Igor Shuryak1, Ruth A Bryan2, Jack Broitman2, Stephen A Marino3, Alfred Morgenstern4, Christos Apostolidis4, Ekaterina Dadachova5. 1. Center for Radiological Research, Columbia University Medical Center, New York, New York. 2. Department of Radiology, Albert Einstein College of Medicine, Bronx, New York. 3. Radiological Research Accelerator Facility, Nevis Laboratories, Irvington, New York. 4. European Commission, Joint Research Centre, Institute for Transuranium Elements, Karlsruhe, Germany. 5. Department of Radiology, Albert Einstein College of Medicine, Bronx, New York; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York. Electronic address: ekaterina.dadachova@einstein.yu.edu.
Abstract
INTRODUCTION: Most research on radioresistant fungi, particularly on human pathogens such as Cryptococcus neoformans, involves sparsely-ionizing radiation. Consequently, fungal responses to densely-ionizing radiation, which can be harnessed to treat life-threatening fungal infections, remain incompletely understood. METHODS: We addressed this issue by quantifying and comparing the effects of densely-ionizing α-particles (delivered either by external beam or by (213)Bi-labeled monoclonal antibodies), and sparsely-ionizing (137)Cs γ-rays, on Cryptococcus neoformans. RESULTS: The best-fit linear-quadratic parameters for clonogenic survival were the following: α = 0.24 × 10(-2) Gy(-1) for γ-rays and 1.07 × 10(-2) Gy(-1) for external-beam α-particles, and β = 1.44 × 10(-5) Gy(-2) for both radiation types. Fungal cell killing by radiolabeled antibodies was consistent with predictions based on the α-particle dose to the cell nucleus and the linear-quadratic parameters for external-beam α-particles. The estimated RBE (for α-particles vs. γ-rays) at low doses was 4.47 for the initial portion of the α-particle track, and 7.66 for the Bragg peak. Non-radiological antibody effects accounted for up to 23% of cell death. CONCLUSIONS: These results quantify the degree of C. neoformans resistance to densely-ionizing radiations, and show how this resistance can be overcome with fungus-specific radiolabeled antibodies.
INTRODUCTION: Most research on radioresistant fungi, particularly on human pathogens such as Cryptococcus neoformans, involves sparsely-ionizing radiation. Consequently, fungal responses to densely-ionizing radiation, which can be harnessed to treat life-threatening fungal infections, remain incompletely understood. METHODS: We addressed this issue by quantifying and comparing the effects of densely-ionizing α-particles (delivered either by external beam or by (213)Bi-labeled monoclonal antibodies), and sparsely-ionizing (137)Cs γ-rays, on Cryptococcus neoformans. RESULTS: The best-fit linear-quadratic parameters for clonogenic survival were the following: α = 0.24 × 10(-2) Gy(-1) for γ-rays and 1.07 × 10(-2) Gy(-1) for external-beam α-particles, and β = 1.44 × 10(-5) Gy(-2) for both radiation types. Fungal cell killing by radiolabeled antibodies was consistent with predictions based on the α-particle dose to the cell nucleus and the linear-quadratic parameters for external-beam α-particles. The estimated RBE (for α-particles vs. γ-rays) at low doses was 4.47 for the initial portion of the α-particle track, and 7.66 for the Bragg peak. Non-radiological antibody effects accounted for up to 23% of cell death. CONCLUSIONS: These results quantify the degree of C. neoformans resistance to densely-ionizing radiations, and show how this resistance can be overcome with fungus-specific radiolabeled antibodies.
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