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R Greil

Publications and source records attributed to R Greil.

At least 55 records · Page 3Linked to original sources
PubMed1998

On the role and significance of Fas (Apo-1/CD95) ligand (FasL) expression in immune privileged tissues and cancer cells using multiple myeloma as a model.

Our knowledge in immunology has been dramatically increased by several excellent investigations elucidating the role of the Fas (Apo-1/CD95) receptor/ligand (FasL) system in complex immunological processes such as the acquisition of self tolerance in T cells, progression of autoimmunity, clonal deletion of activated T cells, B-cell regulation and the establishment of "immune privileged" sites such as testis or retina. In addition to these regulatory immunological activities, Fas/FasL interaction was also shown to participate in active defense mechanisms of the host against infected or transformed cells thereby inducing apoptosis in target cells. However, the same mechanism seems also to be part of an escape strategy utilized by tumor cells in various neoplastic malignancies of both hematopoetic as also non-hematopoetic origin. We ourselves were able to demonstrate that neoplastic plasma cell lines, as well as native malignant myeloma cells constitutively express FasL mRNA and protein. The FasL molecule is functionally active and able to induce programmed cell death in Fas sensitive target T cells in vitro. These target T cells were protected from programmed cell death by preincubation of T cells with a Fas-blocking monoclonal antibody (mAb) or of myeloma cells with a FasL-neutralizing mAb. respectively. Furthermore, overexpression of the caspase inhibitor, cowpoxvirus protein CrmA, also protected target T cells from being killed by myeloma cells, identifying Fas/FasL mediated signaling as the effector pathway utilized by malignant plasma cells. Our observations strongly suggest the engagement of Fas/FasL interaction in the escape strategy of this malignancy. The molecular basis of this evasive mechanism differs in essential respects from those described in melanoma, lung cancer, hepatocellular carcinoma, or astrocytoma, since downregulation of Fas or instrinsic insensitivity towards Fas-mediated signaling were not prerequisites for the occurrence of this phenomenon in Fas-sensitive multiple myeloma cell lines. However, myeloma cell lines resisted cocultivation with FasL-expressing target T cells in vitro. The aim of this review is to discuss the role of Fas/FasL interaction in the establishment of malignant disease, in the light of our findings on myeloma cells and also by drawing upon similar observations of other investigators on different kinds of tumor cells and cell lines and further to consider its possible relevance in formulating novel approaches to cancer therapy.

Animals↗
PubMed1997

Drug-induced apoptosis is associated with enhanced Fas (Apo-1/CD95) ligand expression but occurs independently of Fas (Apo-1/CD95) signaling in human T-acute lymphatic leukemia cells.

Induction of apoptosis is considered to be the underlying mechanism that accounts for the efficiency of chemotherapeutic drugs. It has recently been proposed that induction of Fas ligand (FasL) expression with subsequent autocrine and/or paracrine induction of cell death through binding to the Fas (Apo-1/CD95) membrane accounts for chemotherapy-associated apoptosis. In the present study, we analyzed the significance of FasL expression in the mediation of drug-induced apoptosis in the T-acute lymphatic leukemia model CEM. In particular, we examined the potential of the tumor drugs fludarabine, doxorubicin, and cisplatin to induce FasL expression. We also raised the question of whether apoptosis induced by these drugs occurs through the Fas pathway and hence can be blocked by the cowpox virus protein CrmA, a specific inhibitor of this pathway. All tumor drugs examined led to an increase in FasL protein. However, overexpression of CrmA had no effect on drug-induced apoptosis. Moreover, neither incubation with inhibitory monoclonal antibodies against Fas that completely prevented Fas-induced apoptosis in these cells nor pretreatment with a monoclonal antibody to FasL affected drug-induced cell death. Our observations suggest a Fas/FasL-independent mechanism for drug-induced apoptosis and exclude the involvement of caspase 1 and caspase 8 in this process in T-acute lymphatic leukemia cells.

