Pharmacology of Chemoprevention

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Carcinogenesis is a chronic and multistep process that results in malignancy. Malignant cells acquire the ability to invade or metastasize. Metastasis is often the first evidence of malignant disease. During the continuum of carcinogenesis, therapeutic interventions can be used to arrest or reverse this process. This is known as cancer chemoprevention. Effective cancer chemoprevention should suppress or block the clinical manifestation of malignancies by treating lesions before clinical signs or symptoms arise. A strong rationale for cancer chemoprevention as an attractive therapeutic strategy stems from considerable preclinical, clinical, and epidemiological findings. Cancer chemoprevention has been shown to be a valid clinical approach in the use of tamoxifen in a randomized phase III trial that demonstrated how this selective estrogen receptor modulator (SERM) reduced the risk of breast cancer in high-risk women. Other clinical trials have demonstrated favorable activity in the treatment of certain premalignant diseases, as will be discussed. Effective cancer chemoprevention should involve lifestyle, dietary, nutritional, pharmacological, and other interventions. This article focuses on the pharmacological basis for clinical cancer prevention by emphasizing candidate classes of agents that are promising for use in cancer chemoprevention.

I. INTRODUCTION

Cancers arise as a result of carcinogenesis, a chronic and multistep process. This stems from mutagenic damage to growth-regulating genes and their products that alters gene expression and ultimately confers changes that lead to the development of invasive or metastatic malignant disease. This process leads to progressive changes of cells that result in premalignancy and eventually overt malignancy. The steps defined in this process include (1) initiation, where DNA damage occurs; (2) promotion, where genetic or epigenetic alterations confer additional genomic damage; and (3) progression to invasive or metastatic disease. Conceivably, each of these steps would be attractive pharmacological targets for cancer chemoprevention.
It has been recognized that carcinogenic exposure leads to fields of altered cells that exist before malignancies are clinically evident. This concept was first proposed by Slaughter in 1953 and provided a basis for understanding how carcinogen-exposed cells that result from failure to repair genomic damage are of clonal origin. Some of these genetically altered cells may progress to a malignant phenotype. It is possible that markers of these carcinogenic changes at affected tissues will determine clones of genetically altered cells that are at especially high risk for malignant conversion. It is not known what precise cassette of carcinogenic or genetic changes are required for the maintenance or progression of premalignant lesions.       
Distinct changes may be required for each affected tissue or carcinogenic agent. These alterations likely involve dominant genetic changes through the activation of oncogenes and recessive genetic events through the inactivation of tumor suppressor genes. The underlying genetic properties of a cell may promote susceptibility for malignant transformation such as in inherited cancer-prone syndromes. Tumor- matrix interactions and neoangiogenesis also have important roles in the maintenance or progression of premalignant cells. Because carcinogenesis is of a chronic nature, pharmacological interventions are attractive to arrest or reverse these progressive changes evident following genomic damage. The concept of cancer chemoprevention, coined by Sporn, stresses therapeutic interventions at the earliest steps of carcinogenesis, as this would avoid the clinical consequences of malignancies.       
A clinical validation of the concept of cancer chemoprevention was shown through a randomized trial using the SERM tamoxifen to reduce breast cancer risk in high-risk women. Risk reduction was found only for hormone-sensitive breast cancers and provided a basis for Federal Drug Administration (FDA) approval. Undesirable estrogenic effects, such as those involving the endometrium, have resulted in an active search for a SERM that would preserve the chemopreventive effects of tamoxifen in the breast while retaining desirable estrogenic effects, such as those in preventing osteoporosis and promoting hypocholesterolemia. This clinical finding in reduction of hormone sensitive breast cancer risk has underscored the need to identify other pharmacological agents that would be effective in preventing hormone-resistant breast cancers.       
Many interventions could reduce specific cancer risk, including lifestyle changes, dietary interventions, and effective screening of high-risk individuals, as will be discussed elsewhere in this encyclopedia. This article focuses on chemopreventive agents that exert their actions through specific pharmacological mechanisms. Representative classes of chemoprevention agents will be discussed, including specific agonists or antagonists for members of the steroid receptor superfamily of nuclear receptors, selective cyclooxygenase-2 (COX-2) or inducible nitric oxide synthase (iNOS) inhibitors, and other agents.

