EXOGENOUS MODIFIERS AND CANCER PREVENTION

27 May

Although the effective therapy of cancer is an ultimate goal of medical science, the prevention of cancer is, at our present state of knowledge, the most effective and, relatively, the most inexpen- sive mode of controlling this disease. The prevention of cancer has been discussed by a number of authors (Schottenfeld, 1981; Hirayama, 1992; Doll, 1996). Optimistically, our knowledge of the incidence of neoplasia in the human suggests that age-specific incidence rates might be re- duced by as much as 80%, half of this reduction  coming through the application  of existing knowledge (Doll, 1996). In fact, such knowledge has already been applied to specific popula- tions with significant results (Hirayama, 1992). As has been noted (Pitot, 1993), cancer preven- tion may occur passively  or actively.  Passive  prevention  of cancer involves  a cessation  or restriction of exposure to potentially carcinogenic influences, such as the cessation of smoking, dietary modification, and avoidance of excessive sunlight. Active cancer prevention involves a positive activity on the part of the individual by such things as vaccination against oncogenic viruses, dietary modification and supplements, or the administration of agents externally and/or internally that are known to prevent neoplastic development. This last subject is most pertinent to our discussion in this chapter.

Chemoprevention of Cancer by Exogenous Modifiers

Chemoprevention  in relation to cancer is “the inhibition or reversal of carcinogenesis  (before malignancy) by intervention with chemical agents” (Kelloff et al., 1996). From this definition it is obvious that the active prevention of neoplastic development by the administration of exogenous chemical modifiers  of carcinogenesis  is effective at the stages of initiation and/or promotion. However, because of the ubiquitous nature and occurrence of the stage of initiation in the mam- malian population  (Chapter 7), it may not be realistic at the present time to attempt to utilize chemicals to prevent the spontaneous initiation of cells. However, it is clear that a reduction in the number of initiated cells is feasible by a number of the agents noted earlier in this chapter. Thus, for chemoprevention to be effective in most cases, it must exert an effective inhibitory action on the stage of promotion. As developed earlier in this chapter, numerous examples of exogenous modifiers inhibiting the stage of promotion have been demonstrated. Furthermore, a combination of passive prevention  formats such as those noted above, together with the administration  of chemopreventive agents, may be the most effective approach to cancer prevention at this time.

In addition to the many naturally occurring exogenous modifiers that can serve as chemo- preventive agents, a number of synthetic chemopreventive agents have now been developed from both human and animal studies. A number of these are listed in Table 8.12. Aspirin and other nonsteroidal anti-inflammatory  drugs (NSAIDs), when administered for extended periods, have been shown to reduce the risk of colon cancer and polyps in humans (Giovannucci et al., 1995; Suh et al., 1993). As with dietary fiber (see above), the experiments in animals largely followed this observation in humans, and, as noted from the table, NSAIDs caused significant inhibition of both colon and bladder carcinogenesis as well as inhibition of the development of polyps in mice genetically prone to develop such lesions. Since NSAIDs appear to exert their effects by an

inhibition of the prostaglandin pathway, their mechanisms may be similar to those noted in the different effects of ω3 and ω6 fatty acids (see above; Lands, 1992). The synthetic organosulfur compounds utilized in chemoprevention are analogous to those occurring naturally and presum- ably exert similar effects (cf. Wattenberg, 1992). Difluoromethylornithine  (DFMO) is an effec- tive inhibitor  of the early steps in polyamine  synthesis  necessary  for the stabilization  and function of RNA and DNA (cf. Pegg, 1988). Thus, DFMO exerts its effects in the stages of initi- ation and promotion  because of its inhibition  of DNA synthesis and cell proliferation.  When DFMO is given in the diet together with selenite, the inhibition of DMBA-induced  mammary neoplasms in rats is inhibited to a much greater extent than if either chemopreventive  agent is administered alone (Ip and Thompson, 1989). This and other studies thus suggest that chemo- prevention may be more effective when more than one agent is administered,  an effect analo- gous to the enhanced efficacy of combinations of chemotherapeutic drugs used in the treatment of cancer (Chapter 17). Oltipraz, which is actually an organosulfur compound, protects against chemically induced carcinogenesis in lung, trachea, forestomach, colon, breast, skin, liver, and urinary bladder in rodents (Kensler et al., 1992). Its effects also appear to involve both initiation and promotion. The synthetic steroid finasteride is known to inhibit the conversion of testoster- one into dihydrotestosterone,  and its administration significantly inhibits the chemical induction of prostatic carcinomas in rats induced by 3,2′-dimethyl-4-aminobiphenyl (DMAB). Tamoxifen alters the interaction of estrogen with its receptor and inhibits the development of neoplasia in tissues wherein estrogen plays a significant role in neoplastic development. Finally, as alluded to earlier in this chapter,  a variety of synthetic  retinoids  have also been shown to be effective chemopreventive agents.

All of the synthetic exogenous modifiers noted in Table 8.12 exerted an inhibitory effect during the stage of promotion in chemical carcinogenesis. Several also alter the stage of initia- tion. This further reinforces  the observation  that the stages of neoplastic  development  most sensitive to prevention and modification of neoplastic development are initiation and promotion. Another critical target of such agents, whose importance becomes more evident in the next two chapters,  is the transition  of cells  in the stage  of promotion  to the irreversible  stage  of progression.

Table 8.12 Some Synthetic Chemopreventive  Agents

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