Antineoplastic Agents↗
PubMed1997

Constitutive expression of Fas (Apo-1/CD95) ligand on multiple myeloma cells: a potential mechanism of tumor-induced suppression of immune surveillance.

The Fas (Apo-1/CD95) ligand (FasL) plays a central role in the elimination of target cells by effector T lymphocytes and in the suppression of cellular immune responses against nonmalignant and malignant cells. We show the expression of FasL on the surface of neoplastic plasma cells. We provide evidence that the FasL is functionally active because five of five neoplastic plasma cell lines tested killed CEM-C7H2 T-acute lymphoblastic leukemia (T-ALL) cells. The effect was mediated via the Fas (Apo-1/CD95) receptor molecule because blocking of Fas on the target cells or the FasL on the tumor cells by receptor- and ligand-specific monoclonal antibodies (MoAbs), respectively, protected T cells from being killed by myeloma cells. In addition, overexpression of the cowpox virus protein CrmA, a molecule with inhibitory potential on caspase-1 and caspase-8, specifically involved in Fas-induced signaling, protected T cells from being destroyed by the neoplastic cells or the agonistic anti-Fas MoAb. The potential of the malignant plasma cells to extinguish target T cells was independent of their own sensitivity to the agonistic anti-Fas MoAb, and FasL-positive (FasL+) CEM-C7H2 T cells were incapable of killing myeloma cells. Our results suggest that tumor cell-induced suppression of the immune system may be exerted via the FasL active on malignant plasma cells. Furthermore, loss of Fas expression or insensitivity to the agonistic anti-Fas MoAb do not seem to be prerequisites for myeloma cells to defeat T cells via Fas/FasL interaction.

Aged↗
PubMed1997

The interleukin 1beta-converting enzyme inhibitor CrmA prevents Apo1/Fas- but not glucocorticoid-induced poly(ADP-ribose) polymerase cleavage and apoptosis in lymphoblastic leukemia cells.

Glucocorticoids (GC) induce programmed cell death (apoptosis) in immature lymphocytes and are an essential component in the therapy of acute lymphatic leukemia. The mechanism underlying GC-induced apoptosis particularly in leukemia cells is, however, not well understood. Most forms of apoptosis seem to employ a common final effector pathway characterized by specific proteolytic events mediated by interleukin 1beta-converting enzyme (ICE) and/or other ICE-like cysteine proteases. These events may result in the morphologic changes characteristic of apoptosis. To determine whether a similar proteolytic pathway is activated during GC-induced leukemia cell apoptosis, we investigated poly(ADP-ribose) polymerase (PARP), a typical target of ICE-like proteases, during GC-induced apoptosis of the human acute T-cell leukemic cell line CEM-C7H2. Our studies showed proteolytic PARP cleavage suggestive of activation of ICE-like proteases that preceeded morphologic signs of apoptosis. We further established stably transfected CEM-C7H2 sublines expressing the cowpox virus protein CrmA that inhibits some, but not all, ICE-like proteases. GC-induced PARP cleavage and apoptosis were neither inhibited nor delayed in crmA-expressing cell lines. In contrast, crmA expression rendered the same lines resistant to Apo1/Fas-induced PARP cleavage and apoptosis. Thus, different proteases might be activated during the effector phases of GC-and Apo1/Fas-induced apoptosis in human leukemia cells.

Apoptosis↗
PubMed1997

Randomized open label phase III trial of CEOP/IMVP-Dexa alternating chemotherapy and filgrastim versus CEOP/IMVP-Dexa alternating chemotherapy for aggressive non-Hodgkin's lymphoma (NHL). A multicenter trial by the Austrian Working Group for Medical Tumor Therapy.

