Document Detail


Induction of apoptosis by flavopiridol unrelated to cell cycle arrest in germ cell tumour derived cell lines.
MedLine Citation:
PMID:  15868376     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Germ cell tumours (GCTs) are highly sensitive to cisplatin-based chemotherapy. The inability to arrest the cell cycle at the G1/S-check-point due to a lack of retinoblastoma gene product RB has been suggested as one potential explanation for this feature. Flavopiridol (FP), an inhibitor of cyclin dependent kinases, causes cell cycle arrest or apoptosis depending on the relation of the transcription factor E2F1 and RB. METHODS: The effect of FP was evaluated in GCT-derived cell lines NT2, 2102 EP and NCCIT in comparison to cell lines derived from ovarian cancer (SKOV), breast cancer (MCF7), and cervical cancer (HeLa) using the MTT-assay. Cell cycle progression and induction of apoptosis were assessed by flow cytometry and immunoblot analysis of PARP-cleavage. RESULTS: FP did not affect cell cycle progression and proliferation of GCT cell lines at sublethal doses. At higher concentrations, cell death occurred independent of cell cycle progression. The IC50 was approximately fivefold lower for the three GCT cell lines (60/60/70 nM) than for the other tumour cell lines tested (350/280/300 nM). Lethal doses in vitro were markedly lower than plasma concentrations of FP achieved in clinical studies. In vitro sensitivity to FP did not correlate with that to cisplatin. The cell lines NTera2 and NCCIT showed comparable responses to FP despite differing in their IC50 to cisplatin by factor 4. Flow cytometry and immunoblot for PARP indicated apoptotic cell death induced by FP. Synergism between either cisplatin or paclitaxel and FP was not observed. However, at low concentrations, cytotoxicity of FP and cisplatin appeared to be additive. CONCLUSION: These prelinical investigations suggest a significant antitumour activity of FP in GCT. GCT derived cell lines were far more responsive to FP than cell lines derived from other solid tumours. In contrast to other models, FP did not induce cell cycle arrest in the GCT-derived cell lines tested, possibly due to the known lack of RB-expression in GCTs. However, apoptosis was induced unrelated to cell cycle progression already at low concentrations. No cross resistance between FP and cisplatin was observed. A clinical trial evaluating the activity of FP in patients with cisplatin-refractory GCTs appears to be warranted.
Authors:
Frank Mayer; Sandra Mueller; Elke Malenke; M Kuczyk; Jörg T Hartmann; Carsten Bokemeyer
Related Documents :
14640936 - Novel chemotherapeutic agents for the treatment of glioblastoma multiforme.
9443026 - Adult granulosa cell tumours of the ovary.
16640496 - Inhibition of tumour metastasis by targeted delivery of antioxidant enzymes.
7626686 - Evidence for quiescent s- and g2-phase cells in human colorectal carcinomas: a flow cyt...
18367656 - Label-retaining cells of the bladder: candidate urothelial stem cells.
3349466 - Epithelial polarity, villin expression, and enterocytic differentiation of cultured hum...
Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Investigational new drugs     Volume:  23     ISSN:  0167-6997     ISO Abbreviation:  Invest New Drugs     Publication Date:  2005 Jun 
Date Detail:
Created Date:  2005-05-03     Completed Date:  2005-10-07     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8309330     Medline TA:  Invest New Drugs     Country:  United States    
Other Details:
Languages:  eng     Pagination:  205-11     Citation Subset:  IM    
Affiliation:
Department of Oncology, Hematology, Immunology, and Rheumatology, University of Tübingen Medical Center, Otfried-Mueller-Str. 10, Tübingen, Germany.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Breast Neoplasms / pathology
Carcinoma, Embryonal / pathology*
Cell Cycle / drug effects*
Cell Line, Tumor
Cisplatin / pharmacology
Dose-Response Relationship, Drug
Drug Synergism
Female
Flavonoids / pharmacology*
Humans
Inhibitory Concentration 50
Ovarian Neoplasms / pathology
Paclitaxel / pharmacology
Piperidines / pharmacology*
Uterine Cervical Neoplasms / pathology
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Flavonoids; 0/Piperidines; 146426-40-6/flavopiridol; 15663-27-1/Cisplatin; 33069-62-4/Paclitaxel

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  A mutated p53 status did not prevent the induction of apoptosis by sulforaphane, a promising anti-ca...
Next Document:  Cryptophycins-309, 249 and other cryptophycin analogs: preclinical efficacy studies with mouse and h...