| First Author | Naoe Y | Year | 1998 |
| Journal | Jpn J Cancer Res | Volume | 89 |
| Issue | 6 | Pages | 666-72 |
| PubMed ID | 9703365 | Mgi Jnum | J:48945 |
| Mgi Id | MGI:1276241 | Doi | 10.1111/j.1349-7006.1998.tb03269.x |
| Citation | Naoe Y, et al. (1998) Cytotoxic mechanisms of FK317, a new class of bioreductive agent with potent antitumor activity. Jpn J Cancer Res 89(6):666-72 |
| abstractText | FK317 is a member of a new class of bioreductive agents that exhibit strong cytotoxicity against various human cancer cells. The effect of FK317 was found to be stronger than that of mitomycin C (MMC), adriamycin (ADR) or cisplatin (CDDP). Alkaline elution analysis indicated that FK317 formed interstrand DNA-DNA and DNA-protein cross-links in cells. On the other hand, no DNA single-strand breaks were observed in the cells treated with FK317. In a cell-free system the deacetylated metabolites produced cross-linked DNA under reductive conditions, though FK317 itself did not form DNA-DNA cross-links. In order to elucidate the metabolic activation mechanisms, we established an FK317-resistant subline from human non-small cell lung cancer cells (Lu99) by stepwise and brief exposure (1 h) to FK317. The resistant subline (Lu99/317) showed cross-resistance to MMC and carboquone (CQ), but not to ADR or CDDP. DT-diaphorase, which is one of the activation enzymes of MMC and CQ, was deficient in Lu99/317 cells as determined by enzyme activity assay. However, the levels of NADPH:cytochrome P450 reductase, which is another activation enzyme for MMC and CQ, were comparable in resistant and parent cell lines. Treatment of the cells with dicumarol, an inhibitor of DT-diaphorase, reduced the cytotoxicity of FK317 to Lu99 cells, but not to Lu99/317 cells. These results indicate that deacetylation of FK317 is necessary for its reductive activation, and deacetylated FK317 is reduced by DT-diaphorase to form an active metab-olite, which produces DNA-DNA interstrand and DNA-protein cross-links that lead to cell death. |