Primary end point of this trial was to reduce neutropenic infections during the treatment of aggressive NHL with CEOP/IMVP-Dexa (cyclophosphamide, epirubicin, vincristine, prednisolone ifosfamide, methotrexate, VP-16, and dexamethasone). Further, we studied the influence of filgrastim on dose intensity of CEOP/IMVP-Dexa, on the rate of complete remissions, on the time to relapse, and on survival. Eighty-five patients with untreated large-cell NHL were randomized to one of two treatment arms; 74 patients were eligible. Thirty-eight patients in arm 1 were treated with CEOP/IMVP-Dexa chemotherapy and filgrastim, 36 in arm 2 with CEOP/IMVP-Dexa chemotherapy alone. In arm 1 filgrastim was self-injected by the patients at 5 micrograms/kg body wt. s.c. daily, except on the days when cytotoxic drugs were given. During treatment we did weekly complete blood counts. Median leukocyte counts were 10.91 x 10(9)/l and 5.46 x 10(9)/l in arm 1 and 2, respectively (p = 10(-6)). Median neutrophil counts were 7.7 x 10(9)/l in arm 1 and 2.72 x 10(9)/l in arm 2 (p < 10(-6)). Median neutrophil nadirs were 0.199 x 10(9)/l and 0.213 x 10(9)/l in arm 1 and 2, respectively (p = 0.09). Mean platelet nadirs were 95 and 152 x 10(9)/l (p = 0.000004) and mean hemoglobin nadirs 83.95 g/l and 92.78 g/l (p = 0.00558) in arm 1 and 2, respectively. Dose intensity of CEOP/IMVP-Dexa was 82.3% and 76.2% in arm 1 and 2, respectively (p = 0.041). Forty-two percent and 58% of patients experienced a febrile neutropenia in arm 1 and 2, respectively (not significant, NS). Median time to first neutropenic infection was in treatment week 11 and 6 in arm 1 and 2, respectively (NS). There was no significant difference in rate, duration, and kind of infection, duration of hospitalization, or antibiotic treatment. Seven toxic deaths occurred, all due to neutropenic infection, 6 and 1 in arm 1 and 2, respectively (p = 0.0732). Four of the six patients, who died of infection in arm 1 were older than 60 years. Complete remission rate was 83% and 66.7% in arm 1 and 2, respectively (NS). After a median observation time of 3 years there was no difference in time to relapse or survival. Filgrastim increases leukocyte and neutrophil counts and dose intensity, if used with CEOP/IMVP-Dexa chemotherapy in high-grade lymphomas. There was no significant effect on febrile neutropenia or infections. The more frequent fatal neutropenic infection rate in the filgrastim arm was not statistically significant. It is most appropriate to explain it by the patient's age in combination with the high dose intensity. The small increase in dose intensity had no effect on survival but probably decreased hemoglobin levels and platelet counts in arm 1. We were unable to show a benefit for filgrastim in combination with CEOP/IMVP-Dexa.

Adolescent↗
PubMed1997

Interferon-alpha-2C and LD ara-C for the treatment of patients with CML: results of the Austrian multi-center phase II study.

Small pilot studies of patients with CML have reported on encouraging response rates after treatment with interferon-alpha (IFNalpha) in combination with low-dose cytosine arabinoside (LD ara-C). We therefore initiated a multi-center phase II trial in order to investigate the efficacy and tolerability of this combination in newly diagnosed patients with Ph-positive chronic myelogenous leukemia (CML). Eighty-four patients were treated with IFN-alpha-2c at daily subcutaneous doses of 3.5 MU and LD ara-C added subcutaneously for 10 days every month at a dose of 10 mg/m2, following an initial reduction of WBC to less than 20 x 10(9)/l with hydroxyurea (HU). Within a median observation period of 28 (5-59) months the patients received a median of 7 (1-35) IFNalpha and LD ara-C cycles. Treatment was stopped due to side effects in 16 cases (19%) and to primary or secondary treatment failure in 38 cases (45%). In 45 patients (54%) complete hematological response (CHR) was achieved; in 39 patients (46%) cytogenetic responses including 15 (18%) complete cytogenetic responses (CHR) were observed. Median duration of cytogenetic responses was 15 months. Relapses were seen in 8/15 patients (53%) with complete cytogenetic remission (CCR), in 3/6 patients (50%) with partial cytogenetic response and in 9/18 patients (50%) with minor cytogenetic response. In conclusion, the combination of IFNalpha and LD ara-C resulted in encouraging rates of hematological and cytogenetic responses in patients with CML with low to moderate toxicity.

