Female C3H strain mice, which do not spontaneously exhibit frequent bone tumors and myeloid leukemias, were injected intraperitoneally with various doses of 10 to 12000 Bq/animal of monomeric ²³⁹Pu citrate to clarify lifetime carcinogenesis caused by alpha-particles distributed mainly in the skeleton. Survival time was reduced significantly at mean skeletal doses of more than 2.93 Gy and was accompanied by marked life-shortening as compared to the controls due to an earlier increase in neoplastic or non-neoplastic death. Bone tumors, almost all of which were osteosarcomas, were not found in the controls, whereas their incidence increased sharply to a maximum of 96% at 6.92 Gy, then dropped at higher doses (20% at 42.4 Gy). Although lymphoid tumors were present in 20% of the control animals, their incidence dropped to zero at 6.92 Gy, then increased at higher doses (36% at 25.5 Gy). Non-thymic, mostly pre-B cell type, leukemic lymphomas mainly occurred at early time after ²³⁹Pu-injection; whereas, in the controls thymic, lymphocytic or histiocytic lymphomas occurred only at a later time. Of the other soft tissue tumors, neither myeloid leukemias nor myelogenous neoplasms were found in the controls or the ²³⁹Pu-injected animals. Tumors affecting the lungs, liver, ovaries, and skin were much fewer or not found at mean doses of more than 2.93 Gy. These results indicate dose-dependent, differential tumor induction resulting from bone and lymphoid tumor competition after an injection of plutonium.

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We investigated the effects of continuous exposure to γ-rays during corticogenesis on the migration of neuronal cells in developing cerebral cortex. Pregnant mice were injected with 0.5 mg of bromodeoxyuridine (BrdU) on day 14 of gestation to label cells in the S phase. The mice were then exposed to ¹³⁷Cs γ-rays (dose rates of 0.1, 0.3, and 0.94 Gy/day) continuously for 3 days. Brains from 17-day-old embryos and from offspring at 3 and 8 weeks after birth were processed immunohistochemically to track the movements of BrdU-labeled cells. Comparative analyses of the distribution pattern of BrdU-labeled cells in the cerebral cortex revealed that (1) the migration of neurons was delayed during the embryonic period in mice irradiated at 0.94 Gy/day, (2) in 3-week-old mice, there was a significant difference in the distribution pattern of BrdU-labeled cells in the cerebral cortex between the mice irradiated prenatally and control, and (3) in 8-week-old mice, there were no differences in the distribution pattern of BrdU-labeled cells between control and animals irradiated with 0.1 and 0.3 Gy/day. In contrast, in the animals irradiated with 0.94 Gy/day, the significant difference in the distribution pattern of the labeled cells relative to control was maintained. These results suggest that the migration of neuronal cells in mouse cerebral cortex is disturbed by continuous prenatal irradiation at low-dose and some modificational process occurred during the postnatal period.

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Deterioration in the clonogenic ability of Chinese hamster V79 cells was observed after treatments with low concentrations of H₂O₂ (0.06-0.2 mM) for 1 h and subsequent incubation for 6-8 days, whereas no loss of ability of the cells to exclude trypan blue after treatments with H₂O₂ for 1 h and subsequent incubation for 6 h was observed in this concentration range. The loss of the dye-exclusion ability became observable when the cells were treated with concentrations greater than 0.9 mM H₂O₂ for 1 h and subsequently incubated for 6 h. Agarose gel electrophoresis of DNA extracted from cells treated with 1-5 mM H₂O₂ showed specific regular fragmentation of DNA, suggesting that apoptotic cell death was induced. The induction of apoptotic cell death was further confirmed by observing the protective effects of several modifiers, a protein synthesis inhibitor (cycloheximide), a Ca²⁺-chelator (BAPTA-AM) and an antioxidative compound (PBN), against cell survival and DNA fragmentation. From these results, it was concluded that apoptotic cell death was induced by H₂O₂ in Chinese hamster cells at high concentrations, where their clonogenic ability completely disappeared.

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We report that the relative biological effectiveness (RBE) of accelerated heavy ions for inactivation of cells can be analyzed by using the quadratic dependence on the linear energy transfer (LET) of the cellular effect. For high-LET radiation in low-dose regions, the inactivation cross section (σ) can be approximately expressed as σ_max [1-exp[-k·(LET/ L₁)²]; here, k is the number of heavy-ions traversed in a cell nucleus and L₁ is a geometrical parameter related to the DNA structure, which depends on cell type. This original expression was first presented by Powers et al [Int. J. Radiat. Biol. 14 (1968)]. Using this expression and the Poisson distribution for the stochastic property of particle hitting, the mortality of cell populations was calculated.The numerical results were compared to the RBE values recently obtained with Chinese hamster V79 cells, and an L₁ value of 152 keV/μm was found to give the best fit. At LETs of between 30 and 500 keV/μm, the D₁₀ values (10% survival dose) agreed with the experimental data within an error range of -15%∼+8%.

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Flow cytometric analysis showed that the treatment of irradiated mice with a heat-killed Lactobacillus casei preparation (LC 9018) accelerated the recovery of granulocytic cell populations in peripheral blood, spleen and femur bone marrow. The recovery of the lymphocytic cell population was not accelerated while the recovery of the B-lymphocytic cell population was inhibited. Histological analysis also showed that the LC-9018 treatment markedly enhanced granulopoiesis in the spleen and bone marrow of irradiated mice. The same LC-9018 treatment significantly increased 30-day survival rates of athymic nude mice after lethal whole-body irradiation. The recovery of the granulocytic cell population in peripheral blood of irradiated athymic nude mice was also accelerated by LC-9018 treatment. Our results suggest that LC 9018 protected lethally irradiated mice from bone marrow death by enhancing granulopoiesis rather than lymphopoiesis and that the contribution of activated T lymphocytes to the enhancement of the granulopoiesis was small.

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The four 2''-deoxyribonucleosides were γ-irradiated or were aerobically treated with Fenton-type-reagents, Fe(II)-EDTA or a renal carcinogen Fe(II)-nitrilotriacetic acid (NTA) under the neutral conditions. The reaction mixtures were immediately analyzed by reverse-phase HPLC. Major products detected were 2-hydroxydeoxyadenosine (2-OH-dA), 8, 5''-cyclodeoxyadenosine (cyclo-dA), 8-hydroxydeoxyadenosine (8-OH-dA), 5-formyldeoxyuridine (5-CHO-dU), 5-hydroxydeoxycytidine (5-OH-dC), 8-hydroxydeoxyguanosine (8-OH-dG), 8, 5''-cyclodeoxyguanosine (cyclo-dG), and glyoxal and its adduct with dG. Ratio of these oxidized products were dramatically changed depending upon the agents used. For example, 2-OH-dA was a modified nucleoside produced most efficiently by Fe(II)-EDTA, while 5-CHO-dU and 5-OH-dC were the major products by the Fe(II)-NTA treatment and γ-irradiation, respectively. Glyoxal itself was estimated to be produced most frequently (13 folds of 8-OH-dG) when treated with Fe(II)-EDTA, but its formation was not detected by the treatment with Fe(II)-NTA or by γ-irradiation. 8-OH-dA was not produced by Fe-EDTA or Fe-NTA but was produced by γ-irradiation. In contrast, 2-OH-dA was not produced by γ-irradiation. These results suggest that triphosphates of 2-OH-dA, cyclo-dA, 8-OH-dA, cyclo-dG, 5-CHO-dU, 5-OH-dC, and glyoxal-dG as well as 8-OH-dG may be produced in cells with different ratio by various types of oxidative stress and involved in mutagenesis and carcinogenesis.

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