The Shape of the Dose–Response Curve for Radiation-Induced Neoplastic TransformationIn Vitro: Evidence for an Adaptive Response against Neoplastic Transformation at Low Doses of Low-LET Radiation

Abstract

A dose-response curve for gamma-radiation-induced neoplastic transformation of HeLa x skin fibroblast human hybrid cells over the dose range 0.1 cGy to 1 Gy is presented. In the experimental protocol used, the spontaneous (background) frequency of neoplastic transformation of sham-irradiated cultures was compared to that of cultures which had been irradiated with (137)Cs gamma radiation and either plated immediately or held for 24 h at 37 degrees C prior to plating, for assay for neoplastic transformation. The pooled data from a minimum of three repeat large-scale experiments at each dose demonstrated a reduced transformation frequency for the irradiated compared to the sham-irradiated cells for doses of 0.1, 0.5, 1, 5 and 10 cGy for the delayed-plating arm. The probability of this happening by chance is given by 1/2(n), where n is the number of observations (5); i.e., 1/32 congruent with 0.031. This is indicative of an adaptive response against spontaneous neoplastic transformation at least up to a dose of 10 cGy of gamma radiation. The high-dose data obtained at 30 and 50 cGy and 1 Gy showed a good fit to a linear extrapolation through the sham-irradiated, zero-dose control. The delayed-plating data at 10 cGy and below showed a statistically significant divergence from this linear extrapolation.

An Examination of Radiation Hormesis Mechanisms Using a Multistage Carcinogenesis Model

“…These in vitro experiments show a reduction of induced transformation frequencies at low doses to values below that observed spontaneously (Azzam et al, 1996;Redpath and Antoniono, 1998;Redpath et al, 2001Redpath et al, , 2003aRedpath et al, , 2003b. DNA repair mechanisms are highly conserved among all eukaryotes (Mitchel, 1995;Mitchel et al, 1997), and if these phenomena arise as the result of adaptations in DNA repair, it is not unreasonable to expect that some or all of these phenomena will also occur in humans.…”

“…In this model, HR is up-regulated by radiation and impacts on the repair of DSBs produced through endogenous processes. The protective effects of low doses of γ -rays delivered at low dose rates, as discovered by Azzam and colleagues, have been confirmed by studies in human (HeLa) cells (Redpath and Antoniono, 1998;Redpath et al, 2001). Yamaoka et al (1991) report increased superoxide dismutase (SOD) activities induced by low doses of X-rays in rat organs.…”

“…In this section, the genomic instability model is extended to account for putative toxicant-induced adaptations in cellular repair systems as well as for toxicant-induced adaptations in the radical scavenging capacity of a cell. The experimental evidence suggesting the existence of radioprotective effects mainly comes from experiments performed with low doses of low-linear-energy-transfer (LET) radiation (e.g., Azzam et al, 1994aAzzam et al, , 1996Redpath and Antoniono, 1998;Redpath et al, 2001Redpath et al, , 2003aRedpath et al, , 2003bMitchel et al, 2003;Pant et al, 2003), and the proposed model may be more appropriate for-and X-rays than for high-LET radiations, such as α-particles from randon progeny.…”

Low dose gamma irradiation enhances defined signaling components of intercellular reactive oxygen-mediated apoptosis induction

“…They thus might represent the basis for the protective low dose radiation effects observed in vitro and in vivo [32][33][34][35][36][37][38][39][40][41][42][43][44]. However, it is also shown in this paper that cells with certain specific signaling features, ratios between specific signaling components as well as certain situations with respect to the density of cells may lead to protection of malignant cells rather than to their destruction.…”

“…There is an ongoing discussion on the effects of low dose radiation during carcinogenesis [31,32]. Potential controlling effects of low dose radiation on transformation and tumorigenesis have been well established in the literature [33][34][35][36][37][38][39][40][41][42][43][44]. Low dose radiation has been shown to induce a decrease in observable transformation frequency [33-36.41-43].…”