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C Dittrich

Publications and source records attributed to C Dittrich.

At least 37 records · Page 2Linked to original sources
PubMed1997

Tyrosine kinase signaling pathways control the expression of retinoic acid receptor-alpha in SK-BR-3 breast cancer cells.

Breast carcinomas are frequently characterized by hyperactivated c-erbB receptor tyrosine kinase signaling. Combination of anti-proliferative retinoids with growth-inhibitory c-erbB-specific agents might induce therapeutic benefit. We demonstrate close interactions between the c-erbB and the retinoic acid receptor system in SK-BR-3 breast cancer cells. Epidermal growth factor and heregulin-beta1 activate c-erbB receptors and dose- and time-dependently up-regulate retinoic acid receptor-alpha (RAR-alpha) mRNA. Similar effects have been found for the growth-inhibitory c-erbB-2 receptor tyrosine kinase-activating antibody 4D5 and the tyrosine phosphatase inhibitor orthovanadate. In contrast, the tyrosine kinase-inhibitor herbimycin A reduces tyrosine-specific protein phosphorylation and down-regulates RAR-alpha. Our data demonstrate that the expression of RAR-alpha, which represents a key mediator of the anti-proliferative effects of retinoids in breast cancer cells, is regulated by modulators of tyrosine kinase signaling. The levels of RAR-beta and -gamma mRNAs, however, are not affected by such agents.

Breast Neoplasms↗
PubMed1997

Octreotide combined with goserelin in the therapy of advanced pancreatic cancer--results of a pilot study and review of the literature.

The two hormone analogues octreotide and goserelin have been shown to decelerate growth of human pancreatic cancer in vitro and in vivo. The objective of this pilot study was to investigate the efficacy and toxicity of the combination of these two agents in patients with advanced pancreatic cancer. Octreotide was injected subcutaneously in dosages increasing weekly, starting with 50 micrograms twice daily, until the level of maintenance therapy of 500 micrograms three times a day was reached. In addition, 3.8 mg goserelin acetate was administered subcutaneously at monthly intervals. A median of 7 cycles (range 1-27 cycles) were applied; 13 out of 14 patients entered into the study were evaluable for response and all 14 were evaluated for toxicity. In one patient with initially non-resectable pancreatic cancer, systemic therapy yielded a partial remission lasting 9 months. The degree of tumour regression then allowed a consecutive macroscopic radical tumour resection followed by an additional 6 months of no evidence of disease while the same drug combination was continued. In an additional 9 patients, no change of disease was observed, in some cases for a remarkably long time (up to 27 months). Nevertheless, the objective response rate of 7% (95% confidence interval 0 +/- 21%) was low. In 5 patients a clear improvement in their performance status was seen soon after the start of therapy; 3 patients showed progression of the disease at first evaluation or earlier and 1 patient was not evaluable at the time of study assessment. According to the product-limit method of Kaplan and Meier, the time to progression was 3.0 +/- 1.8 months [median +/- asymptotic standard error (ASE)] and overall survival was 6.0 +/- 1.5 months (median +/- ASE). Toxicity was rare and only of mild to moderate degree. Overall, the regimen under investigation did not meet the criteria for sufficient antitumoural effectiveness. Nevertheless, this study reinforces the concept that pancreatic cancer is principally responsive to endocrine therapy and therefore the further investigation of hormonal manipulation seems worth while in the future.

Aged↗
PubMed1997

[Diploma of continuing education from the Society of Physician of Thüringia].

The diploma of continuing medical education (DCME) gives the possibility to describe and document the effort of the physicians to accomplish continuing medical education and quality assurance which is a claim of the professional rules for physicians. Stimulation of the physicians to participate lectures is a further goal of the DCME. The DCME which can't be used as a title, is supposed to be for physicians, who finished their specialisation. Acquisition of DCME is voluntary. For the DCME, the candidates have to participate 100 hours of continuing medical education with given theme setting for 3 years. The DCME represents an useful proof for the fulfilling of the duty of continuing education as well as for evaluation of given lectures.

