Biomedical subjects
P Bunn
Publications and source records attributed to P Bunn.
A phase II multicenter study of CAMPATH-1H antibody in previously treated patients with nonbulky non-Hodgkin's lymphoma.
CAMPATH-1H is a humanized antilymphocyte monoclonal antibody (mAb) directed against the CD52 antigen expressed on normal and malignant lymphocytes. We report the results of a multicenter phase II trial using intravenous CAMPATH-1H in previously treated patients with nonbulky non-Hodgkin's lymphoma (NHL) or minimal residual NHL. Sixteen previously treated patients with nonbulky NHL and two patients with minimal residual NHL, were treated with CAMPATH-1H. Changes in peripheral blood lymphocyte subsets were analyzed by multiparameter flow cytometric techniques in eleven patients. The 18 patients enrolled in the studies received CAMPATH-1H for a median duration of 6 weeks (range, 3 to 14 weeks), and a median cumulative dose of 470 mg (range, 180 to 1185 mg). Two of the sixteen patients with nonbulky NHL achieved a complete response (CR) and one patient achieved a partial response (PR). One of the two patients with minimal residual NHL achieved a molecular CR. Infusional complications were seen with the majority of patients but were more common with initial infusions. Significant hematologic toxicity was also observed with grade (3/4) thrombocytopenia (n=10), grade (3/4) neutropenia (n=4) and grade 3 anemia (n=3). Due to excessive infectious complications observed with the patients enrolled, the trials were terminated early. Anti-tumor activity was demonstrated in a small subset of previously treated low-grade lymphoma patients with nonbulky or minimal residual disease. Future studies evaluating the effect of different drug schedules, modes of mAb administration, and concurrent use of prophylactic antibiotics/antiviral/antifungal agents to optimize anti-tumor activity and limit infectious toxicities are planned.
Altered HOX and WNT7A expression in human lung cancer.
HOX genes encode transcription factors that control patterning and cell fates. Alterations in HOX expression have been clearly implicated in leukemia, but their role in most other malignant diseases remains unknown. By using degenerate reverse transcription-PCR and subsequent real-time quantitative assays, we examined HOX expression in lung cancer cell lines, direct tumor-control pairs, and bronchial epithelial cultures. As in leukemia, genes of the HOX9 paralogous group and HOXA10 were frequently overexpressed. For HOXB9, we confirmed that elevated RNA was associated with protein overexpression. In some cases, marked HOX overexpression was associated with elevated FGF10 and FGF17. During development, the WNT pathway affects cell fate, polarity, and proliferation, and WNT7a has been implicated in the maintenance of HOX expression. In contrast to normal lung and mortal short-term bronchial epithelial cultures, WNT7a was frequently reduced or absent in lung cancers. In immortalized bronchial epithelial cells, WNT7a was lost concomitantly with HOXA1, and a statistically significant correlation between the expression of both genes was observed in lung cancer cell lines. Furthermore, we identified a homozygous deletion of beta-catenin in the mesothelioma, NCI-H28, associated with reduced WNT7a and the lowest overall cell line expression of HOXA1, HOXA7, HOXA9, and HOXA10, whereas HOXB9 levels were unaffected. Of note, both WNT7a and beta-catenin are encoded on chromosome 3p, which undergoes frequent loss of heterozygosity in these tumors. Our results suggest that alterations in regulatory circuits involving HOX, WNT, and possibly fibroblast growth factor pathways occur frequently in lung cancer.
Bradykinin antagonists: present progress and future prospects.
Bradykinin (BK) antagonist peptides have been powerful tools for delineating roles of kinins in both normal and pathological physiology and offer promise of drug development for a variety of inflammatory conditions and cancers. At the present time, potent peptide antagonists are available that are either specific for BK B1 or B2 receptors, or are effective on both receptor classes. Non-peptide BK B2 antagonists are now being announced and are under investigation in several companies. The best peptide B1-B2 peptide antagonist is stable against all kininases, is orally available, and has a very long lifetime in vivo. Certain dimers of this antagonist, as well as several smaller molecules, are active against several cancers, both in vitro and in vivo.
5th I.A.S.L.C. Lung Tumor Biology Workshop, August 13-17, 1996, Ermatingen, Switzerland.
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Fifth I.A.S.L.C. Lung Tumor Biology Workshop, August 13-17, 1996, Ermatingen, Switzerland.
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Novel bradykinin antagonist dimers for the treatment of human lung cancers.
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Combined modality therapy in small cell lung cancer.
