Carcinogenesis, Vol 19, 1609-1615, Copyright © 1998 by Oxford University Press
YY Maxuitenko, AH Libby, HH Joyner, TJ Curphey, DL MacMillan, TW Kensler and BD Roebuck
Oltipraz and related dithiolethiones are an important class of
chemopreventive agents. Studies were undertaken to identify cancer
chemopreventive dithiolethiones more active than oltipraz. Largely based
upon enzyme induction activities in vitro, 17 dithiolethiones, including
oltipraz, were analyzed for their ability to induce hepatic phase II enzyme
activities in vivo. Of these compounds, 15 produced greater induction of
NAD(P)H:quinone reductase and 11 yielded greater induction of glutathione
S-transferase than oltipraz. All 17 dithiolethiones were then tested for
their ability to inhibit acute hepatotoxicity by aflatoxin B1 (AFB1), which
previously has been shown to be an intermediate predictor of
chemopreventive activity. Rats were pretreated with dithiolethiones (0.3
mmol/kg body wt, three times a week per os) and challenged with two acutely
toxic doses of AFB1 (0.5 mg/kg body wt, once daily for two successive days
per os). Inhibition of hepatotoxicity was measured by changes in body
weight gain during AFB1 challenge, reduction in levels of hepatic enzymes
in serum and diminution of bile duct cell proliferation. Nine
dithiolethiones spanning a range of responses in this toxicity screen were
further tested for their ability to prevent AFB1-induced tumorigenicity, as
assessed by a reduction in hepatic burden of putative preneoplastic foci.
Six dithiolethiones were found to be considerably more effective than
oltipraz in preventing AFB1-induced tumorigenesis. In general,
dithiolethiones that were very effective in inhibition of acute
hepatotoxicity were also found to be effective in prevention of hepatic
tumorigenesis.
ARTICLES
Identification of dithiolethiones with better chemopreventive properties than oltipraz
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03755, USA.
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