Combined radiation and antiangiogenic therapy

1. Research group name/project:
Combined radiation and antiangiogenic therapy

2. Group leader and some key members (incl. from other depts./inst.):
Einar K. Rofstad (prof.), Jon-Vidar Gaustad (Ph.D. stud.), Trude G. Simonsen (Ph.D. stud.), Camilla Mollatt (techn.)

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

4. Department/Institute:
Department of Biophysics, Institute for Cancer Research

4b. Hospital (HF):
Det norske radiumhospital HF

5. Main aim of research group:
Angiogenesis is a necessary prerequisite for tumor growth and metastasis. The main aim of the project is to investigate the potential usefulness of combined radiation and antiangiogenic therapy in the treatment of metastatic cancer.

6. Some important recent results (with a few key references):
Tumors produce and secrete a large number proangiogenic factors, and the number of factors and their secretion rates may differ significantly among tumors of the same histological type (Danielsen and Rofstad, Int. J. Cancer 76:836-841, 1998). Treatment with antibodies against proangiogenic factors may inhibit primary tumor growth and prevent metastatic dissemination (Rofstad and Halsør, Cancer Res. 60:4932-4938, 2000). Treatment with the antiangiogenic factor thrombospondin-1 may prevent macroscopic growth of dormant micrometastases (Rofstad and Graff, J. Invest. Dermatol. 117:1042-1049, 2001). Thrombospondin-1 can potentiate the effect of radiation treatment by inducing apoptosis in tumor endothelial cells and by reducing the fraction of radiobiologically hypoxic tumor cells (Rofstad et al, Cancer Res. 63:4055-4061, 2003). Future plans include studies of radiopotentiating effects of antibodies against proangiogenic factors and their receptors, low-molecular inhibitors of the receptor-tyrosine kinase activity of proangiogenic factors, and COX-2 inhibitors.

7. Methods in current use:
Human melanomas xenografted intradermally into BALB/c-nu/nu mice are used as preclinical models of human cancer. Melanoma cells transfected with green fluorescence protein are transplanted to dorsal window chambers and studied by vital microscopy. Molecular mechanisms are studied by using cDNA microarrays and conventional methods (immunohistochemistry, Western blotting, Northern blotting).

8. Available equipment:
Light microscopes, high resolution CCD cameras, and filter blocks for vital microscopy.

9. Some key search words:
Radiation therapy, antiangiogenic therapy, endothelial cell apoptosis, thrombospondin-1, COX-2 inhibitors, proangiogenic factors.