Adolescent↗
PubMed1997

Expression of Apo-1/Fas (CD95), Bcl-2, Bax and Bcl-x in myeloma cell lines: relationship between responsiveness to anti-Fas mab and p53 functional status.

The down-regulation of apoptosis may be an essential mechanism for tumour cell expansion in slowly proliferating tumours such as multiple myeloma. We studied eight myeloma cell lines for the presence of Bcl-2, which inhibits apoptosis, of Bax, which counteracts Bcl-2, of Bcl-x(L) and Bcl-x(S), which act in an anti- and pro-apoptotic fashion, respectively, and of Apo-1/Fas, which induces programmed cell death, when activated by the Apo-1/Fas ligand or the relevant monoclonal antibody (mab). All cell lines constitutively expressed homogenous amounts of Bcl-2, but displayed different amounts of Bax and Bcl-x proteins. The Apo-1/Fas antigen could be detected in seven out of eight myeloma lines, but expression levels varied considerably. The relative expression levels of Apo-1/Fas correlated with that of Bax, but not with that of Bcl-2 or Bcl-x subtypes. Furthermore, the effectiveness of the Apo-1/Fas mab was associated with the relative expression levels of the Apo-1/Fas and with that of the Bax antigen, but not with that of the Bcl-2 and Bcl-x antigens. We further showed that wild-type p53 function is not required for Apo-1/Fas-induced apoptosis, nor is it necessary for the expression of Bax or Apo-1/Fas antigens in myeloma. In conclusion, our results suggest a p53-independent co-regulation of Apo-1/Fas and Bax, as well as a role for Bax in Apo-1/Fas-induced apoptosis in myeloma.

Apoptosis↗
PubMed1997

Cytokine priming of the granulocyte respiratory burst in myelodysplastic syndromes.

Increased susceptibility to infections in patients with myelodysplastic syndromes (MDS) is thought to be due to neutropenia as well as functional abnormalities of neutrophils. In the present study we examined the effect of two different stimulants (fMLP, PMA) and three cytokines (alphaTNF, G-CSF and GM-CSF), both singly and in combination on granulocyte (RB) in 25 MDS patients compared to seven healthy controls. Single fMLP and PMA-stimulation showed similar results for both groups. Preincubation with cytokines enhanced fMLP-stimulated RB in most MDS patients and controls, but in patients to a significantly lesser extent when compared to the control group (p < or = 0,05). Combinations of alphaTNF + GM-CSF and alphaTNF + G-CSF were highly synergistic in priming fMLP-stimulated burst in both groups. But again, as with the single cytokine priming this effect was markedly reduced in MDS patients compared to controls (p < or = 0,05). A specific priming defect for one of the cytokines or a cytokine combination could not be demonstrated. Serum alphaTNF levels were measured in 18 and neutrophil alkaline phosphatase (NAP) index in 23 patients. Results did not correlate with variations of the RB in MDS patients. We conclude that reduced alphaTNF, GM-CSF and G-CSF priming of granulocyte RB is a frequent finding in MDS and may contribute to the enhanced susceptibility to bacterial infections.

Adult↗
PubMed1996

Constituents of autocrine IL-6 loops in myeloma cell lines and their targeting for suppression of neoplastic growth by antibody strategies.

