Title: RADIATION-INDUCED HEMOPOIETIC LESIONS IN FISH.

This work was aimed at investigating radiation-induced hemopoietic and immune dysfunction in the dog model. One project was to produce monoclonal antibodies directed against canine hemopoietic precursor cells and specific for pluripotent stem cells. Antibodies obtained reacted with different myeloid and erythroid precursor cells; unfortunately, none of the antibodies were specific for pluripotent hemopoietic stem cells. Positive selections for these cells were performed using magnetic beads and an antibody against class 2-antigen. Transplantation of class 2 positive marrow cells into otherwise lethally irradiated dogs led to sustained recovery in only 1 of 5 dogs. A second project established and investigatedmore » long-term marrow cultures in the dog. Culture conditions were studied and optimized, and marrow cells were transplanted into otherwise lethally irradiated dogs to investigate stem cell survival in long-term cultures. Engraftment was observed only with short-term marrow cultures.« less

The primary cause of death after radiation exposure is infection resulting from myelosuppression. Because granulocytes play a critical role in host defense against infection and because granulocyte proliferation and differentiation are enhanced by granulocyte colony-stimulating factor (G-CSF), this agent was evaluated for the ability to accelerate hemopoietic regeneration and to enhance survival in irradiated mice. C3H/HeN mice were irradiated and G-CSF or saline was administered on days 3-12, 1-12 or 0-12 post-irradiation. Bone marrow, splenic and peripheral blood cellularity and bone marrow and splenic granulocyte-macrophage progenitor cell recoveries were evaluated in mice exposed to 6.5 Gy. Mice exposed to 8more » Gy were evaluated for multipotent hemopoietic stem cell recovery (using endogenous spleen colony-forming units) and enhanced survival. Results demonstrated that therapeutic G-CSF (1) accelerates hemopoietic regeneration after radiation-induced myelosuppression, (2) enhances survival after potentially lethal irradiation and (3) is most effective when initiated 1 h following exposure.« less

The risk for liver disease from internally deposited beta-emitting radionuclides is unknown because there are no human populations exposed to hepatotropic beta-emitting radionuclides available for study. In this report, we discuss the hepatic lesion in dogs exposed to a beta-emitting radionuclide, {sup 144}CeCl{sub 3}, and held for their life spans.

Adenine (Ade), 2'-deoxyadenosine (dAdo) and 5'-deoxyadenosine monophosphate (5'-dAMP) were irradiated with 50 to 15,000 Gy under oxic and hypoxic conditions. HPLC procedures providing satisfactory separation of the adenine damage products formed during irradiation of DNA model compounds were found. Structures of some of the damage products were confirmed to include 8-OHAde, 4,6-diamino-5-formamidopyrimidine, and 8-OH-5'-dAMP. Two damage products of dAdo (8-OHdAdo and the major isomer of 8,5'-cdAdo), the formation of which depends on the presence or absence of oxygen, were determined quantitatively by HPLC. The limit for HPLC detection was estimated as 4 to 50 pmoles for these compounds. This correspondsmore » to a detection limit of about 50 Gy in radiation dose units. These two products were also detected in mixtures of all four nucleosides irradiated with 50 Gy.« less

This progress report recovers the period July 1, 1989 to July 1, 1990 because the last award was for a 16 month period. Our past specific aims have been: (1) to develop or adapt reliable and sensitive assays for specific types of radiation-induced DNA base lesions; (2) to determine the influence of conformation and base sequence on the types and yields of DNA base lesions produced by ionizing radiation under oxic and anoxic conditions; (3) to determine if the sequence-induced structure of the DNA affects its thermal stability after exposure to {gamma}-radiation; and (4) to develop an in vitro cellmore » model for testing both the accessibility hypothesis and mechanisms of cell lethality.« less