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SUMMARYWe have previously reported the antimetastatic effects and augmentation of immune responses, which would be a mechanism of the antimetastatic effects, of 0.1 to 0.2 Gy total body irradiation. To elucidate the cellular mechanisms of the augmentation of immune response, we investigated the effects of low-dose irradiation on gene expression of interleukin-1␤ (IL-1␤) and IL-6 using mouse peritoneal macrophages in vitro. Absolute mRNA quantification was carried out using competitive polymerase chain reaction. Gene expression of IL-1␤ and IL-6 was increased 1 to 2 hr after 2.0 Gy irradiation and then decreased to below the basal expression level 4 hr after irradiation. Irradiation with 0.1 Gy increased IL-6 expression 2 hr after irradiation, but it did not affect IL-1␤ expression. Downregulation of IL-1␤ and IL-6 observed 4 hr after 2.0 Gy irradiation was not observed with 0.1 Gy irradiation. The protein kinase C (PKC) inhibitor H7 and the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor wortmannin inhibited induction of IL-1␤ and IL-6 expression, which suggests that radiation-induced IL-1␤ and IL-6 expression is achieved by PKC-and PI3-kinase-mediated signaling.

ATM and DNA‐dependent protein kinase catalytic subunit (DNA‐PKcs) have been shown to have sequences homologous to the catalytic domains of mammalian phosphatidylinositol 3‐kinase (PI3‐kinase). In order to determine the contribution of ATM and DNA‐PKcs to the increased sensitivity of cells to DNA‐damaging agents observed in the presence of PI3‐kinase inhibitors, we examined the effects of a PI3‐kinase inhibitor, wortmannin, on cellular sensitivity to bleomycin (BLM), mitomycin C (MMC), X‐irradiation and ultraviolet (UV)‐irradiation using 2 human tumor cell lines (T98G and A172), a human fibroblast cell line (LM217), an ataxia telangiectasia (AT) cell line (AT3BISV), a scid murine cell line (SCF) and a control murine cell line (CBF). Wortmannin sensitized all of the cells, including AT3BISV and SCF, to BLM and X‐irradiation, but not to MMC or UV‐irradiation. Hypersensitivity to BLM and X‐irradiation and normal sensitivity to MMC and UV‐irradiation are characteristic phenotypes of both AT and scid mice. DNA‐dependent protein kinase (DNA‐PK) activity was suppressed by wortmannin to 45–65% of the control values in all of the cells except SCF, in which DNA‐PK activity was not detected. Wortmannin also induced radioresistant DNA synthesis, which is a cellular phenotype of AT, in T98G and SCF cells, but did not change the DNA synthesis rates after X‐irradiation in AT3BISV. Our data suggest that wortmannin decreases the activities of both the ATM protein and DNA‐PK, indicating that it might be of use as a sensitizing agent for radiotherapy and chemotherapy. Int. J. Cancer 78:642–647, 1998. © 1998 Wiley‐Liss, Inc.

ATM and DNA‐dependent protein kinase catalytic subunit (DNA‐PKcs) have been shown to have sequences homologous to the catalytic domains of mammalian phosphatidylinositol 3‐kinase (PI3‐kinase). In order to determine the contribution of ATM and DNA‐PKcs to the increased sensitivity of cells to DNA‐damaging agents observed in the presence of PI3‐kinase inhibitors, we examined the effects of a PI3‐kinase inhibitor, wortmannin, on cellular sensitivity to bleomycin (BLM), mitomycin C (MMC), X‐irradiation and ultraviolet (UV)‐irradiation using 2 human tumor cell lines (T98G and A172), a human fibroblast cell line (LM217), an ataxia telangiectasia (AT) cell line (AT3BISV), a scid murine cell line (SCF) and a control murine cell line (CBF). Wortmannin sensitized all of the cells, including AT3BISV and SCF, to BLM and X‐irradiation, but not to MMC or UV‐irradiation. Hypersensitivity to BLM and X‐irradiation and normal sensitivity to MMC and UV‐irradiation are characteristic phenotypes of both AT and scid mice. DNA‐dependent protein kinase (DNA‐PK) activity was suppressed by wortmannin to 45–65% of the control values in all of the cells except SCF, in which DNA‐PK activity was not detected. Wortmannin also induced radioresistant DNA synthesis, which is a cellular phenotype of AT, in T98G and SCF cells, but did not change the DNA synthesis rates after X‐irradiation in AT3BISV. Our data suggest that wortmannin decreases the activities of both the ATM protein and DNA‐PK, indicating that it might be of use as a sensitizing agent for radiotherapy and chemotherapy. Int. J. Cancer 78:642–647, 1998. © 1998 Wiley‐Liss, Inc.

The results suggest that (1) non-homologous endjoining plays a dominant role in G1 to early S-phase and a minor role in late S to G2-phase in repairing DNA double-strand breaks, (2) the role of ATM in repairing double-strand breaks may be almost cell-cycle-independent and (3) the dominant role of non-homologous end-joining during G1 to early S-phase is not due to cell-cycle-dependent fluctuations in DNA-PK activity.