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Biomedical subjects

F Porzsolt

Publications and source records attributed to F Porzsolt.

At least 91 records · Page 5Linked to original sources
PubMed1989

Rationale for combining tamoxifen and interferon in the treatment of advanced breast cancer.

Several investigators have discussed the possible combination of tamoxifen and interferon (IFN) in the treatment of breast cancer patients. The rationale in combining these drugs is that IFN induces the expression of estrogen receptors and therefore increases the sensitivity of breast cancer cells toward the growth-inhibitory activity of tamoxifen. In this paper we review the literature on the IFN-mediated expression of estrogen receptors and the postulated synergism of tamoxifen and IFN in the growth inhibition of breast cancer cell lines. Our results indicate that neither type I nor type II IFN increases the expression of estrogen receptors in MCF-7 cells. Together with tamoxifen both type I and type II IFN mediate additive but not synergistic growth inhibition of MCF-7 cells. On the basis of these results it is feasible to test tamoxifen and IFN as combined therapy in breast cancer patients. Preliminary clinical data show that the combination of 30 mg tamoxifen and 2 x 10(6) IU IFN-alpha as daily doses may induce WHO grade 3 leukopenia and thrombopenia in patients who are pretreated with polychemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Neurophysiological effects of recombinant interferon-gamma and -alpha in man.

Treatment of malignant tumors with interferon (IFN) is in some patients accompanied by serious neurological side effects. The present study assessed neurophysiological changes in spontaneous EEG activity, visual-evoked cortical potentials (VEPs), and brainstem auditory-evoked potentials (BAEPs) during IFN-gamma or IFN-alpha therapy in 9 patients. In addition, blood pressure, heart rate and body temperature were monitored. In all sessions under IFN, the latency of the P100 component of the VEP was shortened as compared to baseline conditions. IFN also reduced latencies of BAEP components, and diminished amplitudes of the spontaneous EEG activity within the alpha and beta frequency band. These latter effects were somewhat less consistent than those on VEPs. The major neurophysiological changes appeared to be similar for IFN-gamma and IFN-alpha. The results are in accord with an excitatory effect of IFN on central nervous activity. The magnitude of changes excludes a neurotoxicity of IFN-gamma or IFN-alpha at the doses used in this study.

Adult↗
PubMed1989

Tumor necrosis factor induces proliferation of neoplastic B cells from chronic lymphocytic leukemia.

The biologic effects of recombinant tumor necrosis factor-alpha (rTNF-alpha) and the expression of specific TNF membrane receptors on isolated neoplastic B cells from previously untreated patients with chronic lymphocytic leukemia (CLL) were investigated in vitro. Isolated B cells were incubated up to six days with various concentrations of rTNF-alpha (0.1 to 100 ng/mL). B cells from most patients proliferated ranged from two to 104 times that of unstimulated cells from the same patients. An optimal proliferative effect was achieved at 25 ng/mL rTNF-alpha and an incubation time between 96 and 120 hours, whereas a low concentration of rTNF-alpha (1 ng/mL) reduced [3H]TdR incorporation in four cases. Metaphase cells were detected in the rTNF-alpha-stimulated cultures that proliferated in response to rTNF-alpha. B cells from three of ten patients proliferated spontaneously and proliferation was further enhanced in two patients by rTNF-alpha. TNF binding assays gave a value of approximately 390 to 1,400 binding sites/cell for TNF and a dissociation constant (kd) of approximately 60 pmol/L. These data indicate that rTNF-alpha, in contrast to its cytotoxic/cytostatic effects, can also induce proliferation of tumor cells.

Adult↗
PubMed1989

Interferon-alpha antibodies in autoimmune diseases.

Circulating autoantibodies constitute a prominent feature of many autoimmune diseases. Recently, antibodies to interferon (IFN) have been recognized as an additional variant occurring spontaneously in about 10% of patients with autoimmune disorders. The reactivity of these antibodies appears to be restricted to IFN-alpha, with antibodies of individual patients recognizing unique epitope patterns. IFN antibodies are preferentially of the IgG type, and they likely constitute part of the normal B-cell repertoire. Whereas antibody titers differ largely among patients, the affinity of IFN binding has not been determined. Likewise, the mechanisms involved in IFN antibody synthesis as well as the clinical impact of these antibodies in autoimmune disorders remain elusive. Based on recent reports and our own observations, this article reviews current knowledge regarding occurrence and properties of IFN antibodies associated with autoimmune conditions. From clinical and experimental evidence, mechanisms possibly involved in IFN antibody production are derived and the significance of antibody-mediated sequelae is evaluated.

Aged↗
PubMed1988

Different antitumor mechanisms of interferon-alpha in the treatment of hairy cell leukemia and renal cell cancer.