II. PHARMACOLOGY

Pharmacological cancer chemoprevention strategies could target multiple steps during carcinogenesis. Agents can act by blocking DNA damage that occurs as an initiating step in carcinogenesis or by blocking or reversing the progression of premalignant cells that have already acquired genomic damage. Agents may also act at the promotion or progression steps of carcinogenesis. In targeting these steps of carcinogenesis, cell-stromal interactions, as well as neoangiogenesis, would play important roles in the development of invasive malignancy. An empirical approach to cancer chemoprevention has been replaced by clinical strategies that emphasize the mechanisms of action of candidate chemopreventive agents in the design of clinical trials. These strategies build on basic scientific insights into pathways involved in cancer chemoprevention.       
Several examples illustrate this point. Inducible COX-2 is involved in the synthesis of prostaglandins from arachidonic acid and is often activated during inflammation. Evidence exists for COX-2 as a therapeutic target for cancer chemoprevention. Genetic findings implicate a role for COX-2 in preventing colon carcinogenesis. Genetically modified mice have been engineered to harbor defects of the adenomatous polyposis coli (APC) gene, which results in intestinal adenomatous polyps as well as an increase in COX-2. The relevancy of this genetically modified mouse model to disease in humans is shown by the finding that COX-2 overexpression relative to adjacent normal tissues was found as frequent in clinical colon cancers.       
The role of COX-2 in colon carcinogenesis was examined further by engineering mice with defects in COX-2 and APC. In contrast to the increase in intestinal polyps observed in APC-deficient mice, a reduction in polyp formation occurred in mice deficient in COX-2. These and other studies provided a basis for clinical trials that target inducible COX-2 with pharmacological inhibitors in selected patients at risk for colon carcinogenesis. These findings were extended to the clinical setting. Beneficial clinical effects have been reported with selective COX-2 inhibitors in the treatment of patients with the familial adenomatous polyps (FAP) syndrome.


FIGURE 1 Structures of candidate cancer chemoprevention agents. These are representative pharmacological agents that target distinct pathways and exhibit specific mechanisms of action. Several interact with nuclear receptors, others affect enzymatic pathways, and some have mechanisms of actions that are currently under active investigation.

