Preventing Blood Cancers and Other Malignancies in Military Personnel at Risk Due to Occupational Radiation Exposure
Abstract
Despite decades of research to identify safe and effective drugs to protect military personnel, nuclear industry workers and civilians from the toxic effects of accidental or intentional radiation exposures, little progress has been made in protecting them from the immediate or long term adverse effects on their bone marrow. Further, cancer patients who receive chemotherapy or radiotherapy are put at risk of side effects due to bone marrow suppression and very little is done to prevent or treat bone marrow damage. Although patients who have suffered even major injury to their bone marrow often survive with supportive care, they may succumb to bone marrow failure or blood cancer as a late effect of exposure. Efforts to study links between bone marrow damage, bone marrow failure, and blood cancer using mice have shown that whether animals are treated early after their bone marrow injury can determine whether they will suffer failure or cancer much later. One possible cause of late onset bone marrow disease in young mice is that the damage and recovery process rapidly ages the bone marrow, leading to an accelerated loss of bone marrow function as if the mouse had already lived a normal lifespan. Preventing the aging and/or rejuvenating the bone marrow appears to protect mice from late onset disease. This leads to the hypothesis that preventing this aging process in human patients after bone marrow injury might similarly prevent the rapid onset of bone marrow failure and blood cancer. Here, we propose a new strategy to protect the bone marrow from late-effects of radiation by speeding up recovery and preventing accelerated aging, using a natural compound as an oral drug. The sugar N-acetylglucosamine (GlcNAc) is completely nontoxic and a normal metabolite in human cells. GlcNAc has multiple functions in the cell, but one is to modify proteins in cells, typically to make them more stable and thereby, more active. It is used as a sweetener and is a major component of breast milk. GlcNAc is produced industrially from the chitin in shrimp, lobster or crab shells, or synthesized chemically. Much like the related sugar glucosamine, GlcNAc is sold in health food stores and online as a treatment for inflammatory disease. Thus, GlcNAc has an almost ideal safety profile. Our laboratory has shown that increasing the levels of GlcNAc in cells accelerates the repair of DNA after irradiation, allowing cells to recover from otherwise lethal radiation doses. Here we propose to test this effect on bone marrow cells in petri dishes and in mice to determine if GlcNAc can protect bone marrow stem cells from radiation. In the key experiments, mice prone to leukemia will be fed GlcNAc or drugs that increase levels of the GlcNAc modification of proteins and then irradiated with a dose that would otherwise cause bone marrow failure and blood cancer. We will determine whether the treatment can protect the bone marrow and prolong lifespan. We will also examine whether treating mice after irradiation with GlcNAc can mitigate radiation toxicity. Success in these studies may lead to experiments in non-human primates and US Food and Drug Administration approval as a protective agent. This might lead to providing anyone at risk of radiation exposure with access to GlcNAc or oral drugs that increase the protein modification so that they can enhance their DNA repair and decrease radiation toxicity if they are exposed. Potentially, GlcNAc might also be made available for use by the population in the case of large scale radiation exposures.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010556
Entities
People
- Stephen J. Kron
Organizations
- United States Army
- University of Chicago