Although the general radiobiologic principles underlying external beam therapy and radionuclide therapy are the same, there are significant differences in the biophysical and radiobiologic effects from the two types of radiation. In addition to the emission of particulate radiation, targeted radionuclide therapy is characterized by (i) extended exposures and, usually, declining dose rates; (ii) nonuniformities in the distribution of radioactivity and, thus, absorbed dose; and (iii) particles of varying ionization density and, hence, quality. This chapter explores the special features that distinguish the biologic effects consequent to the traversal of charged particles through mammalian cells. It also highlights what has been learned when these radionuclides and radiotargeting pharmaceuticals are used to treat cancers.

Over the past 40 years, a small and highly committed group of scientists has pursued various investigations focused on understanding the physical phenomena underlying the emission of Auger electrons, the dosimetric implications of their submicroscopic deposition of energy, their radiobiological effects at the molecular and cellular levels, and their therapeutic potential in tumor-bearing animals and patients with cancer. Herein, I present an overview--historic vignette--of the exciting findings reported in this field and outline the unique opportunities given to the fortunate few who have, mostly through serendipity, been working within the fascinating world of Auger electron emitters.

, and (iii) the overall radiation dose deposited by radiolabeled cells in the unlabeled cells within the growing tumor is <10 cGy, we conclude that the results obtained are a consequence of a bystander effect that is generated in vivo by factor(s) present within and͞or released from the 125 IUdR-labeled cells. These in vivo findings significantly impact the current dogma for assessing the therapeutic potential of internally administered radionuclides. They also call for reevaluation of the approaches currently used for estimating the risks to individuals and populations inadvertently exposed internally to radioactivity as well as to patients undergoing routine diagnostic nuclear medical procedures. Studies in recent years have demonstrated that a radiobiologic phenomenon termed the ''bystander effect'' can be observed in mammalian cells grown in vitro. Bystander damage describes biologic effects, originating from irradiated cells, that occur in unirradiated neighboring cells. Several investigators have reported that when ␣-particles traverse a small fraction of a cell population in vitro, lower rates of survival and higher rates of genetic change are observed than those predicted from directionization-only models (1-6). These changes include increased levels of sister chromatid exchanges, mutations, and micronuclei formation, changes in gene expression, and oncogenic transformation. Cell survival is likewise compromised when cells are cocultured with tritiated thymidine-labeled cells (7, 8) and iodine-125 (9). Similarly, the bystander effect has been reported for microcolonies that have been ␥ irradiated (10) and for cells exposed to media from ␥-irradiated cells (10, 11). Evidence from these reports challenges the past half-century's tenet that radiation produces effects only in cells whose DNA has been damaged either through direct ionization or indirectly (for example, through hydroxyl radicals produced in water molecules in the immediate vicinity of the DNA).Whether radiation-induced bystander effects represent a phenomenon that occurs only ex vivo, i.e., are a byproduct of in vitro conditions and manipulations, or whether they are factual in vivo events has not been fully examined. Consequently, the extension of conclusions derived from in vitro studies to the in vivo situation is uncertain. The demonstration of a bystander effect with an in vivo system and the elucidation of the underlying mechanisms of an in vivo bystander effect would go a long way in translating its implications for humans.Recently, Watson et al. (12) demonstrated chromosomal instability in the progeny of unirradiated bone marrow cells mixed with cells exposed ex vivo to neutrons and transplanted into recipient mice. In this novel system, a sex-mismatch transplantation protocol provides a three-way marker system and allows the investigators to distinguish not only host-derived cells from donor-derived cells, but also irradiated donor stemcell-derived cells from nonirradiated donor stem-cell-derived cells. These studies thus provide the...

The radiotoxicity of 125I in Chinese hamster V79 lung fibroblasts has been studied following extracellular (Na125I), cytoplasmic [125I]iododihydrorhodamine (125I-DR), and nuclear (125IUdR) localization of the radionuclide. Exposure of the cells for 18 h to Na125I (less than or equal to 7.4 MBq/ml) had no effect on survival. A similar exposure to 125I-DR produced a survival curve with a distinct shoulder and with a mean lethal dose (D37) of 4.62 Gy to the nucleus. While this value compares well with the 5.80 Gy X-ray D37 dose, it is in contrast to the survival curve obtained with DNA-bound 125IUdR which is of the high LET type and has a D37 of 0.80 Gy to the nucleus. Furthermore, when the uptake of 125I into DNA is reduced by the addition of nonradioactive IUdR or TdR to the medium and the survival fraction is determined as a function of 125I contained in the DNA, a corresponding increase in survival is observed. This work demonstrates the relative inefficiency of the Auger electron emitter 125I when located in the cytoplasm or outside the cell. It indicates that a high dose deposited within the cytoplasm contributes minimally to radiation-induced cell death and that radiotoxicity depends not upon the specific activity of IUdR but upon the absolute amount of 125I that is associated with nuclear DNA.

The kinetics of uptake, retention, and radiotoxicity of 125IUdR have been studied in proliferating mammalian cells in culture. The radioactivity incorporated into the DNA is directly proportional to the duration of incubation and to the extracellular concentration of 125I. The rate of proliferation of cells is related to the intracellular radioactive concentration and is markedly reduced at medium concentrations greater than or equal to 0.1 mu Ci/ml. At 37% survival the high LET type cell survival curve is characterized by an uptake of 0.035 pCi/cell, and the cumulated mean lethal dose to the cell nucleus is about 80 rad compared to 580 rad of X-ray dose for this cell line. The strong cytocidal effects of the decay of 125I correlate with localized irradiation of the DNA by the low energy Auger electrons.