Education, Continuing↗
PubMed1996

Synergistic activation of interleukin-8 gene transcription by all-trans-retinoic acid and tumor necrosis factor-alpha involves the transcription factor NF-kappaB.

Induction of interleukin-8 (IL-8) by IL-1 or tumor necrosis factor (TNF), and repression by interferons or glucocorticoids have been shown to involve sequences between nucleotides -94 and -71 of the 5'-flanking region, and the transcription factors NF-IL-6 and NF-kappaB. The A3 cell line was derived from the human melanoma cell line G-361 by stable transfection with part of the IL-8 promoter (nucleotides -101 to +40 from transcription start) fused to the luciferase coding region. These regulatory sequences were sufficient for transcriptional activation by all-trans-retinoic acid (ATRA), 9-cis-retinoic acid, IL-1beta, or TNF-alpha. Simultaneous treatment of A3 cells with ATRA and TNF-alpha resulted in a dose- and time-dependent synergistic increase in luciferase expression and IL-8 mRNA levels. Transient transfections of the parental cell line demonstrated that the NF-kappaB binding site is essential for this synergistic transactivation. Electrophoretic mobility shift assays with nuclear extracts of A3 cells showed that stimulation with ATRA and TNF-alpha for more than 16 h resulted in enhanced NF-kappaB binding compared to that induced by TNF-alpha alone. The simultaneous treatment with ATRA and TNF-alpha also resulted in changes in the composition of NF-kappaB complexes bound to the IL-8 NF-kappaB site, preventing the formation of two TNF-alpha-inducible binding activities. We suggest that these complexes consist of repressive factors which, when removed, allow enhanced binding of NF-kappaB to its cognate site.

Drug Synergism↗
PubMed1996

Vinorelbine-induced neurotoxicity in patients with advanced breast cancer pretreated with paclitaxel--a phase II study.

Vinorelbine (VNB) shows high antitumoral activity in advanced breast cancer due to its high affinity for mitotic tubulin and differs from the other vinca alkaloids with regard to its low degree of neurotoxicity because of its low affinity for axonal tubulin. Preclinical data show the existence of different binding sites on tubulin for vinca alkaloids and paclitaxel (P), suggesting a lack of cross-resistance. Thus, VNB was chosen eligible for a phase II study to evaluate both the therapeutic efficacy and the toxicity of VNB in patients (pts) with advanced breast cancer failing first- or second-line chemotherapy with P. A total of 14 pts with advanced breast cancer pretreated with P were entered into the study. Therapy consisted of VNB at 30 mg/m2 diluted in 500 ml of normal saline given over 30 min after a minimal interval of 4 weeks since the last application of P. For the first four cycles, injections were repeated at 2-week intervals; thereafter they were repeated at 3-week intervals until evidence of progressive disease or severe toxicity developed. All but one pt was considered assessable for response and all pts were evaluable for toxicity. No objective response was observed; two pts showed no change in their disease. In four pts therapy had to be stopped because peripheral neurotoxicity increased from a pretherapeutic level after therapy with P from National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 1 (n = 3) and 2 (n = 1) to neurotoxicity grade 3 after 1, 2 (n = 2), and 3 cycles of therapy with VNB, respectively. In addition, constipation of grade 2 occurred in 10 pts. Hematologic toxicity was negligible. No other evaluable toxicity exceeded NCI-CTC grade 1. Both observations of this study, the complete resistance to VNB and the increase in peripheral neuropathy, let us assume the existence of a preclinically not anticipated but clinically relevant cross-resistance between these two spindle poisons and the presence of common functional targets. Therefore, P-pretreated pts should be excluded from consecutive VNB-containing therapies.

Adult↗
PubMed1996

Genes related to growth and invasiveness are repressed by sodium butyrate in ovarian carcinoma cells.