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Aggressive non-Hodgkin's lymphomas in AIDS: the University of Colorado experience.
The authors performed this retrospective study to further investigate the relationship between non-Hodgkin's lymphoma (NHL) and the Acquired Immunodeficiency Syndrome (AIDS). From January 1984 through December 1987 all cases of AIDS and NHL diagnosed at the University of Colorado affiliated hospitals were identified and submitted to chart review. Twenty-five patients fulfilled criteria for the diagnosis of AIDS and 24 had biopsy-proven NHL, an additional patient met criteria for the diagnosis of primary central nervous system lymphoma and was included in the analysis. All patients had known risk factors for the development of AIDS. Of the biopsy proven tumors, 23 were categorized as high grade. Most patients (68%) presented with stage IV disease and 92% with extra nodal involvement. Median survival was 5 months and the cause of death was most often progressive lymphoma and/or opportunistic infections. These data are similar to previously published series. Clinical trials to evaluate effective treatment are warranted.
Heterogeneity of cell surface antigen expression of human small cell lung cancer detected by monoclonal antibodies.
Using immunohistochemistry, radiobinding, and indirect immunofluorescence assays, seven distinct cell surface antigens, detected by monoclonal antibodies, were analyzed for the degree of homogeneity or heterogeneity of antigen expression on a panel of human small cell lung cancers. The panel included 7 tumors taken directly from patients, 21 established cell lines (9 of which were derived from different metastatic sites of 3 patients), and 33 clonal derivatives of 3 lines. With all assays, considerable heterogeneity of antigen expression between tumors from different patients was observed. In both fresh tumors and in cell lines, as well as in cell lines established from different metastatic sites in an individual patient, we observed intratumor heterogeneity finding antigen positive and negative cells and variation in antigenic density, by immunohistochemistry and indirect immunofluorescence assays. Antigenic expression was not cell cycle dependent. In addition, when cell lines or patient samples expressing antigen positive and antigen negative tumor cells were cloned, heterogeneity of antigenic expression was still present in the clonal lines. This suggests that either the expression of the antigen was not heritable and/or the ability to regenerate antigenic heterogeneity is an intrinsic property of the tumor cells. The heterogeneity of antigen expression on lung cancer cells has significant implications for the use of these and other monoclonal antibodies in the study and therapy of lung cancer.
Markedly decreased expression of class I histocompatibility antigens, protein, and mRNA in human small-cell lung cancer.
We have found markedly deficient expression of the class I major histocompatibility antigens HLA-A,B,C and beta 2m on human small-cell lung cancer (SCLC) lines and fresh tumor samples. The deficit of HLA-A,B,C and beta 2-microglobulin (beta 2m) antigen expression was demonstrated with both radiobinding assays and indirect immunofluorescence assays. Immunoprecipitation of metabolically labeled cells with antibodies to class I antigens showed most SCLC lines to have synthesized almost no beta 2m and HLA-A,B,C proteins. Northern blot analysis, using human HLA-A,B, and beta 2m cDNA probes, showed that almost all SCLC lines tested had markedly decreased amounts of HLA and beta 2m mRNA, but both gene products could be induced with interferon treatment of SCLC lines. We conclude that human SCLC, in contrast to other lung cancer types, is characterized by greatly reduced transcription of HLA-A,B,C and beta 2m genes, which suggests the existence of a mechanism for evading the host immune response to the tumor and of an E1a-like product in this type of tumor cell.
Differential metabolism of deoxyribonucleosides by leukaemic T cells of immature and mature phenotype.
Experimental evidence has indicated that T lymphoblasts are more sensitive to deoxynucleoside toxicity than are B lymphoblasts. These data have led to the use of purine enzyme inhibitors as selective chemotherapeutic drugs in the treatment of T cell malignancies ranging from T cell acute lymphoblastic leukaemia to cutaneous T cell lymphomas. We have compared the toxicities of 2'-deoxyadenosine, 2'-deoxyguanosine, and thymidine for T cell lines derived from patients with T cell acute lymphoblastic leukaemia with those for mature T cell lines derived from patients with cutaneous T cell leukaemia/lymphoma. We have found that both deoxynucleosides are far less toxic to the mature T cell lies than to T lymphoblasts and that the mature cells accumulate much lower amounts of dATP and dGTP when exposed to deoxyadenosine and deoxyguanosine, respectively. Similar studies performed on peripheral blood cells from patients with T cell leukaemias of mature phenotype and on peripheral blood T cells demonstrate similar low amounts of deoxynucleotide accumulation. Measurements of the activities of several purine metabolizing enzymes that participate in deoxynucleoside phosphorylation or degradation do not reveal differences which would explain the toxicity of deoxynucleosides for immature, as compared to mature, T cells. We conclude that deoxynucleoside metabolism in leukaemic T cells varies with their degree of differentiation. These observations may be relevant to the design of chemotherapeutic regimes for T cell malignancies.
