THE CHEMOPREVENTIVE AGENT OLTIPRAZ STIMULATES REPAIR OF DAMAGED DNA

Carcinogens may damage DNA either through the production of radicals t hat cause base modification in situ or through the formation of bulky adducts at relatively nucleophilic sites, Preclinical studies have dem onstrated 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 mechan ism involving the induction of detoxicating gene expression. In some m odels, oltipraz treatment following carcinogen exposure may also confe r protection. To investigate a possible mechanism for this observation , we studied the effects of oltipraz on base excision repair and plati num-DNA damage formation and removal, No effect of oltipraz was observ ed on base excision repair as determined by an in vitro assay measurin g the repair of apurinic/apyrimidinic sites by untreated and oltipraz- treated HT-29 whole-cell extracts. Treatment of HT-29 cells with cispl atin in the absence or presence of 30 and 100 mu M oltipraz decreased the accumulation of platinum in DNA. A dose-dependent reduction in DNA platination was also observed in purified DNA treated concurrently wi th cisplatin and increasing concentrations of oltipraz, When DNA was f irst platinated and subsequently incubated with oltipraz, no decrease in platinum content in DNA was found. Preincubation of HT-29 cells wit h oltipraz enhanced the rate of removal of total platinum-DNA adducts and interstrand crosslinks. These data support a novel mechanism throu gh which dithiolethiones may protect carcinogen-exposed animals from t umor formation and may expand their potential role in the clinic.