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Significant evidence indicates that ionizing radiation causes biological effects in nonirradiated bystander cells having received signals from directly irradiated cells. There is little information available hitherto as to the bystander effect of energetic heavy ions; however, our previous work has shown that in confluent cultures of normal human fibroblast AG01522 cells, targeted exposure of 0.0003% of cells to microbeams of 18.3 MeV/u 12 C (103 keV/µm) and 13.0 MeV/u 20 Ne (375 keV/µm) ions can similarly cause almost 10% decreases in the clonogenic survival, and twofold increments in the incidence of apoptosis whose temporal kinetics varies between irradiated and bystander cells. Using this experimental system, here we further report that bystander responses of AG01522 cells to 17.5 MeV/u 20 Ne ions (294 keV/µm) are consistent with those to 18.3 MeV/u 12 C and 13.0 MeV/u 20 Ne ions. We also demonstrate that such bystander-induced reductions in the survival are less pronounced and occur independently of Bcl-2 overexpression in human cervical cancer HeLa cells.

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Abstract. A group of histone deacetylase (HDAC) inhibitors has been shown to suppress the growth of a variety of human tumor lines in vitro and in vivo and they are among the most promising candidates for anti-cancer therapeutic agents. We investigated the ability of scriptaid, a novel HDAC inhibitor and trichostatin A (TSA) to enhance cell killing by radiation in radioresistant SQ-20B cells derived from human head and neck squamous carcinoma. SQ-20B cells were treated with scriptaid or TSA in combination with radiation. Cell survival was determined by a colony formation assay and protein levels were examined by Western blotting. DNA double strand breaks were measured by a Á-H2AX focus assay. Radiosensitization was observed for SQ-20B cells incubated with scriptaid at 5 μM or TSA at 0.1 μM for 24 h. Radiosensitization by scriptaid was accompanied by a prolonged retention of Á-H2AX foci, suggesting that the enhancement of radiation cell killing by scriptaid involved inhibition of DNA double strand break repair. In addition, treatment with scriptaid suppressed expression of Ku80, but not Ku70. Scriptaid may be a useful radiosensitizer in the treatment of radioresistant human carcinomas.

Here we investigated the potential impact of energetic heavy ions on fibroblast differentiation. The differentiation pattern was morphologically determined at days 3 and 5 after exposure to graded dose of γ-rays (0.2 keV/µm) or carbon ions (18.3 MeV/u, 108 keV/µm). The cells irradiated with higher doses progressed toward later differentiation stages as time goes postirradiation, but underwent fewer cell divisions. Thus, radiation exposure accelerated morphological differentiation, for which carbon ions were more effective than γ-rays. The relative biological effectiveness of carbon ions for differentiation was higher than that for the clonogenic survival, and this was the most case for terminally differentiated cells that may not divide any more. The results are suggestive of the distinct mechanism underlying inactivation of clonogenic potential between the radiation quality, such that the contribution of the differentiation to heavy ion-induced reductions in the survival is greater than to those induced by photons. Such accelerated differentiation could be a protective mechanism that minimizes further expansion of aberrant cells.

Biological effectiveness varies with the linear energy transfer (LET) of ionizing radiation. Plentiful evidence has been presented demonstrating that at physically equivalent doses, high-LET energetic heavy ions are more cytotoxic and genotoxic than low-LET photons like X-rays and γ-rays. Notwithstanding, its potential impact at isosurvival doses is yet to be characterized. Here we investigated the cell-killing effectiveness of γ-rays (0.2 keV/µm) and five different beams of heavy ions with LET ranging from 16.2 to 1610 keV/µm in confluent cultures of normal human fibroblasts. The relative biological effectiveness based on the dose giving 10% clonogenic survival peaked at 108 keV/µm. In cultures exposed to the 10% survival doses, the yield of apoptotic cells escalated with time postirradiation but declined with LET. Our results imply that the cell death mode differs with LET at isosurvival levels.