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Glomerular Filtration Rate After Alpha-Radioimmunotherapy with At-211-MX35-F(ab ')(2): A Long-Term Study of Renal Function in Nude Mice

Back, Tom; Haraldsson, Boerje; Hultborn, Ragnar; Jensen, Holger; Johansson, Martin LU ; Lindegren, Sture and Jacobsson, Lars (2009) In Cancer Biotherapy & Radiopharmaceuticals 24(6). p.649-658
Abstract
Besides bone marrow, the kidneys are often dose-limiting organs in internal radiotherapy. The effects of high-linear energy transfer (LET) radiation on the kidneys after alpha-radioimmunotherapy (alpha-RIT) with the alpha-particle emitter, At-211, were studied in nude mice by serial measurements of the glomerular filtration rate (GFR). The renal toxicity was evaluated at levels close to the dose limit for the bone marrow and well within the range for therapeutic efficacy on tumors. Astatinated MX35-F(ab ')(2) monoclonal antibodies were administered intravenously to nude mice. Both non-tumor-bearing animals and animals bearing subcutaneous xenografts of the human ovarian cancer cell line, OVCAR-3, were used. The animals received... (More)
Besides bone marrow, the kidneys are often dose-limiting organs in internal radiotherapy. The effects of high-linear energy transfer (LET) radiation on the kidneys after alpha-radioimmunotherapy (alpha-RIT) with the alpha-particle emitter, At-211, were studied in nude mice by serial measurements of the glomerular filtration rate (GFR). The renal toxicity was evaluated at levels close to the dose limit for the bone marrow and well within the range for therapeutic efficacy on tumors. Astatinated MX35-F(ab ')(2) monoclonal antibodies were administered intravenously to nude mice. Both non-tumor-bearing animals and animals bearing subcutaneous xenografts of the human ovarian cancer cell line, OVCAR-3, were used. The animals received approximately 0.4, 0.8, or 1.2MBq in one, two, or three fractions. The mean absorbed doses to the kidneys ranged from 1.5 to 15 Gy. The renal function was studied by serial GFR measurements, using plasma clearance of Cr-51-EDTA, up to 67 weeks after the first astatine injection. A dose-dependent effect on GFR was found and at the time interval 8-30 weeks after the first administration of astatine, the absorbed doses causing a 50% decrease in GFR were 16.4 +/- 3.3 and 14.0 +/- 4.1 Gy (mean +/- SEM), tumor-and non-tumor-bearing animals, respectively. The reduction in GFR progressed with time, and at the later time interval, (31-67 weeks) the corresponding absorbed doses were 7.5 +/- 2.4 and 11.3 +/- 2.3 Gy, respectively, suggesting that the effects of radiation on the kidneys were manifested late. Examination of the kidney sections showed histologic changes that were overall subdued. Following a-RIT with 211 At-MX35-F(ab')(2) at levels close to the dose limit of severe myelotoxicity, the effects found on renal function were relatively small, with only minor to moderate reductions in GFR. These results suggest that a mean absorbed dose to the kidneys of approximately 10Gy is acceptable, and that the kidneys would not be the primary dose-limiting organ in systemic a-RIT when using At-211-MX35-F(ab')(2). (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
rate, glomerular filtration, renal function, astatine-211, radioimmunotherapy
in
Cancer Biotherapy & Radiopharmaceuticals
volume
24
issue
6
pages
649 - 658
publisher
Mary Ann Liebert, Inc.
external identifiers
  • wos:000272955600002
  • scopus:73649129602
ISSN
1557-8852
DOI
10.1089/cbr.2009.0628
language
English
LU publication?
yes
id
9173709b-a038-4e93-8555-a6cd80d4a224 (old id 1532174)
date added to LUP
2010-01-29 14:25:45
date last changed
2017-06-25 03:53:38
@article{9173709b-a038-4e93-8555-a6cd80d4a224,
  abstract     = {Besides bone marrow, the kidneys are often dose-limiting organs in internal radiotherapy. The effects of high-linear energy transfer (LET) radiation on the kidneys after alpha-radioimmunotherapy (alpha-RIT) with the alpha-particle emitter, At-211, were studied in nude mice by serial measurements of the glomerular filtration rate (GFR). The renal toxicity was evaluated at levels close to the dose limit for the bone marrow and well within the range for therapeutic efficacy on tumors. Astatinated MX35-F(ab ')(2) monoclonal antibodies were administered intravenously to nude mice. Both non-tumor-bearing animals and animals bearing subcutaneous xenografts of the human ovarian cancer cell line, OVCAR-3, were used. The animals received approximately 0.4, 0.8, or 1.2MBq in one, two, or three fractions. The mean absorbed doses to the kidneys ranged from 1.5 to 15 Gy. The renal function was studied by serial GFR measurements, using plasma clearance of Cr-51-EDTA, up to 67 weeks after the first astatine injection. A dose-dependent effect on GFR was found and at the time interval 8-30 weeks after the first administration of astatine, the absorbed doses causing a 50% decrease in GFR were 16.4 +/- 3.3 and 14.0 +/- 4.1 Gy (mean +/- SEM), tumor-and non-tumor-bearing animals, respectively. The reduction in GFR progressed with time, and at the later time interval, (31-67 weeks) the corresponding absorbed doses were 7.5 +/- 2.4 and 11.3 +/- 2.3 Gy, respectively, suggesting that the effects of radiation on the kidneys were manifested late. Examination of the kidney sections showed histologic changes that were overall subdued. Following a-RIT with 211 At-MX35-F(ab')(2) at levels close to the dose limit of severe myelotoxicity, the effects found on renal function were relatively small, with only minor to moderate reductions in GFR. These results suggest that a mean absorbed dose to the kidneys of approximately 10Gy is acceptable, and that the kidneys would not be the primary dose-limiting organ in systemic a-RIT when using At-211-MX35-F(ab')(2).},
  author       = {Back, Tom and Haraldsson, Boerje and Hultborn, Ragnar and Jensen, Holger and Johansson, Martin and Lindegren, Sture and Jacobsson, Lars},
  issn         = {1557-8852},
  keyword      = {rate,glomerular filtration,renal function,astatine-211,radioimmunotherapy},
  language     = {eng},
  number       = {6},
  pages        = {649--658},
  publisher    = {Mary Ann Liebert, Inc.},
  series       = {Cancer Biotherapy & Radiopharmaceuticals},
  title        = {Glomerular Filtration Rate After Alpha-Radioimmunotherapy with At-211-MX35-F(ab ')(2): A Long-Term Study of Renal Function in Nude Mice},
  url          = {http://dx.doi.org/10.1089/cbr.2009.0628},
  volume       = {24},
  year         = {2009},
}