Search PubMed⌕ Search

Biomedical subjects

M Micksche

Publications and source records attributed to M Micksche.

At least 37 records · Page 2Linked to original sources
PubMed1994

Intrinsic MDR-1 gene and P-glycoprotein expression in human melanoma cell lines.

Metastatic malignant melanoma is considered a chemotherapy-refractory malignancy. A few previous studies have delivered contradictory results regarding the presence and functionality of P-glycoprotein (P-gp), a transmembranous protein associated with the classical multidrug resistance (cMDR), in malignant melanoma. Therefore we have investigated this issue on 33 cell lines established from primary and metastatic lesions of human malignant melanoma, comparing different cMDR detection methods. Immunocytochemically 33% of the cell lines stained positive for P-gp. The data correlated with those of a P-gp-radioimmunometric (antibody-binding) assay. When RT-PCR was used for MDR-1 mRNA determination, 76% of the melanoma cell lines scored positive. Slot-blot analysis was seen to be less sensitive than RT-PCR. Results from the functional P-gp assays, using daunomycin (DM) as MDR-substrate, showed no influence of P-gp expression on drug accumulation and cytotoxicity. However, the cMDR-modifier verapamil (VP) significantly increased both parameters in those melanoma cells with the highest P-gp levels. We conclude that cMDR is apparently not the decisive but probably a complementary protective mechanism against toxic agents in malignant melanoma.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Treatment of advanced colorectal cancer with folinic acid and 5-fluorouracil in combination with cisplatinum.

51 patients with metastatic colorectal cancer (stage Dukes D) were treated with intravenous (i.v.) infusion on days 1, 3, 5, 8 and 16 with folinic acid (200 mg/m2) and 5-fluorouracil (600 mg/m2), and on days 1, 8 and 16 with cisplatinum (25 mg/m2 i.v.); cycles were repeated every 4 weeks. All 51 patients were evaluable for toxicity and response criteria. 26 patients had objective responses (3 complete responses, 5.9%; 23 partial responses, 45.1%), relative risk 51% (95% confidence intervals 36.7-65.0%). Response duration ranged from 4 to 28.0 months (median 16.8). Overall median survival of all patients included was 14.7 months (range 3.0-33.0). Toxicity of WHO grade III, requiring dose reduction, occurred in 9 (18%) patients. The regimen described here appears to be active, safe and well tolerated for treatment of patients with advanced colorectal cancer.

Aged↗
PubMed1993

P-glycoprotein regulates chemosensitivity in early developmental stages of the mouse.

The multidrug resistance (MDR) P-glycoprotein (P-gp) is an active transporter associated with chemoresistance of tumor cells. A fundamental aspect not yet entirely clarified is the physiological role of MDR-P-gp in normal mammalian tissues. In this paper we report that multidrug (chemo)resistance is already present in mouse oocytes and early cleavage embryos. Expression of MDR-specific P-gp is detectable by antibody (C219) staining from the primary oocyte onward to the eight-cell embryo. MDR-mRNA is demonstrated in mature oocytes using an Mdr1-specific cDNA probe. Functional activity of P-gp is shown by the efficacy of MDR reversers (verapamil or quinidine) in enhancement of: 1) drug accumulation (daunomycin) in all stages investigated, 2) drug cytotoxicity (daunomycin or mitomycin c-induced developmental impairment) in two-cell embryos cultured for 24 h, and 3) drug cytokinesis-blocking activity (cytochalasin D; our recent findings demonstrate cytochalasins to be substrates for P-gp and to indicate the presence of MDR by their microfilament-disrupting action on cycling cells) in four- and eight-cell embryos cultured for 24 h. Furthermore, functional involvement of P-gp in vivo is demonstrated. Concurrent administration of verapamil increases doxorubicin-induced developmental impairment in the zygote stage during the first cleavage cycle in pregnant females. Results provide evidence that MDR-P-gp has an efficient protective function in early reproduction.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

[New aspects of interferon therapy in malignant diseases].

Recombinant Interferon-alpha (IFN-alpha) preparations are now used for more than 10 years for treatment of hematological, oncological and viral diseases. New insights into the influence of IFN on the metabolism of cytostatic agents, i.e. biochemical modulation, opens a new spectrum of combination therapies. The efficacy of locoregional administration (intraperitoneal, -pleural, perilesional, intravesical) is probably based on a direct effect of this agent on both tumor and effector cells. Inhibition of angiogenesis is one of the proposed mechanisms responsible for the efficacy of IFN in life-threatening hemangiomas and might have also some potency in the adjuvant therapy of cancer. Presently IFN is used in combination with biological response modifiers, cytokines and especially a synergistic therapeutic effect is documented with retinoids. The possibility of direct stimulating effects of IFN on the immune system should be considered particularly in future studies.