Down-regulation of oncogene expression is one of the hallmarks of the process whereby transformed cells are forced into differentiation and/or growth arrest by potent inducers and therefore can represent an interim end point in cancer treatment. The differentiation inducer sodium butyrate (NaB) arrested growth of N.1 ovarian carcinoma cells and repressed expression of cyclin D1/prad1 and the invasiveness-related protease plasminogen activator-urokinase (plau). This was accompanied by the acquisition of a differentiated morphology, all of which characteristics were maintained as long as N.1 cells were exposed to the inducer. In accordance with a differentiated phenotype was the finding that fibronectin expression was increased significantly. Recently, it was shown that NaB represses the transcription factor c-myc by blocking Ca2+ signals and modulating serine threonine kinase activity. We wanted to investigate NaB-mediated interference on signals contributing to the expression on prad1, plau and growth arrest-specific 6 (gas6). Protein kinase A (PKA) inactivation de-repressed prad1 and plau transcript levels. NaB had onlygeneral but no specific influence on PKA-modulated prad1 and plau expression however. Protein kinase C activation up-regulated plau transcript levels, but not that of prad1. Prad1 expression seemed to depend on Ca2+-triggered signals. Constitutive plau expression was insensitive to additional Ca2+-mediated signals, but it became responsive upon NaB treatment.

Adenylyl Cyclases↗
PubMed1996

[Drug therapy of ovarian carcinoma].

Patients with ovarian tumors of low malignant potential should be submitted exclusively to observation, but not to therapy. The same holds true for patients with epithelial ovarian cancer FIGO stages IA, IB with high and intermediate differentiation (G1/G2). All other patients with early stage ovarian cancer should be treated with adjuvant chemotherapy. There exists no standard therapy for these stages so far. The following options are actually under investigation: mono-chemotherapy with cisplatin or cyclophosphamide as well as combination therapy of cisplatin with cyclophosphamide or carboplatin with paclitaxel. The duration of adjuvant therapy is also subject of on-going trials. In patients with advanced ovarian cancer, platin-containing regimens yield longer survival rates than those without platin. Platin-containing combinations are more effective than equally dosed platin-monotherapy. With regard to the antitumoral effectiveness, no significant difference between cisplatin and its less toxic analogue carboplatin was found. Therefore, cisplatin may be substituted with carboplatin. Very recently, the combination of cisplatin with the taxane paclitaxel was shown significantly more efficacious than the old standard of platin plus cyclophosphamide with regard to response and survival rates representing actually the therapy of choice for the primary therapy of advanced ovarian cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Bidirectional interactions between the estrogen receptor and the cerbB-2 signaling pathways: heregulin inhibits estrogenic effects in breast cancer cells.

The responsiveness of estrogen receptor (ER)-positive breast cancer to endocrine therapy is frequently reduced in cells over-expressing c-erbB-2. Stimulation of ER suppresses c-erbB-2, indicating that estrogen controls the activity of c-erbB-2. Heregulin (HRG) has been described to bind to c-erbB-3/c-erbB-4 and to stimulate c-erbB-2. Here we describe the effects of HRG on cell growth and on ER and c-erbB-2 expression in breast cancer cell lines containing distinct levels of c-erbB-2 and ER (BT-474: c-erbB-2 , ER+; MDA-MB-361: c-erbB-2++, ER++; MCF-7: c-erbB-2+, ER ). Proliferation of estrogen-stimulated, c-erbB-2 and ER-positive cells is inhibited by HRG in a dose-dependent manner. In addition, HRG dose-dependently inhibits ER expression. Estrogen, however, inhibits c-erbB-2. Estrogen-mediated down-regulation of c-erbB-2 is most pronounced in MCF-7 but weaker in BT-474. In the latter cells HRG efficiently blocks the estrogenic effect on c-erbB-2. In MCF-7 cells, however, the inhibition of c-erbB-2 cannot be completely reverted by HRG. This modulation occurs in all 3 cell lines at protein, RNA and transcriptional levels, suggesting that the activity of the c-erbB-2 promoter, which contains an estrogen-responsive region, is affected by HRG. The intensity of the mutual inhibition between the HRG/c-erbB-2 and the estrogen/ER system depends on the relative levels of ER and c-erbB-2 expression in the respective cell lines.

