Cytokines May Modify the Toxic Effects of RT on Hematopoietic Stem Cells
Cytokines May Modify the Toxic Effects of RT on Hematopoietic Stem Cells
Abstract & CommentarySynopsis: The combination of hepatocyte growth factor and Interleukin-11 produced a significant decrease in the radiation sensitivity of CD34+ hematopoietic stem cells from human cord blood.
Source: Goff JP, et al. Radiat Res 1997;147:61-69.
One of the most interesting and unexpected effects of cytokines has been radioprotection. Interleukin-1 (IL-1) was the first cytokine to be shown to exert radioprotective effects. Administration of IL-1 to mice permitted them to survive what would have been an LD100 dose of whole body radiation. Because the bone marrow is the organ with dose-limiting toxicity, it was assumed that the cytokine facilitated the repair of the radiation-induced DNA damage in hematopoietic stem cells.If one exposes cells or a cell line to varying doses of radiation in a single fraction in vitro, fewer cells survive with increasing doses, and a semilog plot of the surviving fraction of cells vs. the dose of radiation yields a line that is logarithmic for most of its descent. Killing by radiation is a random event and the survival of any cell depends on the probability that the cell received a lethal hit. A measure of the sensitivity of a tissue or tumor to radiation is the amount of radiation required to deliver an average of one lethal hit to all the cells in a population. That dose is called D0. Another method to assess the influence of cytokines on radiation sensitivity is to assess the impact of cytokine exposure on D0. The D0 for most cells is between 0.8 and 2.0 Gy.
At low doses of irradiation, the dose-response relationship is not linear. The initial portion of the dose response curve has a shoulder that varies a great deal in size in normal tissues. The shoulder is thought to represent the repair of sublethal or potentially lethal damage. In normal bone marrow there is nearly no shoulder; the same is true in tumors.
Goff and colleagues purified CD34+ cells from human cord blood and exposed them to radiation in vitro. The irradiated cells were then put into culture with single cytokines; combinations of cytokines (including erythropoietin, stem cell factor, IL-3, IL-11, GM-CSF, and hepatocyte growth factor [HGF]), CFU-GM, and BFU-E were measured. They found that the combination of HGF and IL-11 induced a significant increase in the shoulder of the radiation dose-response curve (extrapolation factor, 3.35) and resulted in a significant increase in the survival of hematopoietic stem cells. This was the only combination of factors that had a significant effect on radiation sensitivity.
COMMENT
Hepatocyte growth factor is a pleiotropic cytokine that is a potent mitogen for liver cells, but in addition, regulates the growth and motility of a variety of other cell types. The receptor for HGF is the met proto-oncogene, which is expressed on primitive lineage-negative CD34+ hematopoietic progenitor cells.IL-11 is in clinical trials, at the moment for its ability to stimulate thrombopoiesis. However, it also exerts effects on more primitive stem cells, especially when used in combination with other growth factors. To my knowledge, this paper is the first published report of the use of HGF and IL-11 together. It is clear that hematopoietic trophic factors work best in combination. Synergy is apparent among various combinations depending upon the measured end product.
If HGF can be given to people without intolerable side effects, it is possible that the combination of IL-11 and HGF would produce a significant amelioration of bone marrow toxicity from whole body irradiation.
Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.