PT - JOURNAL ARTICLE AU - Ekaterina Dadachova AU - Roger W. Howell AU - Ruth A. Bryan AU - Annie Frenkel AU - Joshua D. Nosanchuk AU - Arturo Casadevall TI - Susceptibility of the Human Pathogenic Fungi <em>Cryptococcus neoformans</em> and <em>Histoplasma capsulatum</em> to γ-Radiation Versus Radioimmunotherapy with α- and β-Emitting Radioisotopes DP - 2004 Feb 01 TA - Journal of Nuclear Medicine PG - 313--320 VI - 45 IP - 2 4099 - http://jnm.snmjournals.org/content/45/2/313.short 4100 - http://jnm.snmjournals.org/content/45/2/313.full SO - J Nucl Med2004 Feb 01; 45 AB - 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 0–1.2 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 &gt;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.