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Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003.

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Holland-Frei Cancer Medicine. 6th edition.

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Agents for Chemoprevention and Their Mechanism of Action

, MD and , MD.

Types of Chemopreventive Agents

In the broadest sense, agents for chemoprevention of cancer fall into two principal categories 4: (a) those that prevent the mutagenic initiation of the carcinogenic process (“blocking” agents) and (b) those that prevent the further promotion or progression of lesions that have already been established (“suppressing” agents). Since mutation continues as part of the entire chronic process of carcinogenesis, the distinction between the two categories, at least in the dimension of time, is artifactual. However useful the concept of two-stage carcinogenesis (initiation followed by promotion) was in the past to describe relatively simple experimental systems in laboratory rodents, it can no longer be accepted as a valid model for the process of carcinogenesis in human subjects, in whom mutation and continued initiation of molecular lesions play an ongoing role throughout the rest of the individual's life span. Extensive information is now available on the ability of cells, such as neutrophils and macrophages, to generate potent agents, such as superoxide, hydrogen peroxide, hydroxyl radical, and nitric oxide, all of which can damage deoxyribonucleic acid (DNA). It is now clear that endogenous metabolism as well as exposure to exogenous agents can have major influences on the process of carcinogenesis.12

In this chapter, we discuss both types of agents, since both have found clinical application. Although various dietary constituents, such as ascorbic acid, β-carotene, folic acid, and α-tocopherol (vitamin E), have been the subject of many clinical trials to prevent cancer (reviewed in the last part of this chapter), for the most part the results with vitamins and other nutrients have been disappointing. It should be clear by now that if chemoprevention is truly to have a practical impact on the control of cancer, it will be necessary to develop a fundamentally pharmacologic approach to the problem. In the face of the intense mutagenic pressure that drives the process of carcinogenesis, it will be necessary to use agents that either are potent antimutagens or can significantly alter patterns of gene expression.

Retinoids

The molecules that have been most intensively studied for chemoprevention of carcinogenesis are the retinoids, which are defined as natural and synthetic analogues of retinol (vitamin A).2, 13 More than a thousand such molecules have been made by synthetic chemistry,14 and as knowledge of the receptors that mediate their mechanism of action increases, so also does the number of new agents that are ligands for these receptors. Of particular importance to retinoid studies has been the unification of molecular and cell biology that occurred with the discovery of the steroid receptor superfamily.15, 16 This has been a major advance in the attempt to develop new agents for the chemoprevention of carcinogenesis, since it is now apparent that the intracellular receptors for the retinoids, vitamin D, and thyroid hormone—as well as those for the classic steroids such as estrogens, progestogens, androgens, and glucocorticoids—all belong to a superfamily involved in the selective regulation of transcription of specific genes that control cell differentiation and proliferation.15–17 Studies on the mechanism of action of the above ligands with their respective receptors now provide the basis for rational design, development, and testing of new agents for the chemoprevention of carcinogenesis.

The impact of this new knowledge has been especially important in studies of retinoids. Many years ago Wolbach and Howe demonstrated that the normal function of retinoids was essential for the proper regulation of the differentiation and proliferation of all the epithelia that are the common sites of carcinogenesis in men and women.18 They clearly recognized that during retinoid deficiency there was a failure of stem cells to mature into appropriate differentiated cells; this was accompanied by enhanced cellular proliferation, with the formation of lesions resembling those found in malignant or premalignant tissues. It is now known that retinoids are required to maintain normal differentiation and proliferation of almost all cells, including nonepithelial cells of mesenchymal origin, during both embryogenesis and adult life.19

Further advances related to the chemoprevention of carcinogenesis came from organ culture and cell culture studies. It was shown that retinoids could reverse the premalignant lesions induced in mouse prostate organ cultures by carcinogenic hydrocarbons such as 3-methylcholanthrene20 and that retinoids could act directly on cells previously treated with such carcinogens to suppress the appearance of the malignant phenotype.21 The latter cell culture studies were particularly important because they emphasized that the continuing presence of the retinoid was essential for the suppression of malignancy; removal of the retinoids from the cultures allowed the expression of the transformed state in cells that had previously been exposed to carcinogen. This phenomenon of a continued requirement for a retinoid to suppress carcinogenesis has also been seen repeatedly in many studies in intact animals and undoubtedly is clinically relevant. However, there are also some situations in which retinoids can alter the differentiation of invasive neoplastic cells and induce terminal differentiation. The most striking example of this phenomenon is the induction of terminal differentiation in many types of teratocarcinoma and leukemia cells, of both animal and human origin.22–24

Several synthetic retinoids have been successfully used in a large number of studies for the prevention of carcinogenesis in experimental animals. Among those that have potential for clinical application are the following: all-trans-retinoic acid (tretinoin), 4-hydroxyphenyl all-trans-retinoic acid amide (fenretinide), 13-cis-retinoic acid (isotretinoin), and 9-cis-retinoic acid. There are six known retinoic acid receptors (RAR) that mediate the actions of these retinoids. The first receptors to be cloned, RAR-α, RAR-β, and RAR-γ, bind all-trans-retinoic acid and 9-cis-retinoic acid with high affinity,25, 26 but bind neither fenretinide nor 13-cis-retinoic acid. These latter two retinoids are presumably prodrugs; the isomerization of 13-cis- to all-trans-retinoic acid occurs readily. However, the enzymatic hydrolysis of fenretinide to the free acid has yet to be shown, either in cell culture or in vivo.

