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ID 37819
file
creator
Sakamoto, Noriaki
Toge, Tetsuya
Nishiyama, Masahiko
subject
DT-diaphorase
NADPH cytochrome P450
Mitomycin C
Biochemical modulation
NDC
Medical sciences
abstract
The bioreductive activation of mitomycin C (MMC) has been investigated using 10 human cancer cell lines. Except for 2 lines (COLO201 and COLO320DM), the cellular NAD(P)H: quinone oxidoreductase (DTD) activities correlated well with MMC-induced DNA damage and cytotoxicity. In addition, when the DTD activity was inhibited with 50 mM dicoumarol, the MMC activity decreased significantly. On the other hand, no correlation between the NADPH cytochrome P450 reductase (P450) activity and MMC efficacy was observed. We postulate that two electron reduction by DTD may be more important in MMC activation than one electron reduction by P450. The DTD-mediated metabolism was pH-dependent. In a nude mouse experimental model, the pH in the tumor decreased under hyperglycemic conditions due to unique glycolysis. The administration of m-iodobenzyl-guanidine (MIBG) enhanced the decrease in the pH of the tumor without affecting the pH of normal tissue (liver). It also significantly increased the antitumor activity of MMC. However, this biochemical modulation had no effect in the COLO201 and COLO320DM cells. Other mechanisms may be involved in the regulation of MMC activity in these cells. In conclusion, DTD may be an important target of MMC. Biochemical modulation using MIBG and glucose may selectively enhance the activity of MMC within cancer cells.
description
This work was presented in part at the 95th and 96th Annual Meetings of the Japan Society for Surgery, Nagoya, 1994, and Makuhari, 1996.
journal title
Hiroshima Journal of Medical Sciences
volume
Volume 46
issue
Issue 2
start page
67
end page
73
date of issued
1997-06
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
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