Antineoplastic Agents↗
PubMed1993

[Vitronectin in bronchoalveolar lavage--a parameter of disease activity in sarcoidosis].

Vitronectin is a multifunctional glycoprotein which is involved in several of the processes of inflammation and repair. In previous studies we demonstrated that increased concentrations of vitronectin can be detected in bronchoalveolar lavage fluids (BAL) of patients with interstitial lung disease (e.g. sarcoidosis). The outcome of sarcoidosis is generally favorable, however, some patients progress to pulmonary fibrosis. There is a need for markers indicating early fibrotic changes in the lung in patients with sarcoidosis. The present study was designed to evaluate the potential of BAL-vitronectin measurements for the assessment of disease activity in subjects with sarcoidosis. BAL-vitronectin concentrations were determined in 19 patients with biopsy proven sarcoidosis and sequential analysis of BAL-vitronectin levels were performed in 11 patients before and after therapy. Patients with active sarcoidosis had higher BAL-vitronectin concentrations (1.56 +/- 0.89 microgram/ml) than patients with inactive disease (0.68 +/- 0.33 microgram/ml; p < 0.01). Patients with active sarcoidosis received high-dose glucocorticoid treatment for four weeks followed by low-dose glucocorticoid therapy for eleven months. After high-dose medication BAL-vitronectin concentrations fell significantly (1.08 +/- 0.9 microgram/ml; p < 0.01). A further decrease in vitronectin levels resulted when therapy was continued for a year (0.75 +/- 0.48 micrograms/ml). Clinical deterioration correlated with an increase in BAL-vitronectin concentrations. Thus, measurement of BAL-vitronectin levels might be a useful marker for assessing disease activity and response to therapy in patients with sarcoidosis, but does not provide prognostic information.

Adult↗
PubMed1993

[Interferon--a new therapeutic principle].

Interferons (IFNs) have already been discovered 35 years ago. In the seventies, improvements of blood cell- and tissue culture techniques made it possible to obtain sufficient material to be used within clinical therapy studies. Recombinant DNA technology allowed large scale production of this protein in highly purified form and the development of pharmaceutical specialities. These preparations have been used for detailed biological characterisation of IFN. Beside antiviral activity IFN has potent antitumoral effects (inhibition of proliferation, influence on oncogene expression and growth factor production, induction of differentiation, inhibition of transformation). Furthermore, IFNs are potent immunomodulating agents as they augment cytotoxic activity of effector cells, modulate the expression of membrane proteins (tumor-associated antigens, histocompatibility antigens) and have influence on the cytokine cascade. Based on these pleiotropic activities IFNs can be considered new therapeutics principles.

Antineoplastic Agents↗
PubMed1993

[Interferon therapy in multiple myeloma].

Multiple myeloma is a B-cell malignancy characterised by a clonal expansion of plasma cells. Prognosis of the disease can be based upon clinical stage and biological features of myeloma cells as well as of their products. Cytostatic therapy is a standard in the treatment of multiple myeloma. A new aspect is the therapeutic administration of recombinant interferons (rIFNs). Some experience has been gathered that chemotherapy-induced remissions (plateau phase) can be maintained by IFN-therapy. In induction therapy, IFN in combination with cytostatic agents has some therapeutical relevance, either. The administration of IFN in the treatment of multiple myeloma represents a new therapeutic strategy.

Biomarkers, Tumor↗
PubMed1993

[Interferon therapy in malignant melanoma].

The incidence of malignant melanoma in the Caucasian population is rising constantly. As mortality rate, also morbidity rate is elevated. Because of better diagnostic tools the curability in early stages is enlarged quantitatively. For high risk cases in stage I and II and metastatic disease there exists no established therapy regimen. Longtime Interferon-alpha therapy as an adjuvant therapeutic tool had shown an improvement of relapse-free interval and survival. The combination of chemotherapeutic regimen and Interferon in the interval resulted in an increase up to 20% success risk.

Carboplatin↗
PubMed1993

[Diagnostic value of secretory products of eosinophils and neutrophils in bronchoalveolar lavage in patients with idiopathic lung fibrosis].

