| Budget Amount *help |
¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1994: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1993: ¥1,000,000 (Direct Cost: ¥1,000,000)
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| Research Abstract |
Sodium 5,6-benzylidene-L-ascorbate (SBA) has been reported to be effective against human malignant tumors and rat chemically-induced tumors. In order to investigate the mechanism of induction of antitumor activity by SBA,we investigated here possible apoptosis-inducing activity of SBA,using human myelogenous leukemic cell lines (HL-60, ML-1, U-937, THP-1). SBA induced nucleosome-size DNA fragmentation and appearance of apoptotic body in these cell lines, but not in normal human peripheral blood lymphocytes, monocytes nor in polymorphonuclear cells. These data suggest that antitumor activity of SBA might, at least in part, be due to its apoptosis-inducing activity. High-performance liquid chromatographic analysis revealed that ts acetal and lactone ring of SBA were labile especially at acidic or neutral-alkaline pH,respectively (Sakagami et al., submitted for publication). Since no detectable amout of ascorbic acid was produced at neutral pH,ascorbic acid might not play significant role
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for the SBA action. This notion was supported by our finding that catalase completely inhibited the action of sodium ascorbate, but not that of SBA.We unexpectedly found that sodium ascorbate more potently induced the apoptosis of leukemic cells than SBA.Minimum exposure time required for apoptosis induction by sodium ascorbate was 30min. Either sodium ascorbate, hydrogen peroxide, etoposide, hyperthermia or UV irradiation induced nucleosome-size DNA fragmentation in human myelogenous leukemic cell lines, but not in human T-cell leukemia (MOLT-4) nor in human erythroleukemia (K-562) cell lines. Major endonuclease present in these cell lines, was an acidic, cytoplasmic, Ca/Mg- independent endonuclease (Anticancer Res 15 : in pess, 1995). Therefore, it is possible that endonuclease activity in these two groups of cell lines might be regulated by different mechanisms. Hydrogen peroxide induced a rapid, transient increase in intracellular calcium concentration only in the former groups of cells (Sakagami et al. manuscript in preparation). There remains to investigate the signal transduction leading to the activation of Ca/Mg-dependent endonuclease, which has been reported to play significant role for apoptosis in various organs such as thymus and spleens. Less
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