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Myelotoxicity and RBE of 211At-conjugated monoclonal antibodies compared with 99mTc-conjugated monoclonal antibodies and 60Co irradiation in nude mice

Artikel i vetenskaplig tidskrift
Författare Jörgen Elgqvist
Peter Bernhardt
Ragnar Hultborn
H. Jensen
Börje Karlsson
Sture Lindegren
Elisabet Warnhammar Finnborg
Lars Jacobsson
Publicerad i J Nucl Med
Volym 46
Nummer/häfte 3
Sidor 464-71
ISSN 0161-5505 (Print)
Publiceringsår 2005
Publicerad vid Institutionen för särskilda specialiteter, Avdelningen för onkologi
Institutionen för särskilda specialiteter, Avdelningen för radiofysik
Sidor 464-71
Språk en
Länkar www.ncbi.nlm.nih.gov/entrez/query.f...
Ämnesord Animals, Antibodies, Monoclonal/adverse effects/pharmacokinetics, Astatine/*adverse effects/*pharmacokinetics, Body Burden, Bone Marrow/metabolism/*radiation effects, Cobalt Radioisotopes/adverse effects/pharmacokinetics, Female, Leukocytes/metabolism/radiation effects, Metabolic Clearance Rate, Mice, Mice, Inbred BALB C, Mice, Nude, Organ Specificity, Radiation Dosage, Radiation Injuries/etiology/metabolism, Radiometry/*methods, Radiopharmaceuticals/adverse effects/pharmacokinetics, *Relative Biological Effectiveness, Technetium/*adverse effects/*pharmacokinetics, Tissue Distribution, Whole-Body Counting
Ämneskategorier Cancer och onkologi

Sammanfattning

The rationale of this study was to determine the myelotoxicity in nude mice of the alpha-emitter 211At conjugated to monoclonal antibodies (mAbs) and to compare the effect with an electron emitter, (99m)Tc, and external irradiation from a 60Co source, for estimation of the relative biological effectiveness (RBE). METHODS: 211At and (99m)Tc were conjugated to the IgG1 mAbs MX35 and 88BV59. Nude female BALB/c mice, 8- to 12-wk old, were injected intraperitoneally or intravenously. The biodistribution was determined 3, 6, and 18 h after injection. The bone-to-blood and bone marrow-to-blood activity concentration ratios (BBLR and BMBLR, respectively) were determined for simultaneously injected 211At- and (99m)Tc-mAbs. Bone marrow samples were taken from the femur. For each mouse, the whole-body retention was measured as well as the blood activity by repeated blood samples from the tail vein (0), 1, 3, 6, 12, and 18 h after injection. External-beam irradiation from a 60Co source was also performed at 3 different dose levels. White blood cell (WBC) counts, red blood cell counts, platelet counts, and hemoglobin were determined for each mouse initially and on days 1, 4, 5, 7, 15, 22, and 27 after injection. The calculations of the absorbed dose to the bone marrow were based on the BBLR, BMBLR, the cumulated activities, and the absorbed fractions. The absorbed fractions, phi, for alpha-particles and electrons in the bone marrow were calculated using Monte Carlo simulations based on a bone marrow dosimetry model. RESULTS: The BMBLR was 0.58 +/- 0.06 and 0.56 +/- 0.06 for the 211At- and (99m)Tc-mAbs, respectively. No significant variation in BMBLR with time was found. The absorbed fractions for alpha-particles and electrons in the bone marrow were 0.88 and 0.75, respectively. The mean absorbed fractions of the photons from (99m)Tc were 0.033 and 0.52 for 140 and 18.3 keV, respectively. When different amounts of 211At- and (99m)Tc-mAbs (0.09-1.3 and 250-1,300 MBq, respectively) were administered intraperitoneally or intravenously, corresponding to absorbed doses to the bone marrow of 0.01-0.60 and 0.39-1.92 Gy, respectively, the WBC counts was suppressed by 1%-90% and 23%-89%, respectively. When external-beam irradiation with a 60Co source was performed to absorbed doses of 1.4, 1.9, and 2.4 Gy, the WBC counts was suppressed by 47%-90%. These results indicate a myelotoxic in vivo RBE of 3.4 +/- 0.6 for alpha-particles compared with (99m)Tc and 5.0 +/- 0.9 compared with 60Co irradiation. CONCLUSION: The effect on the WBC counts from bone marrow irradiation with 211At-mAbs indicates an in vivo RBE of 3.4 +/- 0.6 in comparison with (99m)Tc-mAbs. The RBE value compared with external irradiation is 5.0 +/- 0.9.

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