Cytokine-based treatment of radiation injury: potential benefits after low-level radiation exposure.
The use of growth factors (GFs) in the treatment of radiation injury has focused on enhancing recovery from acute radiation syndrome. A number of new GFs have shown significant in vivo and in vitro preclinical efficacy; some of these have recently been approved by the Food and Drug Administration, some are in various phases of clinical trials, and some are moving through preclinical evaluations. The most promising new GFs in the context of enhancing the viability of irradiated hematopoietic stem cells (HSCs) are flt-3L, c-kitL, and c-mplL. These GFs, as well as interleukin 3 (IL-3), have been shown to maintain viability, suppress apoptosis, and promote the clonal growth of primitive murine and human hematopoietic progenitor cells. Further evidence suggests that these GFs may also act in synergy with each other. Additionally, three families of chimeric proteins that consist of dual GF receptor (R) agonists have been engineered: myelopoietin, promegapoietin, and progenipoietin. These proteins activate the IL-3 and granulocyte colony-stimulating factor Rs, the IL-3 and mpl Rs, and the flt-3L and granulocyte colony-stimulating factor Rs, respectively. The preclinical data indicate that the chimeric GFR agonists are potent stimulators of hematopoiesis in myelosuppressed nonhuman primates and can effectively alleviate acute radiation syndrome in animals. Acute or protracted low-level radiation exposure does not require the extensive clinical care necessary following radiation-induced myelosuppression. The main question is whether these new GFs will allow for enhanced repair of radiation-induced chromosome aberrations while promoting early survival of HSCs. Other questions include the following: Will an early, brief exposure to GFs suppress p53-dependent apoptosis and induce expression of bcl-2 with a concomitant enhancement of DNA repair capacity? What is the effect of GF stimulation of irradiated HSCs on p53 cell cycle checkpoint activity? Will GFs promote survival of "transformed" cells that would otherwise be eliminated by p53 activation of apoptosis-promoting genes? Relevant animal models and access to appropriate GFs will be required to answer these questions.
MacVittie
Thomas J
TJ
Departments of Radiation Oncology and Pathology, University of Maryland, Greenebaum Cancer Center, 655 West Baltimore Street, Baltimore, MD 21201, USA.
Farese
Ann M
AM
D000818:Animals; D016207:Cytokines / Q000627:therapeutic use*; D006133:Growth Substances; D006801:Humans; D011829:Radiation Dosage; D011833:Radiation Injuries, Experimental / Q000188:drug therapy*
D016207:Cytokines; D006133:Growth Substances