The chemopreventive agent oltipraz stimulates repair of damaged DNA.
Carcinogens may damage DNA either through the production of radicals that cause base modification in situ or through the formation of bulky adducts at relatively nucleophilic sites. Preclinical studies have demonstrated that administration of the dithiolethione oltipraz protects laboratory animals from the development of tumors following subsequent exposure to a variety of carcinogens. This may occur through a mechanism involving the induction of detoxicating gene expression. In some models, oltipraz treatment following carcinogen exposure may also confer protection. To investigate a possible mechanism for this observation, we studied the effects of oltipraz on base excision repair and platinum-DNA damage formation and removal. No effect of oltipraz was observed on base excision repair as determined by an in vitro assay measuring the repair of apurinic/apyrimidinic sites by untreated and oltipraz-treated HT-29 whole-cell extracts. Treatment of HT-29 cells with cisplatin in the absence or presence of 30 and 100 microM oltipraz decreased the accumulation of platinum in DNA. A dose-dependent reduction in DNA platination was also observed in purified DNA treated concurrently with cisplatin and increasing concentrations of oltipraz. When DNA was first platinated and subsequently incubated with oltipraz, no decrease in platinum content in DNA was found. Preincubation of HT-29 cells with oltipraz enhanced the rate of removal of total platinum-DNA adducts and interstrand cross-links. These data support a novel mechanism through which dithiolethiones may protect carcinogen-exposed animals from tumor formation and may expand their potential role in the clinic.
O'Dwyer
P J
PJ
Fox Chase Cancer Center, Philadelphia, Pennsylvania, Thomas Jefferson University 19107, USA.
Johnson
S W
SW
Khater
C
C
Krueger
A
A
Matsumoto
Y
Y
Hamilton
T C
TC
Yao
K S
KS
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology; D018736:DNA Adducts; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects; D006801:Humans; D011719:Pyrazines / Q000494:pharmacology*; D013871:Thiones; D013876:Thiophenes; D014407:Tumor Cells, Cultured / Q000187:drug effects
D016588:Anticarcinogenic Agents; D018736:DNA Adducts; D004273:DNA, Neoplasm; D011719:Pyrazines; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D002945:Cisplatin