Fractionated gamma-irradiation renders tumour cells more responsive to apoptotic signals through CD95.

Signals through the CD95 surface receptor can specifically induce apoptosis. Some tumour cell lines are sensitive to CD95 signals, and insensitive cells can be converted to a sensitive phenotype if given appropriate treatment. To determine whether the apoptotic response of tumour cells to signalling through CD95 might be enhanced by ionizing irradiation, carcinoma cells were treated with either single-dose or fractionated gamma-irradiation. The response to treatment with an agonist anti-CD95 antibody was enhanced by pretreatment with either a single large dose or daily fractionated radiation. Fractionated irradiation induced cumulative and prolonged up-regulation of CD95 expression in cell lines bearing functional p53. Since two of four cell lines exhibiting heightened responsiveness to CD95-mediated signals following fractionated irradiation express mutant p53 and displayed little or no up-regulation of CD95, enhanced responsiveness did not correlate with p53 status and CD95 up-regulation. Continuous inhibition of CD95/CD95-ligand interactions during fractionated irradiation provided no protective effect to cells, arguing that autologous CD95/CD95-ligand interactions did not contribute to the direct lethal effect of irradiation. We conclude that fractionated gamma-irradiation provides an extended period of time when carcinoma cells are more responsive to CD95-mediated signals in vitro.     

The natural anticancer compound rocaglamide selectively inhibits the G1‐S‐phase transition in cancer cells through the ATM/ATR‐mediated Chk1/2 cell cycle checkpoints

Targeting the cancer cell cycle machinery is an important strategy for cancer treatment. Cdc25A is an essential regulator of cycle progression and checkpoint response. Over‐expression of Cdc25A occurs often in human cancers. In this study, we show that Rocaglamide‐A (Roc‐A), a natural anticancer compound isolated from the medicinal plant Aglaia, induces a rapid phosphorylation of Cdc25A and its subsequent degradation and, thereby, blocks cell cycle progression of tumor cells at the G1‐S phase. Roc‐A has previously been shown to inhibit tumor proliferation by blocking protein synthesis. In this study, we demonstrate that besides the translation inhibition Roc‐A can induce a rapid degradation of Cdc25A by activation of the ATM/ATR‐Chk1/Chk2 checkpoint pathway. However, Roc‐A has no influence on cell cycle progression in proliferating normal T lymphocytes. Investigation of the molecular basis of tumor selectivity of Roc‐A by a time‐resolved microarray analysis of leukemic vs. proliferating normal T lymphocytes revealed that Roc‐A activates different sets of genes in tumor cells compared with normal cells. In particular, Roc‐A selectively stimulates a set of genes responsive to DNA replication stress in leukemic but not in normal T lymphocytes. These findings further support the development of Rocaglamide for antitumor therapy.     

The traditional Chinese herbal compound rocaglamide preferentially induces apoptosis in leukemia cells by modulation of mitogen-activated protein kinase activities

With an increasing cancer rate worldwide, there is an urgent quest for the improvement of anticancer drugs. One of the main problems of present chemotherapy in treatment of tumor patients is the toxicity of drugs. Most of the existent anticancer drugs, unfortunately, attack also proliferating normal cells. In recent years, traditional Chinese herbal remedies have gradually gained considerable attention as a new source of anticancer drugs. Although their healing mechanisms are still largely unknown, some of the drugs have been used to help cancer patients fight their disease at reduced side effects compared to other treatments. In our study, we show that Rocaglamide (Roc), derived from the traditional Chinese medicinal plants Aglaia, induces apoptosis through the intrinsic death pathway in various human leukemia cell lines and in acute lymphoblastic leukemia, chronic myeloid leukemia and acute myeloid leukemia cells freshly isolated from patients. Investigation of the molecular mechanisms by which Roc kills tumors revealed that it induces a consistent activation of the stress-response mitogen-activated protein kinase (MAPK) p38 accompanied with a long-term suppression of the survival MAPK extracellular signal-regulated kinase. These events affect proapoptotic Bcl-2 family proteins leading to depolarization of the mitochondrial membrane potential and trigger caspase-mediated apoptosis involving caspase-9, -8, -3 and -2. Importantly, Roc shows no effects on MAPKs in normal lymphocytes and therefore has no or very low toxicity on healthy cells. Up to now, more than 50 different Roc derivatives have been isolated from Aglaia. Our study suggests that Roc derivatives may be promising candidates for the development of new drugs against hematologic malignancies.     

Stellenwert der Galaktographie zur Abklärung pathologischer Sekretion in der komplementären Mammadiagnostik

Background

The survey results of a previous study showed that galactography is now rarely used in Germany and newer methods are applied. The evidential value of galactography should be established and opposed to the evidential value of ultrasound (US) and magnetic resonance mammography (MRM).

Materials and methods

A search was carried out in PubMed and Cochrane involving studies written in English or German. The level of evidence was measured according to the Oxford Centre for Evidence-based Medicine.

Results

A total of 19 studies were included, 14 with results on galactography, 10 on US and 5 on MRM. Almost all studies were retrospective with an evidence assigned to level 3b or lower. The results on the diagnostic values showed a very wide range. Because of very variable numbers of cases and consideration of various pathologies, the studies are only comparable to a limited extent.

Conclusion

Galactography, US and MRM all show a weak level of evidence and no superiority of a particular method can be derived. Therefore, galactography can no longer be considered as a mandatory standard in modern multimodal imaging of the breast. Recommendations for the diagnostic work-up of pathological nipple discharge have to be included in current guidelines and must consider these facts.     

Probiotic drug therapy with E. coli strain Nissle 1917 (EcN): results of a prospective study of the records of 3,807 patients

INTRODUCTION: Living microorganisms that enter the gut in an active state and exert a positive influence on the host are called probiotics. Numerous experimental and clinical studies were performed recently and confirm both the efficacy and modes of action of probiotic drugs. PATIENTS AND METHODS: In a post-marketing-surveillance study with the probiotic Escherichia Coli strain Nissle 1917 (EcN) data on the range of indications as well as on efficacy and tolerance were gathered prospectively in 446 centres. The intended treatment duration was limited to a maximum of 12 weeks. RESULTS: EcN was used in 3,807 patients with more than 20 different indications, n = 3,511 of whom had gastrointestinal complaints: Among others, 1,067 patients presented with chronically recurring (n = 728) or protracted diarrhoea (n = 339), 415 with inflammatory bowel disease, 679 with irritable bowel syndrome, and 253 with chronic constipation. The overall efficacy was assessed as good to very good by an average of 81.4 % of the therapists. The stool frequency and consistency as well as the symptoms of meteorism and abdominal pain were improved in very many patients. Suspected cases of side effects were documented in only 2.8 % of the patients. CONCLUSION: EcN is frequently used in practice for the treatment of various, mostly gastrointestinal, complaints and is well tolerated.