Evaluation of the cancer chemopreventive potency of dithiolethione analogs of oltipraz.
Oltipraz and related dithiolethiones constitute an important class of chemopreventive agents that enhance the expression of carcinogen detoxication and antioxidant genes. Dose-response studies were undertaken to characterize the cancer chemopreventive activities of several dithiolethiones that are at least as active as oltipraz as inducers. Inhibition of formation of pre-neoplastic lesions and formation of DNA adducts in livers of rats exposed to aflatoxin B1 (AFB1) was monitored. In the tumorigenesis experiment, the dithiolethiones were orally gavaged 3 days/week for 3 successive weeks and at four doses ranging from 0.03 to 0.3 mmol/kg body wt. AFB1 was gavaged beginning 1 week after the start of the dithiolethiones and for two successive weeks. The burden of AFB1-induced putative pre-neoplastic lesions (glutathione S-transferase-placental isoform positive foci) was quantified by light microscopy. Reduction in AFB-DNA adduct burden was assessed 24 h following the first dose of AFB1. Both the parent 1,2-dithiole-3-thione (D3T) and its 5-tert-butyl derivative were more potent inhibitors than oltipraz against these endpoints, while two of the seven tested analogs were slightly less inhibitory. D3T, the most potent dithiolethione of this series, was examined by microarray analysis for induction of hepatic genes at an intermediate chemopreventive dose (0.1 mmol/kg). Transcript levels of eight genes, including two known to detoxify aflatoxin, namely, glutathione S-transferase A5 (GSTA5) and AFB1 aldehyde reductase (AFAR) were elevated. Western analysis indicated that induction of hepatic GSTA5 and AFAR were directly related to the dose of D3T. At the highest dose of D3T (0.3 mmol/kg), protein levels of GSTA5 and AFAR were induced by 7- and 27-fold, respectively. While efficacy in humans has yet to be tested, D3T is clearly more potent than oltipraz and serves as a useful molecular probe for determining the key events associated with protection by this class of agents.
Roebuck
B D
BD
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03755, USA. bill.d.roebuck@dartmouth.edu
Curphey
Thomas J
TJ
Li
Yuan
Y
Baumgartner
Karen J
KJ
Bodreddigari
Sridevi
S
Yan
Jian
J
Gange
Stephen J
SJ
Kensler
Thomas W
TW
Sutter
Thomas R
TR
D016604:Aflatoxin B1 / Q000737:chemistry; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000737:chemistry; D015153:Blotting, Western; D002273:Carcinogens; D004247:DNA / Q000737:chemistry; D018736:DNA Adducts; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005982:Glutathione Transferase / Q000378:metabolism; D015151:Immunoblotting; D008099:Liver / Q000378:metabolism; D008297:Male; D008956:Models, Chemical; D009369:Neoplasms / Q000517:prevention & control*; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology*; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013696:Temperature; D013871:Thiones / Q000737:chemistry*; D013876:Thiophenes / Q000737:chemistry; D013997:Time Factors
D016588:Anticarcinogenic Agents; D000975:Antioxidants; D002273:Carcinogens; D018736:DNA Adducts; D011719:Pyrazines; D012333:RNA, Messenger; D013871:Thiones; D013876:Thiophenes; D012313:RNA; C026209:oltipraz; D004247:DNA; D016604:Aflatoxin B1; D005982:Glutathione Transferase