 mo, respectively, which was not statistically different from historical controls. However, when untreated patients are compared to this latter group, a significant survival advantage from diagnosis was found (p = 0.01), stressing the importance of prior therapy as the only unfavorable prognostic factor. Although complete remissions in CLL, as reflected in apparently normal bone marrow B-lymphocyte markers, can be induced wih acceptable morbidity, the majority of patients relapse after cessation of therapy. An alternative approach to the M-2 protocol will be needed to eradicate the disease.

Antineoplastic Agents↗
PubMed1982

Enrichment of hematopoietic progenitor cells (CFUC and BFUE) from human peripheral blood.

Granulocytic (CFUC) and erythroid (BFUE) progenitor cells have been rapidly purified from human peripheral blood approximately 140 fold by combining centrifugation on a density cushion and immunoadherence cell separation methods. An initial light density (d less than 1.071 g/cm3) mononuclear cell fraction, enriched for progenitor cells, was obtained by centrifugation of whole blood on a modified Ficoll-Hypaque density cushion. Cultures of the light-density cells gave cloning efficiencies (defined as the percentage of total cells plated) of 0.008% and 0.015% for CFUC and BFUE respectively. Further purification was achieved by negative selection whereby selective populations of immunocompetent cells were removed. Thus, B cells and monocytes (as well as up to 50% high affinity Fc receptor bearing cells) were simultaneously depleted by immunoadherence to plastic petri dishes coated with rabbit anti-human IgG. Leu-3a positive (helper) and Leu-2a positive (suppressor) T cells were then simultaneously depleted by an indirect "panning" method, whereby the T cell subsets were coated with the corresponding murine monoclonal antibodies prior to their removal by immunoadherence to plastic petri dishes coated with goat anti-mouse IgG. The final cell fraction, which contained approximately 2% of the initial light density cells were highly enriched for CFUC and BFUE, having cloning efficiencies of 0.37% (+/- 0.30) and 0.27% (+/- 0.24) respectively. Overall, the purification procedure used in the present study is relatively rapid, simple and reproducible. As such, it should provide a viable and convenient alternative approach to previously published methods for purifying hematopoietic progenitor cells from human peripheral blood.

Animals↗
PubMed1981

Treatment of acute nonlymphocytic leukemia in adults: response to 2,2-anhydro-1-B-D-arabinofuranosyl-5-fluorocytosine and thioguanine on the L-12 protocol.

Fifty-one adult patients with acute nonlymphocytic leukemia (excluding acute promyelocytic leukemia) were treated on the L-12 protocol. The L-12 differed from the preceding L-6 in that 2,2-anhydro-1-B-D-arabinofuranosyl-5-fluorocytosine (AAFC), replaced arabinosylcytosine (ara-C) together with 6-thioguanine (TG) for remission induction. Achievement of remission was followed by an extended 14-week multi-drug consolidation program. With this more intense regimen, an overall complete remission rate of 49% and a median remission duration of 23.7 months were achieved; these results were not significantly better than the 57% complete remission rate and 8.6 months median remission duration obtained with the L-6 regimen. Four year disease-free survival was 22% on the L-12 compared with 16% on the L-6 protocol. No relationship between prognosis and FAB classification was found on either the L-6 or the L-12 protocol.

Adolescent↗
PubMed1981

Cloning of fresh lymphoma cells.

We attempted to induce in vivo clonal growth of neoplastic lymphoid cells from fresh specimens of involved tissue from 22 patients with no-Hodgkin lymphoma (NHL). Conditioned media derived from two human B-lymphocyte tissue culture lines were tested for their ability to promote colony growth. In addition, we compared the incidence of colony induction to the flash-3H-thymidine labeling index (LI) of the cells in the tissues cultured. Successful colony induction occurred in three-tenths of the cases of diffuse histiocytic lymphoma and one-half of the cases of nodular lymphoma. Cloning efficiencies were low, ranging from 0.0003 to 0.04%. There was no apparent relationship between successful instances of cloning and LI. We have confirmed the observations of Jones et al that lymphoid tumor cells can be cloned from tissues involved by NHL using a soft agar system. The possibility of using such systems for clinical predictive assays of chemotherapeutic drug toxicity toward tumor cells of NHL is discussed. We conclude that further refinements of the assays are desirable before they can be applied to widespread clinical use.

Clone Cells↗
PubMed1981

Methods and clinical relevance of terminal deoxynucleotidyl transferase determination in leukemic cells.

Terminal deoxynucleotidyl transferase (TdT) is a unique DNA polymerase which is only found in immature cells of lymphoid lineage (pre-T/pre-B). Because of this restricted distribution of TdT, biochemical and immunofluorescence techniques have been employed to determine the distribution of TdT phenotypes in human leukemias and lymphomas, showing high levels of TdT in approximately 95% of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL), approximately 50% of patients with acute undifferentiated leukemia (AUL), approximately 10 of patients with acute nonlymphoblastic leukemia (ANLL), and approximately 30% of patients with chronic myeloid leukemia (CML) and other myeloproliferative (MPS) or myelodysplastic (MDS) syndromes in blast crisis. High levels of TdT activity are associated with a clinical response to remission inducing therapy with vincristine and prednisone in a high proportion of patients (50%-90%), irrespective of clinical and morphologic diagnosis. Preliminary studies furthermore suggest that TdT might serve as a sensitive indicator of subclinical disease in ALL in complete remission.

DNA-Directed DNA Polymerase↗