Antineoplastic Agents↗
PubMed1995

Retinoic acid induced death of ovarian carcinoma cells correlates with c-myc stimulation.

In the ovarian adenocarcinoma subline N.I, all-trans retinoic acid (ATRA) induced substantial cell death. This response was elicited only at decreased serum levels. Exposure of N.I cells to increasing concentrations of ATRA was accompanied by a considerable up-regulation of c-myc transcript levels that correlated with the rate of cell killing, which itself was an active process as judged by sustained transcriptional expression. ATRA-triggered rounding and detaching of single cells from the substratum was accompanied by degradation of genomic DNA. We show that the N.I model cell line, which is otherwise highly ATRA-resistant, can undergo an ATRA-triggered suicide program when serum is limited. The accompanying c-myc up-regulation seems to be mediated by retinoic-acid-receptor-independent pathways involving membrane-associated phospholipases instead, because manoalide partly suppressed c-myc induction by ATRA but left constitutive c-myc expression unaffected.

Adenocarcinoma↗
PubMed1995

Regulation of interleukin-8 gene expression by all-trans retinoic acid.

We have studied the relationship between interleukin-8 (IL-8) and interleukin-1 alpha (IL-1 alpha) release after stimulation with all-trans retinoic acid (ATRA) and tumor necrosis factor-alpha (TNF-alpha) in the human epithelial ovarian cancer cell line HOC-7. Both IL-1 alpha and IL-8 protein release were enhanced by treatment with ATRA and TNF-alpha after 48 h exposure. Blocking of IL-1 alpha activity in HOC-7 cells with either IL-1 receptor antagonist (IL-1ra) or a neutralizing antibody directed against IL-1 alpha resulted in a dose-dependent decrease of IL-8 release by ATRA, TNF-alpha and IL-1 alpha treated HOC-7 cells. Expression of IL-8 mRNA was enhanced by the individual stimuli, whereas co-treatment with IL-1ra resulted in a loss of IL-8 specific transcripts, except in TNF-alpha treated cells. Inhibition of de novo protein synthesis by cycloheximide (CHX) and simultaneous blocking of IL-1 alpha activity by IL-1ra for 24 h revealed that ATRA controls IL-8 gene expression transcriptionally and that the extent of IL-8 protein release can be markedly influenced by cellular expressed IL-1 alpha.

Adenocarcinoma↗
PubMed1995

Pharmacokinetics of 4'-O-tetrahydropyranyladriamycin given on a weekly schedule in patients with advanced breast cancer.

Improved quality of life has gained importance over shortly lasting remissions in yet incurable metastatic breast cancer. Fractionation of drug administration is one of the possible approaches to reduce the concentration-dependent toxicity of anthracyclines. We evaluated the pharmacokinetics of 4'-O-tetrahydropyranyladriamycin (THP-ADM) under weekly administration in patients with advanced breast cancer (dose escalation, from 20 to 27 mg/m2 THP-ADM). The concentration-time curves of THP-ADM in plasma were best described by an open three-compartment model [half-life of the first disposition phase (t1/2 alpha), 3.15 min; terminal elimination half-life (t1/2 gamma), 13.9 h] with a mean area under the curve (AUC) of 12.2 ng h ml-1mg-1 m-2, resulting in a mean plasma clearance of 86.9 1h-1 m-2. Metabolism included the formation of Adriamycin (ADM), Adriamycinol (ADM-OH), 13-dihydro-4'-O-tetrahydropyranyladriamycin (THP-OH), 7-deoxyadriamycinone (7H-ADn), and 7-deoxy-13-dihydroadriamycinone (7H-ADn-OH), with maximal plasma concentrations ranging from 2.8 to 5.5 ng/ml. The mean total amount of cytotoxic anthracyclines excreted into urine, mainly as the parent drug, was 5% of the delivered dose. ADM and ADM-OH, but not the parent drug, were observed in urine at up to 4 weeks after the last therapeutic cycle. There was a significant correlation between the leukocyte nadir under therapy and the AUC of ADM-OH (r = 0.800, P < 0.05). Since no shift in the plasma kinetics was observed from the first to the sixth cycle, the favorable ratio of the AUCs of THP-ADM and ADM after fractionation of THP-ADM suggests lower toxic side effects attributable to ADM. This hypothesis was confirmed in a clinical study, where no severe cardiotoxicity and only mild alopecia were observed in 19 patients. Thus, pharmacokinetics studies might be helpful in both individualization of therapy with THP-ADM and optimization of the administration schedule.