These clinical findings obtained in patients with an inherited risk for colon carcinogenesis set the stage for use of COX-2 inhibitors (Fig. 1) in other individuals with high risk for colon cancer. A further rationale for targeting COX-2 in colon carcinogenesis comes from epidemiological findings in individuals who chronically received nonsteroidal anti-inflammatory drugs (NSAIDs) and have reduced incidence of carcinogenesis. While NSAIDs do not selectively inhibit COX-2 rather than COX-1, these and other findings support the view that a selective COX-2 inhibitor would have a beneficial impact in colon cancer prevention. Selective COX-2 inhibitors would be expected to have reduced side effects than a nonselective inhibitor, as the constitutively expressed COX-1 is not targeted. This could favor chronic clinical administration as would be needed for the prevention of colonic or other tumors.      
Another example of successful targeting of a pathway involved in the suppression of carcinogenesis is found in the use of SERMs to reduce breast cancer risk. Administration of the SERM tamoxifen (Fig. 1) has been shown to reduce breast cancer risk in women at high risk for hormone-sensitive breast cancer. A positive proof of a principle randomized trial has provided a basis for additional clinical breast cancer prevention trials that test other SERMs that would exert the desired tissue estrogenic actions, such as in preventing osteoporosis, while antagonizing undesirable estrogenic effects that promote carcinogenesis in breast, uterine, or ovarian tissues. This possibility is under clinical study with the SERM raloxifene. Distinct raloxifene response elements exist and could contribute to different pharmacological effects of this SERM relative to others. In the future, other SERMs will be examined in relevant clinical trials. These could exploit the fact that a second estrogen receptor (ER ) has been identified that may exert distinct biological effects.
An analogous chemopreventive approach could target the androgen receptor in prostate cancer. Prostatic intraepithelial neoplasia (PIN) has been identified as a precursor lesion in prostatic carcinogenesis. Whether antiandrogen-based strategies will prevent the progression of PIN to prostate cancer is the subject of future work in this field. The development of transgenic prostate cancer models should be of assistance in evaluating the efficacy and activities of pharmacological agents that target the androgen receptor in prostate carcinogenesis.      
Antiproliferative, differentiating-inducing as well as proapoptotic agents can target carcinogenesis. The retinoids, derivatives of vitamin A, are a class of prevention agents that could exert desired clinical chemoprevention effects by targeting these and other biological pathways. The retinoids are natural and synthetic derivatives of vitamin A that have diverse chemical structures, pharmacological properties, nuclear receptor affinities, and associated toxicity profiles.      
A strong rationale for a role of retinoids in cancer therapy or prevention stems from results obtained from experimental animal models, epidemiological studies, and clinical trials. Wolbach and Howe focused initial attention on vitamin A-dependent pathways as important in epithelial cell homeostasis in 1925. These investigators found that vitamin A deficiency in rodents caused squamous metaplasia in the trachea as well as at other epithelial sites. Notably, correction of this deficiency by vitamin A treatment reverses these metaplastic changes. These metaplastic changes are similar to those that arise in smokers, implicating a role for vitamin A-dependent signals in suppressing lung carcinogenesis. Further evidence for an association between vitamin A and cancer incidence stems from epidemiological data demonstrating an inverse relationship between vitamin A levels and incidence of cancer at specific epithelial sites.      
These and other findings provided a basis for use of retinoids in cancer prevention. Additional support for a retinoid role in cancer prevention derived from clinical trials conducted using retinoids that resulted in the successful treatment of certain premalignant conditions such as oral leukoplakia, cervical dysplasia, and xeroderma pigmentosum. Other clinical trials revealed retinoid activity in reducing some second primary cancers. These include independent retinoid trials that demonstrated a reduction in second aerodigestive tract cancers in patients having prior head and neck, lung, or hepatocellular carcinomas. In contrast to these promising trials, a randomized intergroup trial conducted in subjects treated with 13- cis retinoic acid following resection of stage I lung cancers did not show clinical benefit in smokers, although a reduction in second cancers was observed in subjects who never smoked. These findings, when coupled with those reported in large randomized trials using β-carotene in primary lung cancer prevention in high-risk individuals, indicate that a negative clinical interaction can exist when a chemopreventive agent is administered to active smokers. There is a need to combine lung cancer prevention agents with smoking cessation.      
Mechanisms responsible for the reported reduction of second cancers by retinoid treatment of nonsmokers need to be determined. A better understanding of relevant mechanisms should prove useful in the selection of the optimal retinoid for use in cancer chemoprevention. Two classes of retinoid nuclear receptors exist. These are the retinoid acid receptors (RARs) and the retinoid X receptors (RXRs). These share homology with other members of the steroid receptor superfamily of nuclear receptors, which include the glucocorticoid receptor, vitamin D receptor, and estrogen receptor, among others. There are three subtypes of RARs (RARα, RARβ, and RARγ) and RXRs (RXRα, RXRβ, and RXRγ) and several isoforms exist. Orphan nuclear receptors have been identified where the physiological ligands remain to be discovered.      
The ligand-binding domain of individual retinoid nuclear receptors is where specific retinoids bind. These nuclear receptors also contain DNA-binding domains that recognize defined responsive elements in genomic DNA. Following these ligand-receptor and receptor-DNA interactions, direct target genes that signal retinoid biological effects are activated or repressed. Retinoid nuclear receptors can heterodimerize or homodimerize and associate with two classes of coregulator proteins known as inhibitory corepressors and stimulating coactivators. Protein- protein interactions between retinoid receptors and their coregulators provide another level of regulation to the retinoid signaling pathway, as these can affect the basal transcriptional machinery through chromatin remodeling via changes in the state of acetylation. Coregulators represent additional pharmacological targets in cancer prevention.      
Pharmacological agonists and antagonists have been engineered to affect specific components of the retinoid signaling pathway. For instance, all-trans retinoic acid is an agonist for the RAR but not the RXR pathway, whereas the ligand 9-cis retinoic acid is bifunctional, activating the RAR and RXR pathways. An RXR agonist, known as a rexinoid, has been approved for clinical use by the FDA. Other retinoids target the AP-1 transcription factor. Some retinoids, such as N-(4-hydroxyphenyl)retinamide (4HPR) act through receptor-independent mechanisms (Fig. 1) and preferentially signal apoptosis in responsive cells.      
Randomized cancer chemoprevention clinical trials have emphasized the use of classical retinoids that activate the RAR pathway. Because repressed expression of RARβ is frequent in several epithelial cancers, including lung cancers, this could contribute to the clinical chemopreventive effects observed in subjects entered into trials to reduce primary or second lung tumors. The mechanisms responsible for RARβ repression are under active study. Preclinical evidence points to a role for methylation-induced silencing of this nuclear receptor. Perhaps demethylation agents that target RARβ sequences could be used in conjunction with the optimal retinoid to overcome RARβ repression and elicit the desired clinical chemoprevention effects. Clinical cancer chemoprevention studies could consider the use of retinoids that do not activate the classical retinoid signaling pathway. This approach might bypass a common defect observed in aerodigestive tract tumors, the suppression of RARβ.      
There is a need for additional candidate cancer chemoprevention agents that target specific cellular pathways. A partial list of candidate cancer chemoprevention agents appears in Fig. 1. In addition to pharmacological agents designated as retinoids, rexinoids, or SERMs, agents that act through other nuclear receptors include those affecting the vitamin D receptor (known as deltanoids) and those acting through PPAR-γ. One promising class of potential chemoprevention agents is synthetic triterpenoids, which are derivatives of natural products, known as cyclosqualenoids. Triterpenoids exhibit potent differentiation-inducing, antiproliferative, and antiinflammatory activities. Pertinent to their potential role in cancer chemoprevention, one of the synthesized triterpenoids known as CDDO (Fig. 1) suppresses induction of the inflammatory enzymes iNOS and COX-2. Whether these findings will be extended into the setting of clinical cancer chemoprevention is the subject of ongoing work.

