Development of new antitumor drugs and apoptotic signal transudation - Application to feline leukemia and canine lymphoma -

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Clinically, the combination treatment of solid tumor cells with an anticancer drug and radiation was widely used to enhance cell killing. 1-(3-C-Ethynyl-β-D-ribo-pentofuranosyl) cytosine (ECyd) and 2-chrolo-deoxyadenosine (Cl-Ade) was newly developed as anticancer drugs to induce cell death by inhibiting RNA synthesis. In this study, we examined whether the exposure of these anticancer drugs or /and ionizing radiation to human gastric adenocarcinoma MKN45 cells, human lekemia cell line MOLT-4 cells induce apoptosis and canine lymphoma cell line CL-1. In MOLT-4 cells, Fas expression and caspase 8/3 activation apoptotic cell death was observed after treatment of Cl-Ade, followed by apoptotic cell death. 2Cl-Ade and ECyd showed to induce apoptotic cell death in canine lymphoma cell CL-1 cells. MKN45 cells were treated with 0.1 μM ECyd for 1 h before irradiation. After irradiation with 20 Gy, apoptotic as well as swelling cells were morphologically discriminated by fluorescence microscopy … More combined with propidium iodide staining or electron microscopy and were scored. When cells were treated with ECyd alone, only 5 % of either apoptotic or necrotic cells appeared. When cells were exposed to X rays alone, about 5 % of apoptotic and about 45 % of swelling cells appeared. However, when cells were exposed to X rays in the presence of 0.1 μM ECyd, about 25 % of total cells was apoptotic cells and about 10 % of total cells was swelling cells. Apoptosis induced by treating cells with ECyd and X irradiation was significantly reduced by the treatment with Ac-DEVD-CHO (caspase 3 inhibitor) or TPCK (chymotrypsin-like protease inhibitor).These results suggested that caspase 3 and chymotrypsin-like proteases were responsible for apoptosis induced by co-treatment with ECyd and X rays. In this study, it was demonstrated that co-treatment of MKN45 cells with ECyd and X rays activated G2-phase-linked apoptotic signaling associated with caspase 3 and chymotrypsin like protease. These data may provide useful information to develop clinical treatment of radiation combined with anticancer drugs for solid tumors. Less