Idiopathic pulmonary fibrosis (IPF) is characterized by a chronic inflammatory process in the lower respiratory tract of unknown etiology and poor prognosis. There is evidence that cytotoxic mediators released by neutrophils and eosinophils, such as myeloperoxidase (MPO) and eosinophil cationic protein (ECP) play a central role in the pathogenesis of this disease. The aim of this study was to assess disease activity in patients with IPF by measuring MPO and ECP concentrations in bronchoalveolar lavage (BAL). 14 patients with IPF had significantly higher concentrations of BAL-MPO and ECP (median = 117.2 micrograms/l, range: 4-217 micrograms/l and median = 16 micrograms/l, range: 4-34 micrograms/l, respectively) than patients with sarcoidosis (n = 9) (median = 6.5 micrograms/l, range: 4-12 micrograms/l and median = 7.1 micrograms/l, range: 2-13 micrograms/l, respectively) or pneumonia (n = 13) (median = 10.8 micrograms/l, range: 5-14 micrograms/l and median = 7.6 micrograms/l, range: 3-10 micrograms/l, respectively) (p < 0.01). Follow-up of MPO and ECP concentrations in BAL was performed in 8 patients with IPF before and after 4 weeks high-dose and 12 months low-dose corticosteroid therapy. Changes in MPO and ECP levels paralleled the clinical course and successful treatment resulted in a significant decrease of both MPO and ECP concentrations (p < 0.05), while clinical deterioration or treatment failure was associated with an increase of BAL-MPO and ECP levels. Increased MPO and ECP concentrations in BAL seem to reflect ongoing disease activity and may be useful prognostic markers in the management of patients with IPF.

Adrenal Cortex Hormones↗
PubMed1993

Granulocytes of critically ill patients spontaneously express the 72 kD heat shock protein.

Polymorphonuclear neutrophils (PMN), through their ability to release oxygen-free radicals and other tissue-damaging molecules, play a major role in the pathogenesis of multiple organ failure syndrome (MOFS). There is evidence that heat shock proteins (stress proteins; HSPs) are involved in cellular repair mechanisms, and are protecting cells against oxidative injury. In this study, we analyzed the spontaneous expression of the 72 kD HSP (HSP72) in peripheral blood PMN of 20 critically ill patients (16 polytrauma victims, four patients after major surgery) admitted to an intensive care unit. The expression of HSP72 was investigated in PMN of patients and healthy donors by immunohistochemistry. We found spontaneous expression of HSP72 in PMN of 12 (60%) of 20 patients. No specific staining was detected in PMN of healthy donors (n = 10). In PMN of six of 12 patients expressing HSP72 without previous heat treatment, we found an impairment of respiratory burst activity (RBA) compared to the control population. These results demonstrate for the first time the in vivo expression of HSP72 in human leukocytes without previous heat treatment, and suggest a possible role of this protein in patients suffering from severe tissue injury.

Adult↗
PubMed1992

Influence of interferon alfa-2b with or without folinic acid on pharmacokinetics of fluorouracil.

Interferon alfa has been demonstrated to enhance the effect of fluorouracil (5-FU) on human colon cancer cell lines as well as in clinical studies. By several authors interest in focussed on the question whether the interaction between these two agents is reflected by changes of 5-FU kinetics. In the present study the pharmacokinetic behavior of 5-FU was investigated in combination with interferon alfa (IFN-alpha-2b) and further after adding the second well-established biomodulating agent folinic acid (FA). Ten patients with advanced gastrointestinal cancer received 5-FU as a weekly bolus injection of 750 mg/m2, IFN-alpha-2b 5 million units three times per week subcutaneously and FA as a short time infusion at 200 mg/m2. 5-FU plasma levels were determined by high performance liquid chromatography as a baseline measurement on day 1 before starting IFN-alpha-2b. Analysis was repeated at the second or third cycle of 5-FU administration 1 hour after the last IFN-alpha-2b injection, and finally after also adding FA immediately infused before 5-FU injection. Biomodulation of 5-FU by IFN-alpha-2b alone resulted in a significant alteration of 5-FU kinetic parameters as demonstrated by an increase of area under the curve by 80%, and of blood concentration (co) by 65%, and a decrease of total clearance at 50%. These data may partly explain the observed enhancement of antiproliferative and toxic effects of this combination. On the other hand, when FA was added to this schedule, no significant changes of 5-FU kinetics could be documented. Therefore the theoretical benefit of such a double modulation cannot be supported by our findings. Further preclinical and clinical investigations are required to define the role of a triple combination of 5-FU with IFN-alpha-2b and FA.

