A: Research interests
Our main research interest now focuses on radiation induced endothelial cell and vascular damage in the development of late normal tissue injury. Vascular injury is the major cause of late radiation morbidity and can seriously impair the quality of life, or even be life threatening, in cancer patients treated with radiotherapy. In large vessels this damage leads to accelerated development of atherosclerosis, whereas in small vessels it manifests as telangiectasia (fragile dilated capillaries prone to bleeding and thrombosis). The aim of our studies is to investigate molecular mechanisms underlying the development and progression of radiation-induced vascular damage, with a view to identifying and testing intervention strategies. Ongoing projects use endothelial cells in culture, mouse models and biopsies of irradiated and control blood vessels from cancer patient’s, to study how radiation induces inflammatory and thrombotic changes in capillaries and large vessels and how these changes lead to progressive development of tissue damage and to atherosclerosis. In a new project we will focus specifically on mechanisms of radiation induced heart damage and the interaction between radiation and anthracycline drugs or herceptin, which are commonly used in the treatment of breast cancer patients.
Until recently our group also ran a pre-clinical program for optimizing treatment protocols for clinical application of photodynamic therapy (PDT). Our work demonstrated that vascular mediated damage is an essential component of curative PDT. This knowledge has had a major influence on the design of optimal clinical and treatment schedules. Our pre-clinical PDT program resulted in the successful introduction and use of clinical PDT for oral cavity and skin tumors in the NKI and a dedicated PDT unit opened in December 2006. Laboratory investigations on this topic have now stopped.
B: Selected references
Kruse JJCM, Stewart FA. Gene expression arrays as a tool to unravel mechanisms of normal tissue radiation injury and prediction of response. World J Gastroenterol, 13:2669-2674, 2007
Stewart FA, Heeneman S, te Poele J, Kruse J, Russell NS, Gijbels M, Daemen M. Ionizing radiation accelerates the development of atherosclerotic lesions in ApoE-/- mice and predisposes to an inflammatory plaque phenotype prone to hemorrhage. American J Pathology, 168:649-658, 2006.
Dorresteijn LD, Stewart FA, Boogerd W. Stroke as a late treatment effect of Hodgkin’s disease. Journal Clinical Oncology, 24:1480-1481, 2006.
Triesscheijn M, Ruevekamp M, Antonini N, Neering H, Stewart FA, Baas P. Optimizing meso-tetra-hydroxyphenyl-chlorin mediated photodynamic therapy for basal cell carcinoma. Photochemistry Photobiology, 82: 1686-1690, 2006.
Triesscheijn M, Baas P, Schellens JHM, Stewart FA. Photodynamic therapy in oncology. The Oncologist, 11:1034-1044 2006.
Triesscheijn M, Ruevekamp M, Out R, van Berkel TJ, Schellens J, Baas P, Stewart FA. Rthe pharmacokinetic behaviour of the photosensitizer meso-tetra-hydroxyphenyl-chlorin in mice and men. Cancer Chemother Pharmacol, 60(1):113-22, 2007.
Triesscheijn M, Ruevekamp M, Aalders M, Baas P, Stewart F. Outcome of mTHPC mediated photodynamic therapy is primarily determined by the vascular response. Photochemistry Photobiology, 81:1161-1167, 2005.
Triesscheijn M, Ruevekamp M, Aalders M, Baas P, Stewart F. Comparative sensitivities of microvascular endothelial cells, fibroblasts and tumor cells after in vitro photodynamic therapy with mTHPC. Photochemistry Photobiology, 80:236-241, 2004.
Krüse, J.J.C.M., Te Poele, J.A.M., Russell, N.S., Boersma, L.J., Stewart, F.A. Microarray analysis to identify molecular mechanisms of radiation-induced micro vascular damage in normal tissue. Int. J. Radiat. Oncol. Biol. Physics, 58: 420-426, 2004.
Krüse, J.J.C.M., Te Poele, J.A.M., Velds, A., Kerkhoven, R., Boersma, L.J. Russell, N.S., Stewart, F.A. Identification of differentially expressed genes in mouse kidney after irradiation using microarray analysis. Radiat. Res., 161: 28-38, 2004.
