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Biomedical subjects

F J Giles

Publications and source records attributed to F J Giles.

At least 91 records · Page 5Linked to original sources
PubMed1994

Interferon-alpha up-regulates bcl-2 expression and protects B-CLL cells from apoptosis in vitro and in vivo.

The bcl-2 oncoprotein, which is involved in the t(14,18) translocation, protects cells against apoptosis. We examined the effects of interferon-alpha (IFN-alpha) on bcl-2 protein expression and apoptosis in B-chronic lymphocytic leukaemia (B-CLL) cells. None of 12 patients with B-CLL examined expressed the t(14,18) translocation; however, all these, and seven other patients, expressed significant levels of bcl-2 protein. In vitro, IFN-alpha (500 U/ml over 18 h) increased bcl-2 expression on CLL cells (to 200 +/- 23% of control MCF, as determined by indirect immunofluorescence and flow cytometry, n = 10, P < 0.001). All of eight patients who received IFN-alpha (3 megaunits subcutaneously three times a week) demonstrated an increase in bcl-2 expression on circulating malignant cells. CLL cells undergo apoptotic cell death when cultured in vitro (35.6 +/- 10.3% DNA fragmentation after 18 h, n = 10). In the presence of IFN-alpha, however, DNA fragmentation was reduced to 6.6 +/- 5.8% (n = 10, P < 0.001). IFN-alpha also protected CLL cells against apoptosis induced by hydrocortisone and gamma irradiation (reducing DNA fragmentation from 63.9 +/- 12.6% to 10.8 +/- 4.5% and from 80 +/- 2.9% to 5.4 +/- 1.6%, respectively, P < 0.001 for both). The protective effect of IFN-alpha was dose dependent, and maintained for up to 24 h. Our data demonstrate that bcl-2 expression and apoptosis of CLL cells can be influenced by cytokines. In addition, it seems unlikely that the observed clinical responses to IFN-alpha in patients with CLL are due to a direct effect on the malignant cells.

Apoptosis↗
PubMed1994

Secondary myelodysplastic syndromes and leukemias.

Although therapy-related (secondary) myelodysplastic syndromes and acute nonlymphocytic leukemias are most frequently observed following therapy of Hodgkin's disease and non-Hodgkin's lymphoma, the therapy of acute lymphocytic leukemia, multiple myeloma, polycythemia vera, cancers of breast, lung, ovary, gastrointestinal tract, testis, and soft tissues is also associated with subsequent development of leukemia. A preceding myelodysplastic syndrome is observed in over 70% of patients who develop therapy-related leukemia, in contrast to patients with de novo leukemia in whom approximately 20% of patients have similar prodromal syndromes. Chemotherapeutic drugs--including alkylating agents, platinum analogs, and epipodophyllotoxins--and ionizing radiation have both been implicated in the etiology of secondary tumors. The median duration from time of chemotherapy or radiation therapy, or both, to diagnosis of secondary leukemia is 3 to 4 years. The risk for development of secondary leukemia is highest between 24 and 72 months following cytotoxic therapy, with a steady decline in incidence thereafter. Of those people who will develop secondary leukemia, approximately 6% of patients do so within the 1st year, whereas 15% of patients will not do so until more than 7 years from commencement of mutagenic therapy. We review here selected recent publications on clinical and therapeutic data in therapy-induced myelodysplasia and acute leukemia.

Antineoplastic Agents, Alkylating↗
PubMed1994

Multiple myeloma and other differentiated B-cell disorders.

Molecular genetic techniques that are used to define the myeloma precursor cell and find its origin are generating new insights into the biology of this generally incurable malignancy. In the absence of curative therapy, new techniques to distinguish between myeloma and more benign plasma cell disorders are particularly valuable. The increasing application of myeloablative therapy as early consolidation therapy is improving survival in myeloma. Interferon alpha maintenance therapy prolongs plateau phase in patients responding to conventional induction therapy and prolongs both remission duration and survival in patients who have received myeloablative consolidation therapy. Patients who show early resistance to induction chemotherapy may particularly benefit from myeloablative therapy. The role of allogeneic bone marrow transplantation in myeloma therapy remains undefined. Attempts to modulate cytotoxic drug resistance seem likely to be clinically successful in the near future. Insights into the roles of cytokines such as interleukin-1 and interleukin-6 will lead to new therapies. Clonal plasma cell expansion results in the plasma cell disorders including overt malignancy, multiple myeloma, plasma cell leukemia, solitary plasmacytoma of bone, or more indolent disorders including monoclonal gammopathy of undetermined significance. Selected important data on the biology and therapy of these disorders are highlighted.

