Biological effect of lead-212 localized in the nucleus of mammalian cells: role of recoil energy in the radiotoxicity of internal alpha-particle emitters.

The radiochemical dipyrrolidinedithiocarbamato-212Pb(II) [212Pb(PDC)2] is synthesized and its effects on colony formation in cultured Chinese hamster V79 cells are investigated. The cellular uptake, biological retention, subcellular distribution and cytotoxicity of the radiocompound are determined. The 212Pb is taken up quickly by the cells, reaching saturation levels in 1.25 h. When the cells are washed, the intracellular activity is retained with a biological half-life of 11.6 h. Gamma-ray spectroscopy indicates that the 212Pb daughters (212Bi, 212Po and 208Tl) are in secular equilibrium within the cell. About 72% of the cellular activity localizes in the cell nucleus, of which 35% is bound specifically to nuclear DNA. The mean cellular uptake required to achieve 37% survival is 0.35 mBq of 212Pb per cell, which delivers a dose of 1.0 Gy to the cell nucleus when the recoil energy of 212Bi and 212Po decays is ignored and 1.7 Gy when recoil is included. The corresponding RBE values compared to acute external 137Cs gamma rays at 37% survival are 4.0 and 2.3, respectively. The chemical Pb(PDC)2 is not chemotoxic at the concentrations used in this study. Because the beta-particle emitter 212Pb decays to the alpha-particle-emitting daughters 212Bi and 212Po, these studies provide information on the biological effects of alpha-particle decays that occur in the cell nucleus. Our earlier studies with cells of the same cell line using 210Po (emits 5.3 MeV alpha particle) localized predominantly in the cytoplasm resulted in an RBE of 6. These earlier results for 210Po, along with the present results for 212Pb, suggest that the recoil energy associated with the 212Bi and 212Po daughter nuclei plays little or no role in imparting biological damage to critical targets in the cell nucleus.

Vitamins as radioprotectors in vivo. II. Protection by vitamin A and soybean oil against radiation damage caused by internal radionuclides.

Tissue-incorporated radionuclides impart radiation energy over extended periods of time depending on their effective half-lives. The capacity of vitamin A dissolved in soybean oil to protect against the biological effects caused by internal radionuclides is investigated. The radiochemicals examined are DNA-binding 125IdU, cytoplasmically localized H125IPDM and the alpha-particle emitter 210Po citrate. As in our previous studies, spermatogenesis in mice is used as the experimental model and spermatogonial cell survival is the biological end point. Surprisingly, soybean oil itself provides substantial and equal protection against the Auger effect of 125IdU, which is comparable to a high-LET radiation effect, as well as the low-LET effects of H125IPDM, the dose modification factors (DMFs) being 3.6 +/- 0.9 (SEM) and 3.4 +/- 0.9, respectively. The protection afforded by the oil against the effects of 5.3 MeV alpha particles emitted by 210Po is also significant (DMF = 2.2 +/- 0.4). The presence of vitamin A in the oil further enhanced the radioprotection against the effect of 125IdU (DMF = 4.8 +/- 1.3) and H125IPDM (DMF = 5.1 +/- 0.6); however, no enhancement is provided against the effects of alpha particles. These interesting results with soybean oil and vitamin A, together with data on the subcellular distribution of the protectors, provide clues regarding the mechanistic aspects of the protection. In addition, the data for vitamin A reaffirm our earlier conclusion that the mechanism by which DNA-bound Auger emitters impart biological damage is primarily indirect in nature.

Relative biological effectiveness of alpha-particle emitters in vivo at low doses.

The therapeutic potential of radionuclides that emit alpha particles, as well as their associated health hazards, have attracted considerable attention. The 224Ra daughters 212Pb and 212Bi, by virtue of their radiation properties which involve emission of alpha and beta particles in their decay to stable 208Pb, have been proposed as candidates for radioimmunotherapy. Using mouse testes as the experimental model and testicular spermhead survival as the biological end point, the present work examines the radiotoxicity of 212Pb and its daughters. When 212Pb, in equilibrium with its daughters 212Bi, 212Po and 208Tl, was administered directly into the testis, the dose required to achieve 37% survival (D37) was 0.143 +/- 0.014 Gy and the corresponding RBE of the mixed radiation field was 4.7 when compared to the D37 for acute external 120 kVp X rays. This datum, in conjunction with our earlier results for 210Po, was used to obtain an RBE-LET relationship for alpha particles emitted by tissue-incorporated radionuclides: RBE alpha = 4.8 - 6.1 x 10(-2) LET + 1.0 x 10(-3) LET2. Similarly, the dependence of RBE on alpha-particle energy E alpha was given by RBE alpha = 22 E(-0.73) alpha. These relationships, based on in vivo experimental data, may be valuable in predicting biological effects of alpha-particle emitters.