There is increasing evidence for the therapeutic effectiveness of Interferon-alpha (IFN-alpha) in malignant diseases. However, the antitumor mechanisms of IFN-alpha are not known. Using two examples, hairy Cell leukemia (HCL) and renal cell cancer (RCC), it is shown that the requirements for successful IFN-alpha therapy of HCL and RCC are different. In HCL low doses of IFN-alpha are sufficient to treat the disease. The reduction of hairy cells in peripheral blood is detectable within the first week of treatment. The endogenous IFN-alpha production in these patients is impaired as demonstrated by the lack of IFN-alpha induction and by low levels of 2-5 oligoadenylate synthetase in peripheral blood mononuclear cells. A possible reason for deficient endogenous IFN-alpha production is the lack of monocytes in HCL patients. It is likely that therapy with low doses of IFN-alpha substitutes for the endogenous IFN-alpha deficiency. In RCC comparatively high doses of IFN-alpha are necessary for a clinical response. There may be differences between the effectiveness of natural and recombinant alpha interferons. High doses given within a week seem to be more important than high single doses, which therefore suggests the need of daily treatment. Responses of RCC to IFN-alpha therapy are usually seen several months after the beginning of therapy. These differences in the effectiveness of IFN-alpha therapy for HCL and RCC suggest that IFN-alpha acts differently in the treatment of each disease.

2',5'-Oligoadenylate Synthetase↗
PubMed1988

Treatment of advanced renal cell cancer with recombinant interferon alpha as a single agent and in combination with medroxyprogesterone acetate. A randomized multicenter trial.

The response rates in metastatic renal cell cancer (RCC) after chemotherapy, hormonal treatment, or immunotherapy rarely exceed 15%. Recently, interferon alpha (IFN alpha) was used for treatment of this disease in several studies which also demonstrated response rates of 15%. In order to test whether IFN therapy combined with hormones would result in higher response rates we compared single agent IFN therapy with a combined therapy of rIFN alpha 2C plus medroxyprogesterone acetate (MPA) in a randomized multicenter trial. The rIFN alpha 2C (2MU) was given s.c. 5 times per week for 8-12 weeks and subsequently once weekly until week 48. In the combined treatment, 750 mg MPA was given p.o. daily until week 48 in addition to the IFN as described. The overall response rate in 93 evaluable patients was 5.4% corresponding to 2 complete and 3 partial responses. Median survival was 7 months in both treatment groups. These data confirm the ineffectivity of low IFN doses for treatment of RCC. The low response rate is not increased by addition of MPA to IFN. The analysis of other IFN studies suggests that not only IFN doses but also IFN sources may influence response rates in metastatic RCC.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Lymphokines as inhibitors of hematopoietic cell proliferation.

Although the identification of lymphokines negatively affecting hematopoiesis is rapidly increasing, efforts to precisely define their action even in vitro have become more and more complicated. Studies of lymphokine abnormalities in aplastic anemia exemplify the modest contribution of experimental hematology to permit access to possible pathogenic mechanisms of hematopoietic failure syndromes. Nevertheless, these results help in the interpretation of clinical observations and to develop alternative therapeutic concepts.

Animals↗
PubMed1987

2'-Deoxycoformycin (Pentostatin) in hairy cell leukemia: response in patients refractory to interferon alpha.

Three patients with advanced hairy cell leukemia received low-dose deoxycoformycin treatment after failure to respond to therapy with interferon alpha. Patients 1 and 2 had progressive disease after splenectomy and subsequent treatment with recombinant interferon alpha (for 7 and 3 months, respectively). DCF was administered at 4 mg/m2 weekly for 3 weeks, and then once every week for 6 weeks. Patient 1 was in complete remission after 9 weeks of treatment and patient 2 in partial remission with normalization of peripheral blood counts. The third patient, also splenectomized, developed hepatotoxicity after therapy trial with interferon for 24 days and no objective improvement was observed at this stage. She subsequently responded to DCF treatment with improvements in blood counts and bone marrow. This report demonstrates that DCF is highly effective in hairy cell leukemia and non-cross-resistant with interferon alpha.

Adult↗
PubMed1987

[Immunosuppressive therapy in panmyelopathy. Experiences with various forms of therapy in 42 patients].

Immunosuppressive treatment according to four different regimens was administered over the course of eight years to 42 patients with aplastic anemia. With treatment protocols which included horse-ALG and horse-ATG, remissions were achieved in most patients, while with rabbit-ATG improvement was obtained, but only minimally, in 15 patients. First results with Cyclosporin A confirmed the effectiveness of this immunosuppressive agent in the treatment of aplastic anemia. The development of remission was, independently of treatment schedule, recognizable 23-88 days after onset of treatment. Often only partial remission was achieved. The long-term course, especially also survival, correlated with the results achieved within the first three months after onset of treatment. Recurrences occurred in 19% of patients but responded to repeated immunosuppressive treatment if preceded by complete remission. Side-effects to ALG and ATG occurred only during the first two weeks and were easily controllable. In some cases Cyclosporin A led to subjectively distressing side-effects.

