@article {Dadachova313, author = {Ekaterina Dadachova and Roger W. Howell and Ruth A. Bryan and Annie Frenkel and Joshua D. Nosanchuk and Arturo Casadevall}, title = {Susceptibility of the Human Pathogenic Fungi Cryptococcus neoformans and Histoplasma capsulatum to γ-Radiation Versus Radioimmunotherapy with α- and β-Emitting Radioisotopes }, volume = {45}, number = {2}, pages = {313--320}, year = {2004}, publisher = {Society of Nuclear Medicine}, abstract = {Fungal diseases are difficult to treat in immunosuppressed patients and, consequently, new approaches to therapy are urgently needed. One novel strategy is to use radioimmunotherapy (RIT) with fungal-binding monoclonal antibodies (mAbs) labeled with radionuclides. However, many fungi manifest extreme resistance to γ-radiation, such that the doses of several thousand gray are required for 90\% cell killing, whereas for mammalian cells the lethal dose is only a few gray. We compared the susceptibility of human pathogenic fungi Cryptococcus neoformans (CN) and Histoplasma capsulatum (HC) to external γ-radiation and to the organism-specific mAbs 18B7 and 9C7, respectively, conjugated to 213Bi and 188Re radionuclides. Methods: CN and HC cells were irradiated with up to 8,000 Gy (137Cs source, 30 Gy/min). RIT of CN with 213Bi- and 188Re-labeled specific mAb and of HC with 188Re-labeled specific mAb used 0{\textendash}1.2 MBq per 105 microbial cells. After irradiation or RIT, the cells were plated for colony-forming units (CFUs). Cellular dosimetry calculations were performed, and the pathway of cell death after irradiation was evaluated by flow cytometry. Results: Both CN and HC proved to be extremely resistant to γ-radiation such that significant killing was observed only for doses of \>4,000 Gy. In contrast, these cells were much more susceptible to killing by radiation delivered with a specific mAb, such that a 2-logarithm reduction in colony numbers was achieved by incubating them with 213Bi- and 188Re-labeled mAb 18B7 or with 188Re-9C7 mAb. Dosimetry calculations showed that RIT was \~{}1,000-fold more efficient in killing CN and \~{}100-fold more efficient in killing HC than γ-radiation. Both γ-radiation and RIT caused cell death via an apoptotic-like pathway with a higher percentage of apoptosis observed in RIT-treated cells. Conclusion: Conjugating a radioactive isotope to a fungal-specific antibody converted an immunoglobulin with no antifungal activity into a microbicidal molecule. RIT of fungal cells using specific antibodies labeled with α- and β-emitting radioisotopes was significantly more efficient in killing CN and HC than γ-radiation when based on the mean absorbed dose to the cell. These results strongly support the concept of using RIT as an antimicrobial modality.}, issn = {0161-5505}, URL = {https://jnm.snmjournals.org/content/45/2/313}, eprint = {https://jnm.snmjournals.org/content/45/2/313.full.pdf}, journal = {Journal of Nuclear Medicine} }