Aged↗
PubMed1992

Pharmacokinetic aspects of interferon alfa-2b after intrahepatic or intraperitoneal administration.

The pharmacokinetics of interferon alfa-2b (IFN-alpha-2b) were determined following intraperitoneal (IP) infusion of escalating doses, ie, 5, 10, and 15 million units (MU) and intrahepatal-intraarterial (IA) (IA, bolus v 24 hours continuous infusion of 3 and 5 MU) administration in patients with metastatic cancer. Pharmacokinetic parameters show that bioavailability of IFN-alpha-2b after IP administration is 30 times higher for the peritoneal fluid (PF) than for peripheral blood (PB) explaining also the low incidence of side effects. The high affinity of IFN-alpha-2b to the peritoneal cavity is furthermore substantiated by the total compartment clearance, which is only about 1 1/minute for the PF in comparison to about 30 1/minute as determined for PB. IFN-alpha-2b is eliminated from the PF with a half life (t1/2) of elimination 10 to 32 hours and from the blood with t1/2 of 5 to 13 hours. After IA bolus, IFN is distributed from the blood with a t1/2 below, 2 hours, with dose-dependent serum peak concentrations (c = 47 IU for 3 MU and 145 IU for 5 MU). Twenty-four-hour infusion leads to a steady state within 4 to 6 hours and maximum concentration of 8.5 or 12.5 IU/mL, respectively. During infusion IFN alpha-2b is slowly eliminated with a t1/2 of 16 hours. The lower area under the curve levels after bolus injection may suggest a better tissue uptake of IFN-alpha-2b by the liver. Further studies on pharmacokinetics are warranted to establish exact dose recommendations for an optimal schedule using this route and mode of IFN-alpha-2b administration in mono- and combination therapies.

Female↗
PubMed1991

Treatment with biologic response modifiers in patients with ovarian cancer.

The therapeutic and immunomodulating potential of biological response modifiers (BRM) such as OK-432 (a streptococcal preparation) and recombinant interferon gamma (rIFN-gamma) has been evaluated in 15 patients with advanced chemotherapy resistant ovarian cancer, presenting malignant ascites and/or pleural effusions. OK-432 was injected intracavitary in 10 patients in increasing doses from 0.2 up to 7.5 mg weekly. Five women were treated intracavitary with rIFN-gamma twice a week. The initial dose was 0.1 mg/m2 which was raised up to 12 mg/m2 over 6 weeks. With OK-432 a complete response was achieved for 14.1 + 8.9 months in 4 patients, a partial response for 1.7 + 0.3 months in 3 patients. The survival time of the 4 responders was significantly longer (21.1 + 8.3 months) than the survival time of the patients with partial or no response (4.9 + 2.7,4.1 + 2.3 months, respectively). In the rIFN-gamma therapy group, we found a partial response in one and no response in 4 patients. Toxicity observed under OK-432 and rIFN-gamma was minimal in all patients, suggesting a lack of systemic effect of intracavitary-applied BRM. With both agents, augmentation of certain immune responses, especially in the peritoneal cavity and to a lesser extent in the peripheral blood, has been documented. In 5 patients treated with OK-432, we found an overall augmentation of the effusion macrophage killer activity. rIFN-gamma augmented natural killer activity in 2 of 3 patients.

Aged↗
PubMed1991

Respiratory burst capability of polymorphonuclear neutrophils and TNF-alpha serum levels in relationship to the development of septic syndrome in critically ill patients.

Activated polymorphonuclear neutrophils (PMN) and neutrophil activating mediators such as tumor necrosis factor-alpha (TNF-alpha) are thought to be involved in the pathophysiology of sepsis and multiple organ failure syndrome (MOFS). In critically ill patients at high risk for the development of septic syndrome (n = 17) peripheral blood PMN were assayed for O2- and H2O2 production after stimulation with phorbol myristate acetate (PMA, 40 nM). Serum TNF-alpha levels were determined by ELISA. At the time of admission to the intensive care unit we found significant higher levels of TNF-alpha (P = 0.0001) in the serum of patients finally developing sepsis correlating to higher respiratory burst capability in comparison to nonseptic patients. Additionally we were able to demonstrate a significant (P = 0.0016) lower dismutation rate of O2- to H2O2 in deceased patients in comparison to survivors. These results give further evidence that elevated levels of circulating TNF-alpha and activated PMN play a significant role in the pathogenesis of septic syndrome in critically ill patients.

Biomarkers↗