Huibert Vriesendorp, Presenter: Nothing to Disclose

Securing a new, higher, therapeutic ratio for radiotherapy

Simple self renewal systems -hemopoiesis, small bowel mucosa, skin and lens of eye- consist of 3 compartments: 1. stem cells, 2. progenitor cells, 3. end cells. Stem cells in normal organs are rare, making morphological identification of stem cells difficult. Compartment 1 cells make self-copies and on differentiation can repair radiation damage. Cells in compartments 2 and 3 have a limited lifespan and play no role in repair of radiation induced damage. In the 70's tumor stem cells were identified, -first in murine tumors, later in human tumor cell lines- with frequencies ranging from 0.3 to 0.005. Initially all tumor cells were considered clonogenic: some actively proliferating, "P"-cells, others quiescent or "Q"-cells. (2) More recently cells isolated from human tumor biopsies were sorted by flow cytometry for stem cell markers. Only the transplantation of stem cells will produce a human tumor nodule in nude mice. (e.g.3) Non-stem -Q cells- do not and should now be called tumor progenitor or end cells.

Hemopoietic stem cells are very radiation sensitive N=1.1, D0=0.7Gy. (1) Stem cells in other normal organs and irradiated tumor cell lines are more radiation resistant. (2, for review) Irradiated, tumor stem cell enriched, cell populations have not been tested yet for their ability to regrow tumors in nude mice. Instead the percentage of tumor stem cells increased and non tumor stem cells decreased in tumor samples 3-5 days after irradiation. (3) This does not indicate tumor stem cells are radiation resistant or that tumor progenitor cells and end cells are radiation sensitive. This type of reasoning would make normal erythrocytes radiation sensitive, which in reality can survive a single fraction of 50Gy. Tumor recurrence after radiation is due to one or more surviving tumor stem cells. Sixty % of patients with end stage Hodgkin's disease respond to radiolabeled anti-ferritin treatment with bone marrow toxicity as the only side effect and no side effects in tumor surrounding normal tissues. (4)

Targeting of tumor stem cells is best achieved with radiolabeled, tumor reactive, immunoglobulins. Normal tissue stem cells surrounding the tumor need to be spared not tumor progenitor cells or end cells, which are irrelevant to tumor response or normal tissue damage. References: 1. Vriesendorp, HM., and van Bekkum, DW. In: Broerse, JJ, and MacVittie, T (eds.) Response to Total Body Irradiation in Different Species. Amsterdam: Martinus Nijhoff, pp43-53, 1984 2. G. Gordon Steel, Growth kinetics of tumours. Oxford University Press, 1977 3. S. Bao et al. Nature. 2006 Dec 7; 444 (7120):756-60. 4. Vriesendorp HM, Quadri SM. Cancer Biotherapy Radiopharm Cancer 2000; 15: 431-445

Vriesendorp, H, The Importance of Stem Cell Targeting.  Radiological Society of North America 2008 Scientific Assembly and Annual Meeting, February 18 - February 20, 2008 ,Chicago IL. http://archive.rsna.org/2008/7000460.html