Molecular targets in radiation biology and therapy

1. Research group name/project:
Molecular targets in radiation biology and therapy

2. Group leader and some key members (incl. from other depts./inst.):
GM Mælandsmo (senior scientist), AH Ree (assoc professor, oncology consultant), Å Bratland (oncology fellow), RV Nome (med stud), K Flatmark (postdoc, surgeon)

3. Home address on the internet:
http://radium.no/malandsmo

4. Department/Institute:
Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital

5. Main aim of research group:
Radiation therapy in cancer is used to prevent metastatic dissemination as well as in treatment of advanced metastatic disease. The tumor cell response to the DNA damage induced by ionizing radiation includes the activation of the cell cycle checkpoints. The aim of the project is to characterize and target the signaling pathways involved to enhance the tumor cell sensitivity to radiation therapy.

6. Some important recent results (with a few key references):
Activation of the cell cycle G2 checkpoint after DNA damage blocks mitotic entry until the DNA is repaired. The mechanism includes inhibition of the enzymatic activity for Polo-like kinase 1 (Plk1), rendering Cdc25C with a basal phosphatase activity that is insufficient for converting Cdc2 to the fully active G2/M transition kinase. Cell cycle arrest at the G2/M boundary after ionizing radiation involves repression of the gene for Plk1, PLK, mediated by the tumor-suppressor protein BRCA1 and its down-stream kinase Chk1 (Ree et al, Oncogene 22:8952-5, 2003). Pharmacological targeting of the BRCA1/Chk1 signaling pathway may minimize the tumor cell delay in the G2 phase, limiting the probability of DNA repair and thereby facilitating mitotic cell death. Moreover, inhibition of tumor cell growth by vitamin D3 analogs involves an arrest in the cell cycle G1 phase, mediated by the Cdk inhibitor p21 (Bratland et al, Cancer Res 60:5578-83, 2000). An alternative therapeutic approach is to use vitamin D3 analogs prior to irradiation to convert the initial growth arrest to apoptotic cell death.

7. Methods in current use:
Therapeutic irradiation of cell lines (by a 60Co source), clonogenic survival analysis, cell cycle analysis by flow cytometry, Northern blot analysis of RNA expression, Western blot analysis of protein expression, Southern blot analysis of DNA amplification, cDNA sequencing, sampling and molecular analysis of tumor specimens before and after therapeutic irradiation (by linear accelerators).

8. Available equipment:

9. Collaborators:
9.1. Among Helse Sør hospitals : At the Norwegian Radium Hospital: Ø. Fodstad (professor, Dept Tumor Biology), T. Stokke and H. Lyng (senior scientists, Dept Biophysics), D.R. Olsen (professor, Dept Medical Physics)
9.2. Other Norwegian collaborators: Text (max. 200 characters)
9.3. Collaborators from other countries: David A. Gewirtz (professor, Dept Pharmacology Toxicology Medicine, Virginia Commonwealth University, Richmond, VA, USA), Gerald A. DeMasters (research fellow, Virginia Commonwealth University).

10. Some key search words:
breast cancer, colorectal cancer, ionizing radiation, cell cycle checkpoints, polo-like kinase, BRCA1, p53, vitamin D, Chk1 inhibitor UCN-01