Anemia, Aplastic↗
PubMed1987

Evidence for the involvement of host-derived OKT8-positive T cells in the rejection of T-depleted, HLA-identical bone marrow grafts.

The recent introduction of a variety of techniques for removing T cells from bone marrow grafts has reduced the incidence of graft-versus-host disease (GVHD)-associated morbidity and mortality. Whether this advance will be translated into improved patient survival is unclear at present, mainly because these procedures increase the risk of graft failure. Since 1983 we have transplanted 25 consecutive leukemia patients with HLA-identical sibling grafts purged of T cells by a single incubation with the monoclonal antibody Campath-1 and donor complement. This approach was successful in reducing T cell contamination of the graft and preventing acute and chronic GVHD. In this group of patients two suffered irreversible graft failure and one developed reversible graft failure. In a similarly sized group of patients previously transplanted with unpurged marrow according to the Seattle protocol, no episodes of graft failure occurred. Since other causes of graft failure, such as drug toxicity or viral infections, could be largely excluded, this suggested that the graft failures were specifically related to the purging process. In haploidentical bone marrow transplantation (BMT) O'Reilly has identified residual host-versus-graft activity (HVG) as a cause of graft failure. The causes and mechanisms of graft failure in T-depleted HLA-identical sibling transplants have not been extensively investigated to date. In the three graft failures observed by us, the loss of the graft was preceded by the appearance of a population of activated lymphocytes. We have determined the phenotype and origin of this population and investigated its interactions with donor hemopoietic tissue in vitro.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1987

[Advantages and problems of multicenter therapy studies exemplified by a study of the treatment of metastasizing renal cell carcinoma with recombinant interferon-alpha-2c].

The advantages of multicenter trials are numerous: quicker recruitment of the necessary number of patients, clearer results which are more convincing and whose acceptance is higher, as the patient sample of multicenter trials is supposed to be representative. However, multicenter trials require strong efforts for quality assurance concerning admission, treatment and follow-up, thus a highly developed coordinating center is needed. Data on recruitment and protocol compliance, i.e. deviations from the study protocol, are presented for the study of the treatment of metastatic renal cell carcinoma and discussed with respect to their impact on the results of the study. 102 patients were randomized either for IFN alpha-2C or IFN alpha-2C plus medroxyprogesteroneacetate. 16% of the patients violated inclusion criteria and essential data were missing in 16% of the patients. Overall treatment results (remission rate of 5.6%, median survival time of 7 months) and the data on adverse events have been biased by lack of protocol compliance. However, the results concerning the lack of differences between treatments remain valid.

Carcinoma, Renal Cell↗
PubMed1987

[Concept of treatment of metastatic breast cancer outside university clinics: description of the method and evaluation of efficacy].

It has been recognized during the past decade that it may be advantageous to develop complex strategies for treatment of metastatic breast cancer (MBC). In these strategies the type and efficacy of preceding therapies and the compliance of the patients have to be considered. Since about 80% of all patients with MBC are treated outside university hospitals it should be tested if a complex strategy for treatment of MBC can be realized in these institutions. The method was based on three principles: There was an exchange of data between participating institutions and study center after each visit of a patient. Second, there was one data sheet for admission of a patient to the study and fifteen sheets for follow-up documentation each with a different bottom line; in the bottom line of these sheets two therapies according to the strategy were proposed, one in case of 'no progression' and another in case of 'progression' of the disease. Third, a copy of completed sheets had to be returned to the study center; the study center provided the next sheet with the appropriate treatment recommendation. 335 evaluable patients were prospectively recruited from 27 participating institutions between January 1983 and December 1985. Based on the estimated incidence of MBC in the region, it was calculated that 45% of all MBC patients of the region had been admitted to the study. Only 27% of these patients were treated at the university hospital indicating that 85% of all MBC patients of the region were treated outside university hospitals.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Strategy for the treatment of hairy cell leukemia.

Both splenectomy and alpha-interferon are efficient treatments for hairy cell leukemia. Since interferon therapy seems to induce remissions of the disease, avoids the risks of surgery, and sustains the spleen, it should be discussed if this therapy may replace splenectomy as primary treatment for this disease. In order to make this decision the biologic relevance of complete remissions in hairy cell leukemia, the reliability of methods to confirm remission, the benefits and risks of both splenectomy and interferon therapy, and some aspects of the pathogenesis of the disease have to be considered. Based on our experimental and clinical results and data from other groups, we conclude that splenectomy should still be recommended as primary therapy in hairy cell leukemia provided that treatment is indicated and the patient is eligible for surgery.