We examined the constitution and biological relevance of an autocrine IL-6/IL6-receptor (r) loop in 7 multiple myeloma and plasma-cell leukemia lines in order to determine its biological role and potential therapeutic impact on antibody strategies. The expression and constitution of the IL-6r [i.e. membrane-bound gp-80, soluble (s)gp-55 and the gp-130 IL-6 signal-transducing element (str)], the binding capacity of the membrane-associated receptor(s) for IL-6, the production and secretion of IL-6 by neoplastic plasma cells, and the effect of IL-6 on tumor-cell proliferation were investigated. In the U-266 cell line, the growth-inhibitory effects of antibodies (Abs) against IL-6 and IL-6-binding subunit of its receptor were compared with each other. From our results the following conclusions may be drawn: (i) Substantial differences in the quantificative assembly of the IL-6r constituents and in the response to recombinant (r) human (h) IL-6 became evident in the 7 myeloma cell lines. (ii) The components of an autocrine IL-6 loop may be regulated in an independent and, in the case of IL-6 and sgp-55, probably counteractive manner. (iii) The level of endogenous IL-6 and the reservoir of recruitable sgp-55 were important for the response to exogenous rhIL-6. (iv) Apart from IL-6, other growth factors are important for the propagation of myeloma cells but at least some of them exert their effect through an IL-6-dependent pathway. Their growth-promoting activity, as well as that of IL-6, may be successfully targeted by immunological means, with Abs against the IL-6r being more efficient than those against the ligand.

Antibodies↗
PubMed1996

Modulation of Apo-1/Fas (CD95)-induced programmed cell death in myeloma cells by interferon-alpha 2.

The Apo-1/Fas (CD95) antigen is known to be involved in the process of T cell-mediated target cell killing and has recently been shown to be expressed on myeloma cell lines and native malignant plasma cells. Several cytokines have been reported to interfere with spontaneous and even Apo-1/Fas-induced apoptosis, but no attempt has been made yet to investigate these interactions and the possible underlying mechanisms in myeloma cells. Since in myeloma patients Interferon (IFN)-alpha2 displays a profound therapeutic effect in vivo, which is usually attributed to its growth inhibitory and/or immunomodulatory capacity, we set out to study the potential interference of IFN-alpha2 with Apo-1/Fas-induced apoptosis. Contrary to expectations, IFN-alpha2 reduced the degree of apoptosis caused by the treatment of five Apo-1/Fas-sensitive myeloma cell lines with a Fas monoclonal antibody (mAb). Simultaneous application of IFN-alpha2 and Fas mAb was superior to the prolonged (i.e. >8 h) preincubation with the cytokine as far as inhibition of Apo-1/Fas-induced apoptosis was concerned. This effect of IFN-alpha2 was neither explained by a down-regulation of the Apo-1/Fas receptor nor caused by modulation of the expression levels of c-myc, bcl-2-, bcl-xL, bax- or p53 genes. IFN-alpha2 did not alter the Apo-1/Fas-induced activity of Mitogen-activated protein kinase (MAPK) 1 and did not inhibit the Apo-1/Fas-mediated proteolytic cleavage of ADP-ribosyltransferase, a substrate of Interleukin-beta1 converting enzyme (ICE) and homologues. However, activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate (PMA) mimicked the effects of IFN-alpha2. Furthermore, the bis-indolylmaleimide GF 109203X, a specific inhibitor of PKC, inhibited the effect of PMA as well as that of IFN-alpha2 on Apo-1/Fas-induced apoptosis. These results point to a PKC-dependent mechanism of transient interaction between the intracellular signaling along the IFN-alpha2 and the Apo-1/Fas pathway (downstream of MAPK signaling as well as of ICE homologues), which becomes exhausted by prolonged stimulation with the cytokine. According to our data IFN-alpha2, applied continuously and in high doses resembling the therapeutic situation in vivo, inhibits myeloma growth. However, based on the observed inhibitory effect of IFN-alpha2 on Apo-1/Fas-induced apoptosis, a partial inhibition of the natural immune surveillance on myeloma cells by endogenous IFN-alpha2 present in the bone marrow microenvironment of this malignancy should be investigated.

