TY - JOUR
T1 - Susceptibility of the human pathogenic fungi Cryptococcus neoformans and Histoplasma capsulatum to γ-radiation versus radioimmunotherapy with α- and β-emitting radioisotopes
AU - Dadachova, Ekaterina
AU - Howell, Roger W.
AU - Bryan, Ruth A.
AU - Frenkel, Annie
AU - Nosanchuk, Joshua D.
AU - Casadevall, Arturo
PY - 2004/2/1
Y1 - 2004/2/1
N2 - 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 >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.
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 >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.
KW - Dosimetry
KW - Infection
KW - Pathogenic fungi
KW - Radioimmunotherapy
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UR - http://www.scopus.com/inward/citedby.url?scp=1542609188&partnerID=8YFLogxK
M3 - Article
C2 - 14960655
AN - SCOPUS:1542609188
SN - 0161-5505
VL - 45
SP - 313
EP - 320
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
IS - 2
ER -