More recently three new retinoid receptors, known as RXR-α, RXR-β, and RXR-γ, have been cloned27; these retinoid × receptors (RXRs) bind only 9-cis-retinoic acid,25, 26 and do not bind any of the other three retinoids just mentioned above. However, since all-trans-retinoic acid can be metabolized to the 9-cis derivative, it is ultimately a potential ligand for the RXRs in vivo. The importance of the RXRs is emphasized by their ability to form heterodimers with many other members of the steroid receptor superfamily, including RARs, the vitamin D receptor, and the thyroid hormone receptor. RXRs and their ligands are thus permissive systems that can modulate the activity of other ligands and receptors in the steroid receptor superfamily. With the recent demonstration that terpenoid molecules other than 9-cis-retinoic acid can act as ligands for RXRs, the functional domain of this system now appears to be even broader than anticipated.

There is an extensive literature on the use of retinoids to arrest or reverse the process of carcinogenesis and to prevent the development of invasive carcinoma in experimental animals.28 Of particular importance are the many studies that have shown efficacy of retinoids when they are administered after animals have been treated with carcinogen; this experimental design is highly relevant to human populations. Significant activity has been shown for all-trans-retinoic acid, 13-cis-retinoic acid, 9-cis-retinoic acid,29 fenretinide, and many other retinoids, as reviewed by Moon and colleagues.28 The epithelial sites studied include breast, skin, lung, bladder, pancreas, liver, oropharynx, esophagus, stomach, and prostate. In addition to efficacy as single agents, retinoids have been particularly effective when used in combination with other preventive agents, especially tamoxifen.

Tamoxifen

Tamoxifen is a nonsteroidal triphenylethylene derivative that binds to the estrogen receptor.30 It has both estrogenic and antiestrogenic actions, depending on the target tissue. It is strongly antiestrogenic on mammary epithelium, hence its use in both the prevention and treatment of breast cancer; it is proestrogenic on uterine epithelium, hence the current controversy regarding its safety in cancer prevention9, especially since an increased incidence of endometrial carcinoma has been found in women treated chronically with tamoxifen..30 It is therefore inappropriate to refer to tamoxifen simply as an antiestrogen. The term selective estrogen receptor modulator is more appropriate.

Tamoxifen was originally screened in a drug development program oriented toward discovering new contraceptive agents. Although it was effective in rats, it was not a useful drug for control of fertility in women, and it was not until the early 1970s that it was shown to be useful for clinical palliation of advanced breast cancer. Subsequently, animal studies performed in rats, using both dimethylbenzanthracene (DMBA) and nitrosomethylurea as carcinogens, showed that tamoxifen was highly effective in preventing the development of experimental breast cancer31, 32 ; these results have also been confirmed in the mouse model in which murine mammary tumor virus is the carcinogen.

The mechanism of action of tamoxifen is complex. Clearly, its principal mechanism of action is mediated by its binding to the estrogen receptor and the blocking of the proliferative actions of estrogen on mammary epithelium. One suggested mechanism for this antiproliferative action is the induction by tamoxifen of the synthesis of the cytokine transforming growth factor-β (TGF-β), which acts as a negative autocrine regulatory molecule.33 However, it has also been shown that tamoxifen can induce synthesis of TGF-β in estrogen receptor-negative cells, such as fetal fibroblasts.34 Moreover, immunohistochemical studies have shown that tamoxifen induces the synthesis of TGF-β in the stromal (mesenchymal) compartment of breast cancers, suggesting a paracrine as well as autocrine mechanism of action, independent of an interaction with the estrogen receptor.35 Reports of some clinical efficacy of tamoxifen in the treatment of women with estrogen receptor-negative breast carcinomas would appear to be in accord with these mechanistic conclusions.36 Other studies that are in accord with these observations are the findings that tamoxifen can lower the circulating levels of insulin-like growth factor I (IGF-I) in breast cancer patients.37, 38 IGF-I is a potent mitogen for breast cancer cells and may act by endocrine, paracrine, and autocrine routes to stimulate their growth.

