このエントリーをはてなブックマークに追加
ID 37862
file
creator
Saeki, Shuji
Nishiyama, Masahiko
Toge, Tetsuya
subject
DT-diaphorase
Mitomycin C
Biochemical modulation
Microenvironmental pH
NDC
Medical sciences
abstract
We studied a selective enhancement of the mitomycin C (MMC)-induced antitumor effect focusing on the intracellular metabolism by NAD(P)H:quinone oxidoreductase (DT-diaphorase, DTD). The level of cellular DTD activity related well to the degree of MMC-induced DNA total cross links and cell growth inhibition in human cancer cell lines, KB, PH101, SH101 and K562. A DTD inhibitor, dicoumarol (DIC) or flavin adenine dinucleotide (FAD), inhibited the MMC-induced DNA damage and cytotoxicity at a non-toxic concentration. The DTD-mediated MMC activation was pH-dependent, and highest at pH 6 and lowest at pH 8. Although an inverse relationship appeared to exist between DTD activity and MMC efficacy in human xenografts implanted into nude mice and 9 fresh human tumor specimens, the investigation in 3 culture cells, HEC-46, HCC-48 and HCC-50, established from those xenografts, showed that DTD activated MMC in a pH-dependent manner as well as the other cell lines. Significant tumor pH reduction from 7.1 to 6.7 by continuous glucose infusion also increased the MMC-induced tumor growth inhibition in the human tumor xenografts. Thus, we conclude that bioreductive activation by DTD in a pH-dependent manner may be of key importance in the MMC-induced antitumor effect and that an increased MMC efficacy at a reduced pH caused by hyperglycemia may be applied to clinical use as a new manipulation for a biochemical modulation of MMC.
description
This work was presented in part at the 40th Annual Meeting of Japan Soc. for Chemotherapy, Nagoya, 1992, the 18th International Congress of Chemotherapy, Stockholm, 1993 and the 52nd Annual Meeting of Japan Cancer Assoc., Sendai, 1993.
journal title
Hiroshima Journal of Medical Sciences
volume
Volume 44
issue
Issue 3
start page
55
end page
63
date of issued
1995-09
publisher
Hiroshima University Medical Press
issn
0018-2052
ncid
language
eng
nii type
Departmental Bulletin Paper
HU type
Departmental Bulletin Papers
DCMI type
text
format
application/pdf
text version
publisher
department
Research Institute for Radiation Biology and Medicine
Graduate School of Biomedical Science
他の一覧