Relevance of DT-diaphorase activity to mitomycin C (MMC) efficacy on human cancer cells: Differences in in vitro and in vivo systems
✍ Scribed by Masahiko Nishiyama; Shuji Saeki; Kenjiro Aogi; Naoki Hirabayashi; Tetsuya Toge
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- French
- Weight
- 510 KB
- Volume
- 53
- Category
- Article
- ISSN
- 0020-7136
No coin nor oath required. For personal study only.
✦ Synopsis
Using 4 human cancer cell lines, 4 tumors xenografted into nude mice, and I I fresh tumor specimens removed at surgery, we investigated the relevance of NAD(P)H:quinone oxidoreductase (DT-diaphorase, DTD) activity (nmoles/min/mg protein) to mitomycin C (MMC)-induced cytotoxicity. In culture cell lines, KB cells had significantly higher levels of DTD activity (8260) than PH I0 I (I 934). SH I0 I (I 805) or K562 (I 796), and the highest sensitivity to MMC. In contrast, the higher the DTD activity of xenografts. the greater their resistance to MMC, while the inhibition rate of relative tumor growth for MMC. as evaluated by the NCI protocol, was highest in SH-6, high in CH-5, lower in C H 4 and lowest in EH-6. The investigation using I I fresh tumor specimens also showed an inverse relationship between lCw values after a 30-min MMC treatment, as evaluated by ATP assay and DTD activities. Moreover, a non-toxic DTD inhibitor, dicoumarol (DIC), or flavin adenine dinucleotide (FAD), suppressed the efficacy of MMC in culture cells, but enhanced it in xenografts. Thus, we suggest that DTD may play an important role in MMC-induced cytotoxicity but MMC metabolism by DTD in solid tumors may differ from that in culture cells.