Cell surface differentiation antigens of the malignant T cell in Sezary syndrome and mycosis fungoides.
Using a panel of monoclonal antibodies and rabbit heteroantisera, we have studied the cell surface markers of peripheral blood (PB) Sezary cells from six patients with mycosis fungoides or Sezary syndrome, disease grouped within the spectrum of cutaneous T cell lymphomas (CTCL). Furthermore, we have studied two cell lines (Hut 78 and Hut 102) derived from malignant Sezary T cells from CTCL patients. The monoclonal antibody 3A1 defines a major human PB T cell subset (85% of PB T cells) while the antigen defined by the monoclonal antibody 4F2 is present on a subset (70%) of activated PB T cells and on circulating PB monocytes. In contrast to normal subjects in whom 60-70% of circulating PB mononuclear cells were 3A1(+) T cells, PB mononuclear cells from six CTCL patients studied had an average of only 10.6+/-3.2% 3A1(+) T cells. Whereas 85% of E-rosette positive cells from normal individuals were 3A1(+), virtually all E-rosette positive T cells from the Sezary patients were 3A1(-). Two patients with high numbers of circulating Sezary T cells had both aneuploid and diploid PB T cell populations present; after separation of PB T cells into 3A1(+) and 3A1(-) cell suspensions, all 3A1(-) cells were found to be aneuploid. In contrast to normal resting PB T cells which were 4F2(-), all PB Sezary cells were 4F2(+), suggesting a state of activation. The 3A1 antigen was on a variety of acute lymphoblastic leukemia T cell lines (HSB-2, RPMI-8402, MOLT4, CEM) but was absent on the Hut 78 and Hut 102 Sezary T cell lines. Using rabbit anti-human T and anti-human Ia (p23, 30) antisera, we found that all malignant Sezary PB cells tested were killed by anti-T cell antiserum plus complement but not by anti-Ia plus complement. In contrast, Sezary cell lines Hut 78 and 102, were killed by both anti-T cell antiserum and anti-Ia plus complement. Similar to 3A1(-) normal PB T cells, 3A1(-) Sezary PB T cells proliferated poorly to phytohemagglutinin and concanavalin A. However, 3A1(-) Sezary T cells were able to provide T cell help towards pokeweed mitogen-induced in vitro B cell immunoglobulin synthesis, an immunoregulatory function limited to 3A1(+) T cells in normal subjects.Thus, the 3A1 antigen is present on 85% of normal PB T cells, and on most T-acute lymphoblastic leukemia lines tested; in contrast the 3A1 antigen is not present on the majority of circulating malignant Sezary PB T cells nor on T cell lines derived from malignant Sezary T cells. The lack of expression of the 3A1 antigen may be associated with malignant transformation of T cells in CTCL and may be an important marker for tracing the clonal origin of the malignant Sezary T cell.
Cytogenetic abnormalities in patients with cutaneous T-cell lymphomas.
Cytogenetic studies were conducted in 36 patients with histologically confirmed cutaneous T-cell lymphomas at the National Cancer Institute-Veterans' Administration Medical Oncology Branch. Aneuploidy was observed in 17 (85%) of the 20 lymph nodes, 23 of the 36 peripheral bloods, and five of the 31 bone marros. Aneuploidy was frequently present even when tumor cells were not noted histologically. These findings indicate that cytogenetic studies can be very useful for the early detection of malignant cells even when only a few such neoplastic cells are encountered. In this study, the cytogenetic abnormalities found to be characteristic of the disease included extensive aneuploidy, with both numerical and structural aberrations, a wide range of heteroploidy, and a lack of clone formation until the terminal phase of the disease. The numerical changes most frequently involved chromosomes 8, 15, 11, 17, 21, and 10, and the chromosome most involved in structural aberrations was chromosome 1, followed by chromosomes 7, 14, 16, 6, and 9. Cytogenetic studies demonstrate that neoplasia in the cutaneous T-cell lymphomas commonly involves areas beyond the skin.
Letter: Meningeal involvement in lymphoma.
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Case reports and technical note. Nocardia asteroides meningitis. A case successfully treated with large doses of sulfadiazine and urea.
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Penicillins in the treatment of bacterial pneumonia.
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