Combined Modality Therapy↗
PubMed1986

Treatment of aplastic anemia with cyclosporin A, methylprednisolone, and antithymocyte globulin.

Twenty-three patients with aplastic anemia (18/23 with severe aplastic anemia) were treated with an immunosuppressive regimen consisting of cyclosporin A (CsA) and methylprednisolone (MP) (n = 7) or CsA, MP, and antithymocyte globulin (ATG; n = 16). Nineteen patients are alive with a follow-up of 4 to 25 months; three patients died of infections and one of a gastrointestinal hemorrhage. Within 3 months, improvement of hematopoiesis was seen in 14 patients (61%). First signs of a response after 23 to 88 days were followed by complete remission in eight patients, partial remission in three patients, and minimal improvement in three patients. Two of the patients with only minimal improvement were treated with a second course of immunosuppression and reached a complete remission and partial remission. Interestingly, remission proved to be dependent on the continued administration of CsA in four of five patients with partial or complete remission who could be evaluated up to now. Thus, CsA must have been effective in the induction and/or maintenance of remission in three patients. This observation is a very strong argument for the role of T cells in the pathogenesis of at least some cases of aplastic anemia and warrants further evaluation of the role of CsA in the treatment of aplastic anemia.

Adolescent↗
PubMed1986

HTLV III antibodies and immunological alterations in hemophilia patients.

The clinical, immunological, and serological status of 28 patients with hemophilia A and of 13 patients with hemophilia B was investigated. Thirty-four patients were treated regularly by clotting factor concentrates and 7 patients had been substituted only 1 to 4 times. Almost all patients with severe hemophilia suffered from hepatopathy. No patient had clinical evidence of the acquired immunodeficiency syndrome (AIDS). Asymptomatic hemophiliacs showed a decreased number of T-helper (OKT 4) cells and an increased number of T-suppressor (OKT 8) cells, which resulted in an inversed OKT 4/OKT 8 cell ratio. Natural killer cell activity of all patients was decreased compared to controls. After culture there was no significant difference of NK cell activity between hemophiliacs and controls. This phenomena was interpreted as a possible maturation defect of NK-cells in vivo. No relationship between immunological alterations and hepatopathy, hepatitis markers, CMV antibodies, amount and source of required factor concentrates, and the kind of hemophilia was observed. IgG immunoglobulins were higher and the OKT 4/OKT 8 ratio lower in the eight patients with lymphadenopathy than in patients without lymphadenopathy. The prevalence of antibodies to human T-lymphotropic virus (HTLVIII) was measured in 35 hemophiliacs and in 25 polytransfused patients, most of whom were suffering from acute leukemia. In 8 of 35 hemophiliacs antibodies to HTLVIII virus were detected by an enzyme linked immunosorbent assay (ELISA) and confirmatory tests. All seropositive patients were treated by blood products from the United States. Eight hemophiliacs treated by factor concentrates from German donors only were seronegative. In comparison 2 of 25 examined non-hemophilia patients receiving multiple blood products from local donors were seropositive for HTLVIII. The results show that hemophilia patients treated by imported clotting factor concentrates have a high risk of HTLVIII positivity. Hemophiliacs substituted by blood products obtained by local donor pools have only a small risk of infection. Because non-hemophiliac polytransfused patients had HTLVIII antibodies, there must be asymptomatic virus carriers in the local donor pool. The HTLVIII antibody screening of all donors and the heat treating of factor concentrates will give better therapeutic safety.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Deficient IFN alpha production in hairy cell leukemia.

Since the application of low doses of IFN-alpha is necessary to maintain remissions in Hairy Cell Leukemia (HCL) it is of interest whether peripheral blood mononuclear cells (MNC) of HCL patients can be induced in vitro to produce IFN-alpha. 9 patients suffering from advanced HCL were included in the study. The diagnoses were confirmed by characteristic findings in peripheral blood and bone marrow biopsies. For IFN treatment we initially used natural IFN-alpha (Bioferon) and switched later to recombinant IFN-alpha2 (Boehringer). MNC of 5 patients before IFN therapy and of 6 patients during IFN therapy (2-47 weeks) were induced by phytohemagglutinin (PHA), Corynebacterium parvum (C.p.), and sendai virus (SV). PHA is known to induce IFN-gamma. Both, C.p. and SV induced IFN-alpha but no IFN-gamma in MNC of healthy controls and of IFN treated breast cancer patients. In HCL patients normal antiviral activities could be induced by PHA. Zero or only low antiviral activities could be induced in MNC from 9 patients tested on 22 occasions. It is concluded that MNC from patients with advanced HCL can be induced to produce IFN-gamma but no IFN-alpha. Since IFN-alpha but not IFN-gamma is produced by monocytes it is likely that reduced numbers of monocytes which were found in our HCL patients before and during IFN treatment account for the described deficiency of IFN-alpha production.

Breast Neoplasms↗