Marrow toxicity of 33P- versus 32P-orthophosphate: Implications for therapy of bone pain and bone metastases

S. Murty Goddu, Anupam Bishayee, Lionel G. Bouchet, Wesley E. Bolch, Dandamudi V. Rao, Roger W. Howell

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Abstract

Several bone-seeking radiopharmaceuticals, such as 32P-orthophosphate, 89Sr-chloride, 186Re-1,1 hydroxyethylidene diphosphonate (HEDP), and 153Sm-ethylene diamine tetramethylene phosphonic acid (EDTMP), have been used to treat bone pain. The major limiting factor with this modality is bone marrow toxicity, which arises from the penetrating nature of the high-energy β particles emitted by the radionuclides. It has been hypothesized that marrow toxicity can be reduced while maintaining therapeutic efficacy by using radionuclides that emit short-range β particles or conversion electrons. In view of the significant clinical experience with 32P- orthophosphate, and the similarity in pain relief afforded by 32P- orthophosphate and 89Sr-chloride, this hypothesis is examined in this study using 32P- and 33P-orthophosphate in a mouse femur model. Methods: Survival of granulocyte macrophage colony-forming cells (GM-CFCs) in femoral marrow was used as a biologic dosimeter for bone marrow. 32P- and 33P- orthophosphate were administered intravenously, and GM-CFC survival was determined as a function of time after injection and, at the nadir, as a function of injected activity. The kinetics of radioactivity in the marrow, muscle, and femoral bone were also determined. The biologic dosimeter was calibrated by assessing GM-CFC survival at its nadir after chronic irradiation of Swiss Webster mice with exponentially decreasing dose rates of γ rays (relative biologic effectiveness equivalent to that of β particles) from a low-dose rate 137Cs irradiator. Dose-rate decrease half-times (T(d)) (time required for 137Cs γ ray dose rate to decrease by one half) of 62,255, and 425 h and infinity were used to simulate the dose rate patterns delivered by the radiopharmaceuticals as dictated by their effective clearance half-times from the mouse femurs. These data were used to experimentally determine the mean absorbed dose to the femoral marrow per unit injected activity. Finally, a theoretical dosimetry model of the mouse femur was developed, and the absorbed doses to the femoral marrow, bone, and endosteum were calculated using the EGS4 Monte Carlo code. Results: When the animals were irradiated with exponentially decreasing dose rates of 137Cs γ rays, initial dose rates required to achieve 37% survival were 1.9, 0.98, 0.88, and 0.79 cGy/h for dose rate decrease half-times of 62, 255, and 425 h and infinity, respectively. The D37 values were 144 (+) 15, 132 (+) 12, 129 (+) 3, and 133 (+) 10 cGy, respectively, compared with a value of 103 cGy for acute irradiation. When 32P and 33P were administered, the injected activities required to achieve 37% survival were 313 and 2820 kBq, respectively. Theoretical dosimetry calculations show that 33P offers a 3- to 6-fold therapeutic advantage over 32P, depending on the source and target regions assumed. Conclusion: The low-energy β-particle emitter 33P appears to offer a substantial dosimetric advantage over energetic β- particle emitters (e.g., 32P, 89Sr 186Re) for irradiating bone and minimizing marrow toxicity. This suggests that low-energy β or conversion electron emitters may offer a substantial advantage for alleviation of bone pain as well as for specifically irradiating metastatic disease in bone.

Original languageEnglish
Pages (from-to)941-951
Number of pages11
JournalJournal of Nuclear Medicine
Volume41
Issue number5
StatePublished - May 1 2000
Externally publishedYes

Keywords

  • Bone
  • Chronic irradiation
  • Dose response
  • Dosimetry
  • EGS4
  • Granulocyte macrophage colony-forming cells
  • Metastases
  • P
  • P therapy
  • Pain
  • Radionuclides

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    Goddu, S. M., Bishayee, A., Bouchet, L. G., Bolch, W. E., Rao, D. V., & Howell, R. W. (2000). Marrow toxicity of 33P- versus 32P-orthophosphate: Implications for therapy of bone pain and bone metastases. Journal of Nuclear Medicine, 41(5), 941-951.