Bystander effect produced by radiolabeled tumor cells in vivo

Abstract

, 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...

Is there a common mechanism underlying genomic instability, bystander effects and other nontargeted effects of exposure to ionizing radiation?

“…They then extended these studies to an in vivo situation and demonstrated that when neutronirradiated cells were mixed with nonirradiated cells in vitro, then transplanted into recipient mice, genomic instability could be found in the unirradiated cell population (Watson et al, 2000). These observations have subsequently been confirmed by Xue et al (2002), who injected mice with a mixture of LS174 T adenocarcinoma cells and LS174 T cells prelabeled with lethal doses of DNA-incorporated 125 Iodine. They observed a distinct inhibitory effect on the growth of the nonlabeled tumor cells, which they concluded was due to a bystander effect produced by radiolabeled tumor cells.…”

Intercellular Communication in Response to Radiation Induced Stress: Bystander Effects in Vitro and in Vivo and Their Possible Clinical Implications

“…Our preliminary results from in vitro fractionation dose experiments, presented in this Chapter indicate that apoptosis is even more effectively induced in human melanoma radiation-targeted and bystander cells when the same dose is delivered in 3 fractions than in one single dose. A growing body of experimental in vitro and in vivo data indicate the occurrence of bystander phenomenon in radionuclide-based radiotherapy (Xue et al, 2002, Gerashchenko and Howell, 2004, Boyd et al, 2006, Mairs et al 2007). However, studies of radionuclide-induced bystander effect demonstrate varying responses (compared to low LET radiation-induced ones), being either damaging or protective depending on dose and type of emitters.…”

Genomic instability and bystander effects: a historical perspective

“…When cells labelled with 125 IdUrd were mixed with unlabelled cells and multicellular clusters formed by centrifugation, a decrease in clonogenic survival occurred in the unlabelled cells that appeared to depend upon GJIC (Bishayee et al, 1999;Howell and Bishayee, 2002). A similar effect was observed in vivo when radiolabelled tumor cells were injected into nude mice and tumor growth was employed as an end point (Xue et al, 2002). In another series of experiments (Watson et al, 2000), a mixture of irradiated and nonirradiated bone marrow cells was transplanted into mice.…”