Adjuvants, Immunologic↗
PubMed1996

2',2'-Difluorodeoxycytidine (gemcitabine) induces apoptosis in myeloma cell lines resistant to steroids and 2-chlorodeoxyadenosine (2-CdA).

The paucity of effective cytotoxic agents for the treatment of steroid resistant multiple myeloma explains the ongoing search for alternative substances for chemotherapy of this disease. In the present study, the purine antagonist 2-chlorodeoxyadenosine (2-CdA, cladribine) and the pyrimidine antagonist 2',2'-difluorodeoxycytidine (gemcitabine) were tested on four myeloma cell lines (i.e., U 266, OPM 2, RPMI 8226, IM 9), one plasma cell leukemia cell line (HS Sultan) and a myeloid control cell line (HL 60), all of which are resistant to 10-6 M dexamethasone. Gemcitabine has been found to be promising in the chemotherapy of other tumors with low proliferative activity, but its effectiveness against myeloma cells has not been analyzed so far. In our tests, gemcitabine induced a significant degree of apoptosis in all cell lines investigated. After incubation for 48 h with 10 microM gemcitabine, the median numbers of apoptotic cells were in the range of 45% in the OPM 2 and 79% in the U 266 cell line. All of the investigated cell lines were responsive to concentrations of 10 microM gemcitabine even after an exposure of only 30 min, three of them (U 266, HS Sultan, IM 9) also responded to a concentration of 10 nM. Higher concentrations and longer exposure times were necessary to suppress the growth of normal hematopoietic bone marrow progenitor cells. In contrast to gemcitabine, standard concentrations of 2-CdA (i.e., 30 and 300 nM) failed to induce a significant degree of apoptosis in the cell lines investigated but inhibited the growth of myeloid progenitor cells. The results suggest that gemcitabine induces apoptosis in myeloma and plasma cell leukemia lines resistant to steroids and 2-CdA. The fact that tumor cell apoptosis was achieved at concentrations clinically achievable and tolerable, which at the same time do not inhibit the growth of normal CFU-GM progenitor cells, favors the initiation of phase I trials with this drug for the treatment of multiple myeloma.

2-Chloroadenosine↗
PubMed1995

Recombinant human erythropoietin in the anemia associated with multiple myeloma or non-Hodgkin's lymphoma: dose finding and identification of predictors of response.

Previous phase I-II clinical trials have shown that recombinant human erythropoietin (rHuEpo) can ameliorate anemia in a portion of patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). Therefore, we performed a randomized controlled multicenter study to define the optimal initial dosage and to identify predictors of response to rHuEpo. A total of 146 patients who had hemoglobin (Hb) levels < or = 11 g/dL and who had no need for transfusion at the time of enrollment entered this trial. Patients were randomized to receive 1,000 U (n = 31), 2,000 U (n = 29), 5,000 U (n = 31), or 10,000 U (n = 26) of rHuEpo daily subcutaneously for 8 weeks or to receive no therapy (n = 29). Of the patients, 84 suffered from MM and 62 from low- to intermediate-grade NHL, including chronic lymphocytic leukemia; 116 of 146 (79%) received chemotherapy during the study. The mean baseline Hb level was 9.4 +/- 1.0 g/dL. The median serum Epo level was 32 mU/mL, and endogenous Epo production was found to be defective in 77% of the patients, as judged by a value for the ratio of observed-to-predicted serum Epo levels (O/P ratio) of < or = 0.9. An intention-to-treat analysis was performed to evaluate treatment efficacy. The median average increase in Hb levels per week was 0.04 g/dL in the control group and -0.04 (P = .57), 0.22 (P = .05), 0.43 (P = .01), and 0.58 (P = .0001) g/dL in the 1,000 U, 2,000 U, 5,000 U, and 10,000 U groups, respectively (P values versus control). The probability of response (delta Hb > or = 2 g/dL) increased steadily and, after 8 weeks, reached 31% (2,000 U), 61% (5,000 U), and 62% (10,000 U), respectively. Regression analysis using Cox's proportional hazard model and classification and regression tree analysis showed that serum Epo levels and the O/P ratio were the most important factors predicting response in patients receiving 5,000 or 10,000 U. Approximately three quarters of patients presenting with Epo levels inappropriately low for the degree of anemia responded to rHuEpo, whereas only one quarter of those with adequate Epo levels did so. Classification and regression tree analysis also showed that doses of 2,000 U daily were effective in patients with an average platelet count greater than 150 x 10(9)/L. About 50% of these patients are expected to respond to rHuEpo. Thus, rHuEpo was safe and effective in ameliorating the anemia of MM and NHL patients who showed defective endogenous Epo production. From a practical point of view, we conclude that the decision to use rHuEpo in an individual anemic patient with MM or NHL should be based on serum Epo levels, whereas the choice of the initial dosage should be based on residual marrow function.

