Selenium-containing
thioredoxin reductase (TrxR) is an important target of
cancer therapy. Many useful
anticancer agents including bis-
alkylating agents,
cisplatin, and
arsenic trioxide are known to interact with the
selenocysteine dipeptide in the carboxy terminal region of
thioredoxin reductase and inactivate its ability to reduce
thioredoxin. Some investigators have postulated that the inactivation of TrxR may add to the cytotoxic potential of these
anticancer agents.
TH-302 is a newly developed
antineoplastic drug which represents a potential new class of
tumor selective
hypoxia-activated
prodrugs (HAPs).
TH-302 is an inactive
prodrug created by the covalent conjugation of
2-nitroimidazole as an
oxygen sensor to bromo-isophosphoramide (Br-IPM). In the presence of severe
hypoxia and near
anoxia, the two
imidazole sensor moiety undergoes reduction and the Br-IPM is released in situ. Bromo-IPM is a more potential analog of Chloro-IPM, the active alkylating moiety that is derived by activation of
ifosfamide (IFO). We previously demonstrated that IFO could inhibit
tumor TrxR activity and chloro-IPM is known to bind covalently to the seleno-
cysteine dipeptide in
thioredoxin reductase. The present study assessed the ability of
TH-302 to activate in the
tumors of mice-bearing
hepatoma 22 (H22) and inactivate the
tumor TrxR. In mice-bearing
hepatoma 22 (H22) solid
tumors, intraperitoneal (i.p.) injection with
TH-302 at the dose of 200 mg/kg administered twice, a regimen which was well tolerated by the mice, significantly inhibited
tumor growth. Also in this mice model, i.p.
TH-302 at the dose of 300 mg/kg, which would be the maximum single i.p. administration dose tolerated by mice, and which induced only 2%
body weight loss, significantly inhibited both TrxR and
glutathione reductase (GR) activities by 46% (P < 0.001) and 60% (P < 0.001) as compared with the controls, respectively, at 3 h after the injection. Since TrxR is a key player in
thioredoxin system and GR is the major
reductase for the reduction of
oxidized glutathione in
glutathione system, the present results imply the anticancer effect of
TH-302 is associated concurrently with modulation of TrxR and GR. These findings suggest that the anticancer activity of
TH-302 in this model system may associate with both
DNA alkylation and the modulation of TrxR and GR. In addition, they suggest that, by inhibition of these two critical
reductases, with less
glutathione available to intercept the reactive intermediates involved in
DNA alkylation, the antitumor effects of the
chemotherapy would be enhanced.