Adult↗
PubMed1995

Evaluation of plasma 5-fluorouracil nucleoside levels in patients with metastatic breast cancer: relationships with toxicities.

This paper describes the relationship between 5-fluorouracil (FUra)-derived toxicities and plasma levels of the FUra anabolites 5-fluorouridine (FUrd) and 5-fluoro-2'-deoxyuridine (FdUrd) monitored in patients receiving continuous infusions of FUra (1000 mg/m2 per 24 h) over 5 days preceded by the administration of cisplatin (100 mg/m2). A total of 63 courses of this treatment were given as second-line chemotherapy to 17 patients with metastatic breast cancer. The active FUra anabolites FUrd and FdUrd were monitored twice daily in the plasma by high-performance liquid chromatography. Data were analyzed using multiple analysis of variance (ANOVA). Only a low proportion of patients exhibited measurable plasmatic levels of FUrd (43%) and FdUrd (70%). The areas under the plasma concentration-time curves (AUC) determined over 120 h for FUrd (AUCFUrd) and for FdUrd (AUCFdUrd) were found to be statistically significantly different for chemotherapy cycles with and those without myelosuppression. Chemotherapy cycles without neutropenia were associated with low AUCFUrd values (mean +/- SEM, 2.9 +/- 0.7 micrograms ml-1 h) and high AUCFdUrd values (14.1 +/- 2.7 micrograms ml-1 h), respectively, whereas courses with myelosuppression (WHO grades 2-4) showed inverse profiles with high AUCFUrd values (16.3 +/- 2.3 micrograms ml-1 h) and low AUCFdUrd values (3.1 +/- 1.0 micrograms ml-1 h), respectively. A statistically significant difference in AUCFdUrd values was also observed between cycles with and those without mucositis (P = 0.0027), with AUCFdUrd values being 22.6 +/- 5.6 and 7.8 +/- 1.9 micrograms ml-1 h, respectively. Whereas hematotoxicity could be correlated with both AUCFUrd and AUCFdUrd values, mucositis was associated with high AUCFdUrd levels. Moreover, a negative correlation was found between the AUCs determined for FUrd and FdUrd (P = 0.002), indicating that activation of FUra via FUrd or via FdUrd may involve competitive processes. Therefore, to follow the development of the major FUra-derived toxicities, measurement of FUrd and FdUrd plasma levels appeared very attractive.

Adult↗
PubMed1995

Macrophage colony-stimulating factor is expressed by an ovarian carcinoma subline and stimulates the c-myc proto-oncogene.

A small, fast-growing and non-differentiated clone (N.1) derived from the heterogeneous human epithelial ovarian carcinoma cell line HOC-7 produces an autocrine/paracrine factor that is secreted into the cell culture supernatant. This factor is capable of enhancing mRNA levels of the proliferation-related oncogene c-myc in the more differentiated clone D3 and in normal human fibroblasts MRC.5, but also in N.1 cells themselves. Supernatants enriched for this paracrine/autocrine factor also confer a mitogenic stimulus as measured by [3H]thymidine incorporation. Trypsin can neutralise the stimulating activity of the secreted factor as well as monoclonal antibodies directed against macrophage colony-stimulating factor (M-CSF). We show that M-CSF and also M-CSF receptor are expressed in N.1 cells and that recombinant M-CSF induces c-myc transcript levels in N.1 cells. This investigation raises the possibility that M-CSF might be an autocrine growth factor in non-differentiated ovarian carcinomas. Inappropriate cytokine production could create a tumour-promoting microenvironment in this cancer type.

Apoptosis↗
PubMed1995

Sodium butyrate inhibits c-myc splicing and interferes with signal transduction in ovarian carcinoma cells.

