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2000 ; 91
(4
): 433-8
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A novel class of antitumor prodrug, 1-(2 -oxopropyl)-5-fluorouracil (OFU001),
that releases 5-fluorouracil upon hypoxic irradiation
#MMPMID10804292
Shibamoto Y
; Zhou L
; Hatta H
; Mori M
; Nishimoto S
Jpn J Cancer Res
2000[Apr]; 91
(4
): 433-8
PMID10804292
show ga
We have been developing prodrugs of anticancer agents such as 5-fluorouracil
(5-FU) that are activated by irradiation under hypoxic conditions via
one-electron reduction. Among them, OFU001 [1-(2'-oxopropyl)-5-fluorouracil] is a
prototype radiation-activated prodrug. In this study, we investigated the
radiation chemical reactivity and the biological effects of OFU001. This prodrug
is presumed to release 5-FU through incorporation of hydrated electrons into the
antibonding sigma * orbital of the C(1')-N(1) bond. Hydrated electrons are active
species derived from radiolysis of water, but are readily deactivated by O(2)
into superoxide anion radicals (O(2).(-)) under conditions of aerobic
irradiation. Therefore, 5-FU release occurs highly specifically upon irradiation
under hypoxic conditions. OFU001 dissolved in phosphate buffer released 5-FU with
a G-value (mol number of molecules that are decomposed or produced by 1 J of
absorbed radiation energy) of 1.9 x 10(-7) mol / J following hypoxic irradiation,
while the G-value for 5-FU release was 1.0 x 10(-8) mol/J following aerobic
irradiation. However, the G-values for decomposition of OFU001 were almost the
same, i.e., 3.4 x 10(-7) mol/J following hypoxic irradiation and 2. 5 x 10(-7)
mol / J following aerobic irradiation. When hypoxically irradiated (7.5 - 30 Gy)
OFU001 was added to murine SCCVII cells for 1 - 24 h, a significant cell-killing
effect was observed. The degree of this cytotoxicity was consistent with that of
authentic 5-FU at the corresponding concentrations. On the other hand,
cytotoxicity was minimal when the cells were treated with aerobically irradiated
or unirradiated OFU001. This compound had no radiosensitizing effect against
SCCVII cells under either aerobic or hypoxic conditions when the drug was removed
immediately after irradiation. Since hypoxia is generally most marked in tumors
and irradiation is applied at the tumor site, this concept of prodrug design
appears to be potentially useful for selective tumor treatment with minimal
adverse effects of anticancer agents.
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