Raloxifene

Although the risks are actually quite small, there is major concern about the safety of the use of tamoxifen as a chemopreventive agent for the prophylaxis of breast cancer, because of its estrogenic effect on uterine epithelium and the attendant increased risk for development of uterine cancer. Thus, there has been a search for new agents that would resemble tamoxifen in their overall mechanism of action, but would be inhibitory to the growth of uterine epithelium. One such molecule is raloxifene, the chemical structure of which is totally different from that of tamoxifen; tamoxifen is a triphenylethylene derivative, but raloxifene is a benzothiophene. Like tamoxifen, raloxifene binds to the estrogen receptor and has both estrogenic and antiestrogenic actions; it is another estrogen response modifier. It has been shown to have both therapeutic and preventive activity on breast tumors induced in rats by chemical carcinogens.32 Most notably, in contrast to tamoxifen, raloxifene does not act as an estrogen agonist in the uterus and does not stimulate the growth of uterine epithelium in ovariectomized rats.39 However, raloxifene is strongly estrogenic in its positive actions on bone and serum lipids; it is a potent agent for prevention of bone loss in the ovariectomized rat.39 Because of this unusual spectrum of pharmacologic activity, raloxifene is an attractive agent for the prevention of bone loss in osteoporotic, postmenopausal women, which is its primary therapeutic application at present. If large numbers of women are treated chronically with raloxifene for the prevention of osteoporosis, this therapy may also provide a clinical trial of the efficacy of this agent for prevention of breast cancer.

Deltanoids (Vitamin D and Its Synthetic Analogs)

Another important ligand of the steroid receptor superfamily is 1,25-dihydroxycholecalciferol (1,25-DHCC), the active metabolite of dietary vitamin D. 1,25-DHCC has potent actions in controlling the expression of many genes and can induce differentiation in many tumor cells, particularly those of myeloid lineage.40, 41 However, because of its marked hypercalcemic activity, it is not a suitable agent for clinical chemoprevention. A large number of synthetic analogs of 1,25-DHCC have been made, with the goal of increasing differentiative activity and decreasing calcemic actions42; we have suggested the term “deltanoids,” analogous to “retinoids,” for the entire family of natural and synthetic molecules related to 1,25-DHCC.43 Many of the new analogs are markedly less calcemic and more active in inducing differentiation, and some have been shown to be active in the prevention of breast cancer in animal experiments.43, 44 The clinical potential for the use of these agents is still unrealized.

Finasteride

Prostate carcinogenesis in both experimental animals and humans is driven by androgen, in much the same way that mammary carcinogenesis is driven by estrogen. The testosterone metabolite 5α-dihydrotestosterone (DHT) has higher binding affinity for the androgen receptor than testosterone and is believed to play a critical role in the development of the prostate gland. DHT is formed from testosterone by the action of the enzyme 5α-reductase, and several androgen analogs have been developed as antagonists of this enzyme. One of these analogs, finasteride, is now in widespread use to treat benign prostatic hyperplasia (BPH).45

Although there are essentially no published studies on the use of finasteride to prevent prostate cancer in experimental animals, this agent is now being evaluated for chemoprevention of prostate carcinogenesis in a large clinical trial because of its known molecular mechanism of action and its known clinical efficacy in the treatment of BPH.

Difluoromethylornithine

Agents that can suppress cell proliferation are obvious candidates for chemoprevention if they have sufficient selectivity. One such molecule is difluoromethylornithine (DFMO), a potent irreversible inhibitor of the enzyme ornithine decarboxylase, which catalyzes the formation of putrescine, a polyamine involved in DNA synthesis.46 There is a very extensive literature on the use of DFMO to prevent carcinogenesis in animal models of colon, bladder, breast, liver, skin, and stomach cancer.47 The National Cancer Institute (NCI) has conducted extensive preclinical and clinical toxicologic evaluations of this drug, and further clinical trials are planned.

Nonsteroidal Antiinflammatory Drugs

A large number of nonsteroidal antiinflammatory drugs (NSAIDs) have shown potent chemopreventive activity in many test systems. Among the NSAIDs that have been studied at length are aspirin, ibuprofen, sulindac, and piroxicam. All of these molecules are cyclooxygenase inhibitors that block prostaglandin synthesis, and they are in widespread clinical use for the chronic treatment of various inflammatory diseases, most notably osteoarthritis or rheumatoid arthritis. There is therefore an abundance of information about the safe dosage for their long-term administration that would be required for a chemoprevention trial. All of these inhibitors of prostaglandin synthesis have been shown to be active in a multiplicity of animal models for the suppression of carcinogenesis, with particular efficacy in preventing experimental colon carcinogenesis. Most recently, attention has been focused on selective cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib, since these have the potential to prevent cancer with less in the way of undesirable side effects than classical NSAIDs.48 Based on these results, a number of clinical trials have been designed.

N-Acetylcysteine and Oltipraz

Glutathione in its reduced form (GSH) is a critical molecule in the chemical deactivation of many carcinogens. Since glutathione itself is not a practical agent for chemoprevention, a great deal of effort has been devoted to the development of exogenous agents that would elevate intracellular GSH levels. This principle, termed electrophile counterattack,49 has been the basis of extensive investigation. N-acetylcysteine and oltipraz are two of the most important such molecules that act by this mechanism. Both of these agents can block the mutagenic activity of a variety of carcinogens by preventing their binding to DNA; a substantial decrease in DNA adducts has been seen if either N-acetylcysteine or oltipraz is given to animals when they are treated with carcinogens such as aflatoxin, benzo[a]pyrene, or acetylaminofluorene.50, 51 Both agents are active in animal test systems for the prevention of cancer, and both are in clinical trial.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2003, BC Decker Inc.
Bookshelf ID: NBK12522

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