Sodium butyrate (NaB), a physiologically produced short chain fatty acid, dramatically changes the growth rate and also the morphology of a fast growing subclone (N.1) derived from the heterogenous human ovarian carcinoma HOC-7. The mRNA of the growth related proto-oncogene c-myc, constitutively expressed in N.1 cells decreased significantly within 24 h of NaB treatment and remained suppressed until the NaB block was released. Down-regulation was accomplished partially by accelerating degradation of c-myc mRNA and by inhibiting splicing of c-myc transcripts. We demonstrated that NaB blocked general mechanisms in signal transduction, such as the release of Ca2+ from intracellular stores, and modulated the activity of serine/threonine kinases. The multiple effects of sodium butyrate on HOC-7 derivatives, as well as on a variety of other cell types investigated by others, may be due to interference with general mechanisms of signal transduction.

Adenocarcinoma↗
PubMed1995

Monoclonal rat antibodies directed against Toxoplasma gondii suitable for studying tachyzoite-bradyzoite interconversion in vivo.

We previously reported the in vitro analysis of stage differentiation of Toxoplasma gondii in murine bone marrow-derived macrophages. The purpose of this study was to generate monoclonal rat antibodies that might be suitable for investigating tachyzoite-bradyzoite interconversion in vivo with the murine model. Immunization of Fischer rats with cysts of T. gondii NTE resulted in the generation of seven monoclonal antibodies of the immunoglobulin G2a, G2b, or M isotype, which were further characterized by the immunoblot technique, immunofluorescence assay, immunohistology, and immunoelectron microscopy. Immunoblots demonstrated specific reactivity of five monoclonal antibodies with proteins with molecular masses of 40, 52, 55, 60, 64, 65, and 115 kDa. One antibody (CC2) appeared to recognize a differently expressed antigen depending on the parasite stage, reacting with a 40-kDa molecule in tachyzoites and a 115-kDa antigen in bradyzoites and oocysts. Several other monoclonal antibodies were shown to be stage specific and to react in immunofluorescence assays or in immunoblots with either tachyzoites or bradyzoites. Kinetics of stage conversion in vitro could be monitored by immunofluorescence with two of these monoclonal antibodies. Preliminary immunohistological investigations of tissue sections from infected mice demonstrated the possible usefulness of these monoclonal antibodies for future in vivo studies on stage differentiation of T. gondii in the murine system.

Animals↗
PubMed1995

[Experiences in organization of medical graduate and continuing education in the new German country (Thüringen)].

The switch from a state controlled to a self responsible continuing medical education could be completed in Thuringia within the first years after the reunification. Higher performances demonstrated by the just mentioned analyses can be observed quantitatively as well as qualitatively. This concept of our academy concerning a professional and regional decentralization in combination with centralized offers for further education has been proved. A good teamwork between the organizers and participants succeeds more and more in finding out the kind of teaching needed. Medical education can be planned globally and according to the needs. New ways of training can be searched and may go beyond country borders.

Education, Medical, Continuing↗
PubMed1994

Amonafide as first-line chemotherapy for metastatic breast cancer.

In a phase II study, 32 patients with advanced breast cancer previously unexposed to palliative cytotoxic chemotherapy were treated with amonafide, 800-900 mg intravenously over 3 h repeated every 4 weeks. Objective response was seen in 8 patients including 1 complete response, 10 patients had stable disease and 14 patients progressed so the overall response was 25% (95% confidence interval, 11-43%). The most frequently encountered side-effects were haematological (granulocytopenia > or = WHO grade 3 was encountered in 7/24 patients at 800 mg/m2 and in 3/8 patients at 900 mg/m2 amonafide) and nausea/vomiting (62%), despite prophylactic use of ondansetron. Non-haematological severe adverse reactions included neurotoxicity WHO grade 3 in 1 patient and orthostatic hypotension WHO grade 4 in another. In summary, the results of this trial suggest a limited therapeutic index of amonafide if used at this dose with this administration schedule.

Adenine↗