B-Lymphocytes↗
PubMed1993

Recombinant interferon alfa 2a in the treatment of patients with early stage B chronic lymphocytic leukaemia.

18 patients with early stage, previously untreated B-CLL were given interferon alfa (IFN alpha) 2a. 3 MU thrice weekly, subcutaneously. The peripheral lymphocyte count decreased in all patients. Response was delayed in three patients until they had received a median of 5 months therapy, one of whom had an initial transient increase in lymphocytes. Two patients normalized their blood lymphocyte counts, but neither achieved complete remission (CR). Responses were transient in eight patients lasting a median of 5 months (3-21). Binding anti-IFN alpha antibodies were present in 9/17 patients tested (53%). Low titre binding antibodies (< 533 IBU/ml) were not associated with LHR, but high titre antibodies (> 4401 IBU/ml) were. Two of 12 patients assessed had a > 3 g/l increase in baseline serum IgG levels during IFN alpha therapy, one of whom reverted to pretreatment levels in association with LHR. Haematological toxicity was moderate, other than in two patients, one of whom developed autoimmune haemolytic anaemia and the other thrombocytopenia. We conclude that IFN alpha lowers the lymphocyte count in early stage CLL, that the response may be delayed and that anti-IFN alpha antibodies may play a role in a proportion of those in whom the response is transient.

Adult↗
PubMed1992

Prospective randomised study of double hemi-body irradiation with and without subsequent maintenance recombinant alpha 2b interferon on survival in patients with relapsed multiple myeloma.

Immediately before first hemi-body irradiation, 59 patients with relapsed multiple myeloma were randomised to receive or not to receive subsequent alpha-2b interferon maintenance. 13 patients (22%) [8 of 31 (26%) controls, 5 of 28 (18%) in the interferon arm] received single hemi-body irradiation alone due to progressive disease and/or persistent cytopoenias following the initial procedure. Mean time between upper and lower hemi-body irradiation was 69 days (range 35-294). Of 23 patients randomised to receive interferon and completing double hemi-body irradiation, 15 (65%) achieved peripheral blood counts adequate to allow interferon administration as per study criteria commencing at a mean 116 days (61-241) from time of study entry. The mean period of interferon therapy, starting at a mean 65 days (26-160) post second hemi-body irradiation, is 16.4 months (2-33.5). There was no significant difference in median survival durations (10 months) from time of initial radiotherapy between control and interferon patients.

Aged↗
PubMed1992

Resistance of chronic lymphocytic leukaemia cells to interferon-alpha generated lymphokine activated killer cells.

Recent studies have shown that, when used in early stage disease, interferon-alpha (IFN-alpha) can produce a fall in the number of malignant cells in the peripheral blood of patients with B-CLL. In this study, we investigated the effect of IFN-alpha on natural killer (NK) cell and lymphokine-activated cell (LAK) activity in patients with B-CLL. In vitro, IFN-alpha (500 U/ml for 18 hours) induced LAK activity in patients with B-CLL (27.7 +/- 9.9%, n = 20), and IL-2 (500 U/ml for 5 days) produced similar activity (35.9 +/- 8.8%, n = 7). Despite the induction of LAK activity by IFN-alpha and IL2 in patients with B-CLL, the malignant cells remained resistant to both allogeneic and autologous LAK effectors. NK activity in patients with B-CLL is also low (23.1 +/- 7.2%, n = 20), and B-CLL cells were resistant to NK cell activity. In cold target competition assays, CLL cells did not compete with labelled K562 or Daudi targets in the NK and LAK assays, suggesting that the malignant cells are not recognised by the effector cells, and this may be related to low level of expression of the adhesion receptors, LFA-1 and ICAM-1. Finally, CLL cells were also resistant to antibody dependent cell mediated cytotoxicity, but were susceptible to antibody dependent complement mediated lysis. These results suggest that it is unlikely that the effects of IFN-alpha in B-CLL are due to the enhancement of NK or LAK activity.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1992

Recombinant alpha 2B interferon in combination with oral chemotherapy in late chronic phase chronic myeloid leukaemia.