Adult↗
PubMed1995

Gastric malt lymphoma with crystalline immunoglobulin inclusions and secondary immunoblastic lymphoma in a cervical lymph node.

A case of gastric B cell lymphoma of the mucosa-associated lymphoid tissue (MALT) with crystalline immunoglobulin inclusions in monotypic plasma cells is reported, which initially presented as a secondary immunoblastic lymphoma in a cervical lymph node. The low-grade MALT lymphoma was diagnosed 14 months after detection of the nodal high-grade lymphoma, but rare crystal-containing plasma cells of identical immunoglobulin isotype found in the immunoblastic lymphoma retrospectively confirmed a common clonal origin. The diagnostic significance of crystalline immunoglobulin inclusions and the unusual initial presentation of MALT lymphoma as a secondary high-grade lymphoma at a distant nodal site are discussed.

Aged↗
PubMed1995

Necrotizing vasculitis associated with hepatitis C virus infection: successful treatment of vasculitis with interferon-alpha despite persistence of mixed cryoglobulinemia.

Type II cryoglobulinemia may be associated with chronic hepatitis C virus (HCV) infection and may be characterized by vascular purpura. We report on a case of histologically proven necrotizing vasculitis associated with type II cryoglobulinemia and HCV infection. Within 14 days of interferon-alpha therapy (3 x 3 million IU/ml/week), purpuric skin lesions disappeared as well as fatigue and arthralgia; 9 months after initiation of therapy, liver enzyme values were nearly normal despite persistence of HCV RNA tested by PCR and mixed cryoglobulinemia. Rheumatoid factor activity, however, decreased markedly. To our knowledge, our patient is the first reported case with histologically proven necrotizing vasculitis with a beneficial effect of interferon-alpha. Because of the persistence of cryoglobulins, but reduction of the IgM fraction in the cryoglobulin complex under interferon-alpha treatment, it would seem worthwhile to further elucidate the pathogenic role of qualitative instead of quantitative changes of cryoglobulins and the mechanism of action of interferon-alpha.

Arthralgia↗
PubMed1994

Apoptosis and therapy of malignant diseases of the hematopoietic system.

Apoptosis is essential in the pathogenesis of hematological diseases. A tumor develops, if the balance between cell division and cell death is disturbed. In recent years many genes involved either in blocking or inducing this process have been identified. Additionally, several cytokines which influence apoptosis have been found. Some of these cytokines could also play a role in the development of resistance to chemotherapeutic agents. Many anticancer drugs exert their action via apoptosis. A strategy to selectively induce apoptosis of tumor cells without altering healthy cells and thus reducing the side effects of therapeutic regimens is a major goal for future development of new therapeutic techniques. Blocking the factors which are responsible for resistance is another promising therapeutic approach and could further improve the clinical outcome and finally prolong the life of patients.

Animals↗