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  • CELL-CYCLE ARREST  (1)
  • CELLS  (1)
  • 1
    Keywords: brain ; APOPTOSIS ; CANCER ; CELLS ; IN-VITRO ; SURVIVAL ; AGENTS ; CELL ; Germany ; IN-VIVO ; VITRO ; DEATH ; DRUG ; SURGERY ; LINES ; TIME ; PATIENT ; LIGAND ; primary ; INDUCTION ; tumour ; treatment ; culture ; ACID ; CELL-DEATH ; PLASMA ; RATES ; RESECTION ; PHARMACOKINETICS ; CISPLATIN ; FUTURE ; TRAIL ; AGENT ; POTENT ; REGRESSION ; IV ; GRADE ; brain tumour ; betulinic acid ; CERAMIDE ; glioblastoma multiforme WHOIV
    Abstract: Background. Glioblastoma multiforme (WHO Grade IV, GBM) is the most malignant brain tumour with a mean survival time of less than one year. Betulinic acid, ceramide and TRAIL (TNF-related apoptosis inducing ligand) represent novel therapeutic agents for potential use in GBM. Method. Primary GBM cells of 21 patients with macroscopically complete tumour resection were tested in vitro for cell death induction by betulinic acid, ceramide, TRAIL and established therapeutics (BCNU, cisplatin, doxorubicin, vincristin and gamma-irradiation). Findings. At peak plasma concentrations (PPC), Betulinic acid, ceramide and TRAIL induced cell death in primary GBM cells at higher rates than established cytotoxic drugs. Specific cell death greater than or equal to75% was observed in 43% (9/21), 38% (8/21), and 19% (4/21) for betulinic acid, ceramide, and TRAIL respectively, while this was only found in 5% (1/21) of gamma-irradiated and cisplatin-treated cells, and in none of the GBM cultures, where BCNU or vincristin were applied in PPC. Conclusion. Due to a markedly improved cell death of GBM cells as compared with established therapeutics, Betulinic acid, ceramide and TRAIL might represent potent substances for future treatment of GBM
    Type of Publication: Journal article published
    PubMed ID: 15197616
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  • 2
    Keywords: APOPTOSIS ; IN-VITRO ; TUMOR-CELLS ; BREAST-CANCER ; p53 ; DNA-DAMAGE ; CANCER-THERAPY ; CELL-CYCLE ARREST ; ARRIVE GUIDELINES ; DRUG-COMBINATIONS
    Abstract: BACKGROUND AND PURPOSE: In polychemotherapy protocols, that is for treatment of neuroblastoma and Ewing sarcoma, Vinca alkaloids and cell cycle-arresting drugs are usually administered on the same day. Here we studied whether this combination enables the optimal antitumour effects of Vinca alkaloids to be manifested. EXPERIMENTAL APPROACH: Vinca alkaloids were tested in a preclinical mouse model in vivo and in vitro in combination with cell cycle-arresting drugs. Signalling pathways were characterized using RNA interference. KEY RESULTS: In vitro, knockdown of cyclins significantly inhibited vincristine-induced cell death indicating, in accordance with previous findings, Vinca alkaloids require active cell cycling and M-phase transition for induction of cell death. In contrast, anthracyclines, irradiation and dexamethasone arrested the cell cycle and acted like cytostatic drugs. The combination of Vinca alkaloids with cytostatic therapeutics resulted in diminished cell death in 31 of 36 (86%) tumour cell lines. In a preclinical tumour model, anthracyclines significantly inhibited the antitumour effect of Vinca alkaloids in vivo. Antitumour effects of Vinca alkaloids in the presence of cytostatic drugs were restored by caffeine, which maintained active cell cycling, or by knockdown of p53, which prevented drug-induced cell cycle arrest. Therapeutically most important, optimal antitumour effects were obtained in vivo upon separating the application of Vinca alkaloids from cytostatic therapeutics. CONCLUSION AND IMPLICATIONS: Clinical trials are required to prove whether Vinca alkaloids act more efficiently in cancer patients if they are applied uncoupled from cytostatic therapies. On a conceptual level, our data suggest the implementation of polychemotherapy protocols based on molecular mechanisms of drug-drug interactions. LINKED ARTICLE: This article is commented on by Solary, pp 1555-1557 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12101.
    Type of Publication: Journal article published
    PubMed ID: 23186127
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