The place of alpha interferon (IFN) therapy in the treatment of chronic myeloid leukaemia (CML) is under intensive investigation at present. It is now established that as a single agent it can provide good disease control in the chronic phase and that cytogenetic responses will occur in a minority of patients. However its impact on long term survival has been less certain. Optimal haematological and cytogenetic results have to date been seen when IFN is used in the early phase of the disease, i.e. within one year of diagnosis. We have performed a prospective single arm study on the effect on survival of the addition of low dose IFN (9 mU/week) to conventional oral chemotherapy in patients who were at a median of 19 months from the initial diagnosis at the time of study entry. Comparison of this cohort with a control group of CML patients treated with oral chemotherapy only at the same participating institutions gave an estimated 72% reduction in the risk of death as a result of IFN therapy. Median survival for the IFN group has not been reached at 43 months compared with a median survival of 33 months for the chemotherapy alone group. These results suggest that the introduction of low dose IFN at any stage in the chronic phase may produce a worthwhile improvement in survival.

Antineoplastic Agents↗
PubMed1992

Cytokine induction of leucocyte adhesion molecule-1 (LAM- 1) expression on chronic lymphocytic leukaemia cells.

Leucocyte adhesion molecule 1 (LAM-1) participates in the binding of human leucocytes to high endothelial venules in peripheral lymph nodes. Other adhesion receptors which are involved include CD44 and the integrin family, CD11/CD18. In this study, B-cell chronic lymphocytic leukemia (B-CLL) cells were examined for the expression of these adhesion molecules, and for the way in which cytokines are able to modulate the levels of these receptors. B-CLL cells express significant but variable levels of LAM-1 and high levels of CD44. In contrast, these cells exhibit very low or absent amounts of surface CD11a, CD11b, or CD11c. Most CLL cells expressed no detectable levels of intercellular adhesion molecule-1 but some cases show levels of up to 30%. Following 24 h incubation with interferon alpha (500 U/ml), surface LAM-1 expression on peripheral blood E-negative cells from CLL patients rose to 330 +/- 127% of levels on control cells incubated with medium alone (n = 13, p less than 0.0005). Interleukin 4 (1 ng/ml) and interferon gamma (100 U/ml) also increased surface LAM-1 levels on these cells to 218 +/- 119% (n = 8, p less than 0.001) and 245 +/- 116% (n = 5, p less than 0.001) of control levels respectively. Induction of LAM-1 expression occurred over 48 h (greater than 50% of the increase was seen in the first 24 h) in a dose-dependent manner and required protein synthesis. The induction of LAM-1 expression on the malignant cells may, by altering the homing behaviour of these cells, relate to the reduction in peripheral leukaemic cells seen following treatment with interferon alpha in CLL.

Cell Adhesion Molecules↗
PubMed1991

Lymphocyte activation and serine-esterase induction following recombinant interleukin-2 infusion for lymphomas and acute leukaemias.

In this study we investigated the pattern of T lymphocyte changes in 16 adult patients with acute myeloid leukaemia (8), non-Hodgkin's lymphoma (4) and Hodgkin's disease (4) treated with continuous infusion of recombinant interleukin-2 (rIL-2). Effects indicative of lymphocyte activation occurred even prior to any rIL-2 therapy in these patients, being most prominent in patients with active diseases. Following each course of cytokine therapy, there were further changes in these parameters. Significant rebound lymphocytoses occurred with a concomitant increase in the cytotoxic functions and induction of the cytotoxicity-linked cytoplasmic serine esterase. Hence, both the natural killer and lectin-dependent cellular cytotoxicity activities were up-regulated. There were also increases in the serum sIL-2 receptor, sCD4 and sCD8 levels. More CD3+ lymphocytes, especially cells bearing CD4, were also recruited to the pool of potential effector cells, as demonstrated by the greater proportion of cells expressing the cytoplasmic serine esterase.

Adult↗
PubMed1991

alpha-Interferon in hematological malignancies.

Recent studies have generated data demonstrating significant clinical activity of alpha-interferon therapy in each of six hematological malignancies, chronic myeloid leukaemia, essential thrombocythemia, polycythemia rubra vera, non-Hodgkin's lymphomas, multiple myelomatosis and hairy cell leukaemia.

Humans↗
PubMed1991

Maintenance therapy in the myeloproliferative disorders: the current options.

Recombinant interferon alfa-2a has been shown to be an effective induction agent in essential thrombocythaemia and thrombocythaemia associated with other myeloproliferative disorders, including chronic granulocytic leukaemia, polycythaemia rubra vera and myelofibrosis. Few data exist on the use of the recombinant interferons as maintenance agents in patients with thrombocythaemia. A cohort of 22 previously untreated patients, with essential thrombocythaemia, were treated with recombinant interferon alfa-2a maintenance therapy for a minimum period of 6 months. Effective long-term control of platelet counts, without evidence of haematological toxicity, was achieved in 19/22 patients. No objective haemorrhagic or thrombotic event occurred in 298 patient-months of interferon therapy. Three patients discontinued interferon alpha therapy due to adverse side-effects. Interferon alfa-2a is an effective maintenance agent in essential thrombocythaemia and is discussed in this context.

