This invention relates generally to the field of molecular biology and more specifically to the field of treatment and prevention of DNA binding agents.
Concern for the detrimental and carcinogenic interaction of drugs and chemicals with oral, respiratory tract, and other tissues continues to encourage the study of systems offering potential reduction of cancer risk. One such approach is the interaction of caffeine and other xanthine-like compounds with polynuclear aromatic hydrocarbons and related carcinogenic materials. This interaction likely occurs through a novel mechanism known as polarization bonding. Polarization bonding is the interaction of two planar molecules via a sandwich-like stacking to form a stable complex. This plane-to-plane packing of alternate polarizing and polarizable molecules results in a shortening of the van der Waals distances and thereby provides for the stability and the strength of the complexes formed. Polynuclear aromatic hydrocarbons (PAH), a class of carcinogens found in smokeless tobacco and tobacco smoke are proposed to be initiators of oral and respiratory tract cancer, respectively. FIG. 1-1 shows chemical structures of same PAHs. It should be noted that both xanthines and PAHs are planar molecules, and that planarity has been described as a requirement for carcinogenicity of PAH's as well as for complexation. The phenomenon of polarization bonding, specifically in the formation of xanthine-PAH complexes, has been observed, but has seldom been studied from a cancer prevention point of view. The complexation of PAH's to deoxyribonucleic acid may also be due to polarization bonding with the purine bases of DNA.
The effects of polarization bonding on carcinogenesis and mutagenesis has not specifically been reported in the literature based on Medline and Cancerlit computer searches, however the interaction of polynuclear aromatic hydrocarbons with caffeine and other xanthine-like compounds has been reported. For example, the measurement of the solubility and optical properties of PAHs in solutions of caffeine, TMU, or DNA indicate similar mechanisms in the formation of complexes. The complexation of PAH's to deoxyribonucleic acid may be due specifically to the purine bases comprising DNA. As noted the xanthines and PAHs are planar molecules, and planarity has been described as a requirement for carcinogenicity of PAH's (Pullman, 1955, 1964) as well as complexation (Jones and Neuworth, 1949; Leela and Mason, 1957; Pullman and Pullman, 1958; DeSantis et al., 1960, 1961; Liquori et al., 1962; Van Duuren and Bardi, 1963; Van Duuren, 1964).
Several laboratories have recently reported on the interaction of xanthines and xanthine analogs with carcinogenic polyaromatic DNA intercalators (Larsen et al., 1996; Traganos et al., 1991a, 1991b, 1993; MacLeod et al., 1991,1993; Kapuscinsid and Kimmel, 1993). FIG. 1-2 shows chemical structures of example xanthines. These same xanthines bind with DNA intercalators through an interaction referred to as polarization bonding (McKeown et al., 1951). Polarization bonding, is the π-π interaction and stacking of two planar molecules, where one is polarizing (xanthine) and the other is polarizable (DNA intercalator). The binding of these carcinogens to certain xanthines has been shown to inhibit or reduce their binding to dsDNA (Booth and Boyland, 1953; Shoyab, 1979; Traganos et al., 1991a; MacLeod et al., 1991). Planarity has been described as a necessary requirement for polarization bonding complexation (McKeown et al., 1951; Harding and Wallwork, 1953, 1955; Wallwork, 1961; Liquori et al., 1962; Miller, 1970; Huberman et al., 1976) as well as for intercalation into dsDNA (Booth and Boyland, 1953; DeSantis et al., 1960, 1961; Van Duuren, 1964; Pullman, 1964). Polarization bonding has been proposed as the mechanism for the bonding of carcinogenic polyaromatic hydrocarbons, such as benzo[a]pyrene and dimethyl benzanthracene to the purine bases adenine and guanine within DNA as well as to other xanthine-like molecules (DeSantis et al, 1960, 1961). The specific mechanism by which xanthine-like molecules inhibit polyaromatic DNA intercalating agents (DNA-IAs) from intercalation into dsDNA has been suggested to be due to the formation of a polarization bonding complex between the xanthine and the DNA-IA (Traganos et al., 1991a, 1991b; Kapuscinski and Kimmel, 1993; Tachino et al., 1994; Larsen et al., 1996). The degree of reversibility of the intercalation of DNA-IAs into DNA, in vitro and in vivo, remains to be established.