Chemoprevention is the use of chemicals to prevent the occurrence and/or the progression of cancer. Numerous naturally occurring and synthetic compounds have been found to protect laboratory animals from chemically induced tumorigenesis. A few of the promising ones are on clinical trial as human cancer chemopreventive agents (see, e.g., Boone, C. W., Kelloff, G. J. and Malone, W. E Cancer Res. 50:2-9 (1990)). However, most of the inhibitors of carcinogenesis are still at the experimental stage of development. Their inhibitory effects on tumorigenesis vary greatly. Many potent inhibitors, after careful scrutiny, have been found to exhibit side effects that preclude further development as human cancer chemopreventatives. A need, therefore, exists to search for inhibitors of carcinogenesis with low or no toxicity, that may be developed into chemopreventive agents for long term human use.
Two classes of enzymes are known to be associated with xenobiotic metabolism. Phase I enzymes functionalize xenobiotic compounds, usually by way of oxidation or reduction. Although their primary role is to detoxify xenobiotics, several phase I enzymes are also known to activate procarcinogens to yield highly reactive carcinogens. Phase II enzymes conjugate functionalized products with endogenous ligands (e.g., glutathione and sulfate) and serve primarily a detoxification role (Jakoby et al., J. Biol. Chem., 265:20715-20718 (1990)). Compounds that induce or enhance the activity of phase II enzymes represent an important class of chemopreventive agents.
A large portion of the effort in the discovery of chemopreventive agents has been devoted to natural products. Research directed toward the development of synthetic compounds prepared using the rationale of structure-activity relationships (SAR) has also been fruitful in expanding the list of potentially useful agents. Synthetic compounds such as phenyl alkyl isothiocyanates (PAITCs) (M. Morse et al., Cancer Res. 51:1846-1850 (1991)), OLTIPRAZ (L. Wattenberg et al., Carcinogenesis, 7, 1379 (1986); T. Kensler et al., Cancer Res. 47:4271(1987)), and difluoromethylornithine (A. Verma et al., Carcinogenesis, 7:1019 (1986); A. Verma et al., Carcinogenesis (Lond.). 1:271 (1980); H. Prochaska et al., P. Cancer Res. 48:4776 (1988)) have been found to have cancer prevention potential. For example, chemopreventive compounds derived from sulforaphane ((-)1-isothiocyanato-(4R)-(methylsulfinyl)butane) are described in U.S. Pat. No. 5,411,986 (Cho et al., issued May 2, 1995); and long chain arylalkyl isothiocyanates that inhibit lung tumor formation induced by exposure to tobacco-specific nitrosamine are described in U.S. Pat. No. 5,231,209 (Chung et al., issued Jul. 27, 1993).
Plant isothiocyanates (ITCs) occur naturally as glucosinolates in cruciferous vegetables. These glucosinolates are subjected to enzymatic hydrolysis by myrosinase during the processing or digestion of foods to yield the corresponding isothiocyanates. Benzyl isothiocyanate, phenethyl isothiocyanate, allyl isothiocyanate, and sulforaphane have been found in cruciferous vegetables that include kale, cabbage, Brussels sprouts, cauliflower, broccoli, and turnips. These natural isothiocyanates are well known phase II enzyme inducers and inhibitors of tumorigenesis induced by polycyclic aromatic hydrocarbons or nitrosamines in several different animal models. Phenethyl isothiocyanate is the hydrolysis product of gluconasturtiin, an abundant natural product present in cruciferous vegetables. Because of its relatively low toxicity, albeit less outstanding inhibitory activity in tumorigenesis studies, it is being considered for Phase I clinical trial. Synthetic PAITCs with the alkylene chain longer than ethylene have been found to improve upon the potency of these compounds as inhibitors of NNK-induced carcinogenesis (M. Morse et al., Cancer Res. 51:1846-1850 (1991); J. Ding et al., Cancer Res. 54:4327-4333 (1994)). Carbon chain length from 3 to 12 in this series have been examined, and all appear to have inhibitory activity.