Kuin, A. Kruse, J.J., Stewart, F.A. Proteinuria and vascular changes after renal irradiation: the role of reacive oxygen species (ROS and vascular endothelial growth factor (Vegf). Radiat. Res. 159: 174-181, 2003.
Schouwink, H., Oppelaar, H., Ruevekamp, M., Van der Valk, M., Hart, G., Rijken, P., Baas, P., Stewart, F.A. Oxygen depletion during and after mTHPC mediated photodynamic therapy in RIF1 and H-MESO 1 tumors. Radiat. Res. 159:190-198, 2003.
Cramers, P., Ruevekamp, M., Oppelaar, H., Dalesio, O., Baas, P., Stewart, F.A. Foscan uptake and distribution in relation to photodynamic therapy. Br. J. Cancer 88: 283-90, 2003
Schouwink, H., Ruevekamp, M. Oppelaar, H., Van Veen, R., Baas, P. Stewart, F.A. Photodynamic therapy for malignant mesothelioma: preclinical studies for optimization of treatment protocols. Photochem. Photobiol. 73 (4): 410-417, 2001.
Kuin, A., Citarella, F., Oussoren Y.G., Van der Wal, A.F., Dewit, L.G.H., Stewart, F.A. Increased glomerular vWF after kidney irradiation is not due to increased biosynthesis or endothelial cell proliferation. Radiat. Res. 156: 20-27, 2001.
Te Poele, J.A.M., Van Kleef, E.M., Van der Wal, A.F., Dewit, L.G.H., Stewart, F.A. Radiation induced glomerular thrombus formation and nephropathy are not prevented by the ADP receptor antagonist clopidogrel. Int. J. Radiat. Oncol. Biol. Phys. 50 (5): 1332-1338, 2001.
Stewart, F.A., Te Poele, J.A.M., Van der Wal, A.F., Oussoren, Y.G., Van Kleef, E.M., Kuin, A., Verheij, M., Dewit, L.G.H. Radiation nephropathy - The link between functional damage and vascular mediated inflammatory and thrombotic changes. Acta Oncologica 40 (8): 952-957, 2001.
Van Kleef, E.M., Zurcher, C., Oussoren Y.G., Te Poele J.A.M., Van der Valk, M.A., Niemer-Tucker, M.M.B., Van der Hage, M.H., Broerse, J.J., Robbins, M.E.C., Johnston , D.A., Stewart, F.A. Long-term effects of total-body irradiation on the kidney of Rhesus monkeys. Int. J. Radiat. Biol. 76:641-48, 2000.
Van Kleef, E., Verheij, M., Te Poele, H., Oussoren, Y., Dewit, L., Stewart, F.A. In vitro and in vivo expression of endothelial von Willebrand Factor and leukocyte adension after fractionated irradiation. Radiat. Res. 154: 375-81; 2000.
Van Kleef, E., Te Poele, J.A.M., Oussoren, Y.G. Van der Wal, A., Dewit, L.G.H., Stewart, F.A. The influence of acetylsalicylic acid on development of radiation nephropathy. Int. J. Radiat. Biol. 76: 1565-73; 2000.
C: Biographic sketch
Fiona Stewart carried out her PhD research at the Gray Cancer Institute, Northwood, England, under the supervision of Prof. Juliana Denekamp, and was awarded her doctorate from London University in 1978 (Thesis: The effect of hyperthermia and ionizing radiation on bladder, skin and an experimental tumour in mice). She then held a 5-year Post-doc position at the Gray Cancer Institute, where she continued her research on radiation-induced damage in bladder and kidneys, focusing on mechanisms to selectively protect normal tissues from damage. In 1984 she moved to the Netherlands cancer Institute with Adrian Begg, to set up a radiobiology group, within the Division of Experimental Therapy. In addition to her research on mechanisms and prevention of radiation damage in normal tissues, her group set up a pre-clinical program for optimization of photodynamic therapy and was actively involved in implementation of this novel therapy in the clinic.
D: Co-workers
Saske Hoving PhD Post-doc
Jacqueline Kruse PhD Senior Post-doc (until May 07)
Marion Scharpfenecker PhD Post-doc (from August 07)
Ben Floot Technical staff
Johannes Te Poele Technical staff