Adult↗
PubMed1991

Bacterial infections in lymphoma patients treated with recombinant interleukin-2.

10 lymphoma patients given a total of 26 courses of intravenous continuous infusion of recombinant interleukin-2 (rIL-2) alone without lymphokine-activated killer cells were analysed retrospectively for the frequency and pattern of bacterial infections associated with the immunotherapy. 4 episodes of septicaemia and 7 episodes of soft tissue infections resulted from the 26 courses of rIL-2 infusion. Although there was no death due to infection, all these infections were clinically significant, needing systemic antibiotic therapy and resulting in prolonged hospitalisation. Gram-positive infections occurred significantly (p less than 0.001) more often than gram-negative infections. Patients with non-Hodgkin's lymphoma had a higher incidence of infection than patients treated for Hodgkin's disease, analysed either as infection per patient treated (p less than 0.05) or infection per course of rIL-2 given (p less than 0.02).

Bacterial Infections↗
PubMed1991

Recombinant alpha-interferons, thyroid irradiation and thyroid disease.

Recombinant alpha-interferons are used as therapeutic agents in an increasing number of benign and malignant disorders. Long-term administration of recombinant alpha-interferon as a maintenance agent is associated with a small number of adverse side-effects which are responsible for patient intolerance of this drug. These include weight loss, alopecia and chronic fatigue, anorexia and depression syndrome. This latter syndrome needs to be distinguished from thyroid disease, which is documented in this report in a number of patients on recombinant alpha-interferon therapy.

Adult↗
PubMed1990

Alpha interferon therapy for haematological malignancies: correlation between in vivo induction of the 2',5'oligoadenylate system and clinical response.

2',5'oligoadenylate (2-5A) synthetase mRNA and enzyme levels have been studied in peripheral blood mononuclear cells from 12 patients with chronic granulocytic leukaemia (CGL), 14 with essential thrombocythaemia (ET) and nine with chronic lymphocytic leukaemia (CLL), undergoing therapy with alpha interferon (alpha IFN). 2-5A synthetase mRNA was assayed by hybridization using the dot-blot technique and the enzyme activity was measured biochemically. A statistically significant difference was observed (P less than 0.05) between the degree of in vivo induction of mRNA by IFN alpha in the total patients between the good and intermediate responders and the poor responders. There was a similar pattern in each of the CGL, ET and CLL groups although this only reached statistical significance in the CGL group. In vitro induction of either mRNA or of enzyme activity, however, did not show a difference between the responders and poor responders in any of the patient groups. Our findings are consistent with the concept that 2-5A has an important role in the anti-tumour activity of alpha IFN and suggest that measurement of in vivo induction of 2-5A synthetase mRNA may be useful in predicting clinical response. In vitro studies, on the other hand, do not provide a reliable predictor of clinical response.

2',5'-Oligoadenylate Synthetase↗
PubMed1990

Chlorambucil lung toxicity.

A 67-year-old man, who had received intermittent courses of oral chlorambucil and prednisone as therapy for chronic lymphocytic leukaemia over a period of 3.5 years, developed fatal lung fibrosis. A case report and brief review of the current data on chlorambucil-induced lung disease are presented.

Aged↗
PubMed1988

Granulocytic sarcoma of the small intestine preceding acute myelomonocytic leukemia with abnormal eosinophils and inv(16).

We report a case of preleukemic granulocytic sarcoma of the small intestine preceding the development of acute myelomonocytic leukemia with abnormal eosinophils and inversion of chromosome 16, inv(16)(p13q22). A literature review suggests that this is a recurring cytogenetic-clinicopathologic association and carries a favorable prognosis, especially if treated aggressively with antileukemic therapy at the time of diagnosis.

Chromosome Inversion↗
PubMed1988

Alpha-interferon therapy for essential thrombocythaemia.

18 patients with symptomatic essential thrombocythaemia were treated with recombinant alpha interferon (2a or 2b). Subcutaneous dosage regimens, which were well-tolerated, selectively lowered the platelet count and relieved symptoms in all patients, whether previously treated or untreated. Recombinant alpha-interferon may offer a non-leukaemogenic alternative therapy for these patients.

Adult↗