Susceptibility of the human pathogenic fungi Cryptococcus neoformans and Histoplasma capsulatum to γ-radiation versus radioimmunotherapy with α- and β-emitting radioisotopes

Ekaterina Dadachova, Roger W. Howell, Ruth A. Bryan, Annie Frenkel, Joshua D. Nosanchuk, Arturo Casadevall

Research output: Contribution to journalArticle

49 Citations (Scopus)

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 0-1.2 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.

Original languageEnglish (US)
Pages (from-to)313-320
Number of pages8
JournalJournal of Nuclear Medicine
Volume45
Issue number2
StatePublished - Feb 1 2004

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Radioimmunotherapy
Histoplasma
Cryptococcus neoformans
Radioisotopes
Fungi
Radiation
Fungal Antibodies
Cell Death
Monoclonal Antibodies
Mycoses
Immunoglobulins
Flow Cytometry
Stem Cells
Apoptosis

Keywords

  • Dosimetry
  • Infection
  • Pathogenic fungi
  • Radioimmunotherapy

ASJC Scopus subject areas

  • Radiological and Ultrasound Technology

Cite this

Susceptibility of the human pathogenic fungi Cryptococcus neoformans and Histoplasma capsulatum to γ-radiation versus radioimmunotherapy with α- and β-emitting radioisotopes. / Dadachova, Ekaterina; Howell, Roger W.; Bryan, Ruth A.; Frenkel, Annie; Nosanchuk, Joshua D.; Casadevall, Arturo.

In: Journal of Nuclear Medicine, Vol. 45, No. 2, 01.02.2004, p. 313-320.

Research output: Contribution to journalArticle

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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 0-1.2 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.",
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AU - Casadevall, Arturo

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