Dithiolethiones: A Promising Class of Human Anti-Cancer Drugs

Wendy A. Smith
University of Kentucky
T32ES07266

Background: DNA adducts result from a covalent binding of carcinogenic chemicals or their metabolites and DNA. This is a critical and early step in the process of carcinogenesis. The compound oltipraz has been shown to have anti-carcinogenic effects by preventing or reducing the formation of DNA adducts. Its effects have been found to be most effective in colon and liver tissue. Oltipraz belongs to a class of compounds known as the dithiolethiones. This paper compares the anticarcinogenic potential of oltipraz to another compound in this class, 3H-1,2-dithiole-3-thione (D3T). Dithiolethiones are currently considered very promising chemopreventive agents because of their effectiveness in a wide variety of tumor models. Dithiolethiones were once thought to be found in cruciferous vegetables such as broccoli, cauliflower, cabbage, etc. However, it is not unlikely that they could be formed in vivo from naturally occurring precursors found in asparagus and garlic.

Advance: The researchers used a potent mammary carcinogen, dibenzo[a,l]pyrene (DBP) to promote DNA adduct formation in laboratory rats. D3T inhibited DNA adduction from 78-82% in liver, lung , and mammary tissues. Oltipraz was found to be equally effective in lung and liver tissue, but less effective in mammary tissue with only a 60% reduction. Other studies from this lab have shown significant reductions (up to 80%) cigarette smoke induced adduct formation by oltipraz in rat lung and trachea.

Implication: These results illustrate that the dithiolethiones afford strong protective effects against DBP induced DNA damage in an animal model. The data, coupled with the low toxicity, broad specificity, and efficacy of D3t and oltipraz support the use of these as well as other similar compounds in cancer chemopreventive studies in humans.

Citation: Smith WA, Arif, JM, and Gupta RC. 1,2-Dithiole-3-Thione and its Structural Analogue Oltipraz are Potent Inhibitors of Dibenzo(A,L)pyrene-DNA Adduction in Female Sprague Dawley Rats. International Journal of Cancer; 2001 January 1; 91(1):132-136.