Radiobiological basis of low-dose irradiation in prevention and therapy of cancer

Abstract

Antimutagenic DNA damage-control is the central component of the homeostatic control essential for survival. Over eons of time, this complex DNA damage-control system evolved to control the vast number of DNA alterations produced by reactive oxygen species (ROS), generated principally by leakage of free radicals from mitochondrial metabolism of oxygen. Aging, mortality and cancer mortality are generally accepted to be associated with stem cell accumulation of permanent alterations of DNA, i.e., the accumulation of mutations. In a young adult, living in a low LET background of 0.1 cGy/y, the antimutagenic system of prevention, repair and removal of DNA alterations reduces about one million DNA alterations/cell/d to about one mutation/cell/d. DNA alterations from background radiation produce about one additional mutation per 10 million cells/d. As mutations accumulate and gradually degrade the antimutagenic system, aging progresses at an increasing rate, mortality increases correspondingly, and cancer increases at about the fourth power of age. During the past three decades, genomic, cellular, animal and human data have shown that low-dose ionizing radiation, including acute doses up to 30 cGy, stimulates each component of the homeostatic antimutagenic control system of antioxidant prevention, enzymatic repair, and immunologic and apoptotic removal of DNA alterations. On the other hand, high-dose ionizing radiation suppresses each of these antimutagenic protective components. Populations living in high background radiation areas and nuclear workers with increased radiation exposure show lower mortality and decreased cancer mortality than the corresponding populations living in low background radiation areas and nuclear workers without increased radiation exposure. Both studies of cancer in animals and clinical trials of patients with cancer also show, with high statistical confidence, the beneficial effects of low-dose radiation.

Figures

FIGURE 1

The antimutagenic DNA damage-control biosystem. Estimates are based on data in the literature.

FIGURE 2

Antioxidant SOD and lipid peroxide response to age and radiation of rat brain cortex

FIGURE 3

Low dose induced DNA repair

FIGURE 4

Mean chromosomal aberrations per cell in lymphocytes before and after exposure to 150 r. Lymphocytes were obtained from Ramsar residents in a high background γ radiation area of about 10 mGy/y and residents in a normal background γ radiation area of about 1 mGy/y.

FIGURE 5

Eight month old, mammary tumor-susceptible, female C3H/He mice were first adjusted in a stepwise manner to chronically restricted diet (calorically 70% of ad libitum diet) over a period of 3 weeks. The mice were maintained on CRD until completion of the study. After their diet was adjusted, the mice were exposed to TBI (0.04 Gy, 3 alternating days/week, 4 weeks) and were observed for 35 weeks. Tumor regression of the CRD + TBI group was very rapid and large numbers of CD8+ T cells were found infiltrating the regressing tumors, which were not seen in mice of the untreated control, LDR and CRD groups.

FIGURE 6

The antimutagenic DNA damage-control biosystem response to high background radiation = 120%. Estimates based on data in the literature.

FIGURE 7

Immune system response to radiation. Mouse splenic cells primed with antigenic sheep red blood cells.

FIGURE 8

Effect of 0.15 Gy upon response of A/J mice to subimmuno-genic and immunogenic numbers of non-viable mitomycin-treated fibrosarcoma (SaI) tumor cells. Groups of 60 mice were exposed to whole-body irradiation or sham-irradiated and inoculated subcutaneously with the indicated numbers of mitomycin-treated tumor cells. Twenty-one days later, all animals received 104 untreated SaI cells and were followed for tumor size. A control group did not receive mitomycin-treated cells.

FIGURE 9

TBI given 12 days after tumor cell transplantation into axilla. Lung colonies counted 20 days after TBI. Low dose TBI ineffective with spleen blocked. Low dose splenic irradiation, half-body irradiation (HBI) and TBI equally effective.

FIGURE 10

Dose-response analysis of splenic T cell proliferative response 3–5 days after the last radiation exposure of immunologically normal, long-lived C57B1/6J+/+ mice. Results are expressed as the mean percent increase in 3H-thymidine uptake relative to 0 Gy control group as 100%. The vertical bars = 1 SEM.

FIGURE 11

Reduced breast cancer mortality of tuberculosis patients who received LDI during fluoroscopy24, 25

FIGURE 12

The number and incidence of metastases in lung and lymph nodes of mediastinum and axilla 50 days after intramuscular (leg) tumor implantation in rats, and the number of tumor infiltrating lymphocytes 21 days after implantation. Total body or localized tumor irradiation with 0.2 Gy was given 14 days after implantation of 5 × 105 allogenic hepatoma cells.

FIGURE 13

Comparison of TBI with CHOP chemotherapy. CHOP remains the best available chemotherapy treatment for patients with advanced-stage intermediate-grade or high-grade non-Hodgkin's lymphoma.

FIGURE 14

Treatment of patients with non-Hodgkin's lymphoma with half (HBI) or total (TBI) body irradiation. Adapted from Sakamoto et al

FIGURE 15

Utility of low-dose irradiation of HBI or TBI for patients with non-Hodgkin's lymphoma. Patients in both groups received chemotherapy and localized tumor high-dose radiation.

FIGURE 16

CT scans of upper nasal cavity before and after HBI therapy. Though entirely outside the HBI field, the nasal tumor completely disappeared.