III. CLINICAL CONSIDERATIONS

Clinical cancer chemoprevention trials have features distinct from therapeutic trials. To exert the desired clinical effects, chemoprevention agents are often administered on a chronic basis and should have few, if any, associated clinical toxicities. For individuals who are at increased risk for cancer, primary cancer prevention with chemopreventive agents, when coupled with lifestyle or dietary changes, would be an attractive approach to reduce cancer risk. Even in individuals at high risk for a primary cancer, a cancer chemoprevention agent would not be clinically adopted when clinical side effects are evident when used in cancer chemoprevention. In contrast, subjects who have already had a cured primary cancer may accept some side effects of chemoprevention agents if this would reduce the risk of a second primary cancer. Because candidate cancer chemopreventive agents are often selected for use based on mechanisms of action, one way to limit clinical toxicities of cancer chemopreventive agents would be through combination therapy. Agents targeting different chemopreventive pathways would each be administered at dosages lower than when these are used as single agents. This could yield more than additive chemopreventive activities while retaining acceptable clinical toxicity profiles. Perhaps synergistic clinical actions would be exerted by pharmacological agents that affect distinct chemopreventive pathways.      
Cancer chemoprevention trials are of a large size and require long clinical follow-up. If clinical outcome is the sole end point for the assessment of chemopreventive activity, then progress in this field will not be rapid. For this reason, biomarkers or intermediate end points have been proposed as ways to assess chemoprevention responses even before the clinical outcome is known. Biomarkers and intermediate end points are indicative of changes that increase the risk of cancer development in affected cells or tissues. Examples could indicate genomic instability that leads to additional chromosomal abnormalities (such as aneuploidy or loss of heterozygosity), cell cycle deregulation that alters the proliferative state, or changes in transcription due to the basal methylation or acetylation status of the genome, among other changes. Specific genetic alterations that occur in carcinogenesis include those affecting oncogenes (ras family, myc family, epidermal growth factor receptors, and others) or tumor suppressor genes, such as p53. These changes might be targets for cancer chemoprevention or surrogate markers for response to cancer chemopreventive agents.

IV. CONCLUSIONS

Pharmacological interventions can be used to reverse or arrest the progression of carcinogenesis at specific cell or tissue sites. Cancer chemoprevention is an attractive approach to reduce the societal burden of cancer by treating carcinogenesis before lesions become clinically evident. Given the chronic nature of interventions for cancer chemoprevention, pharmacological agents should be administered with few, if any, associated clinical toxicities. Biomarkers or intermediate end points could prove useful to identify chemopreventive targets as well as highlight those changes that would place cells or tissues at high risk for malignant transformation. Changes in these markers represent potential surrogate end points for clinical cancer chemoprevention trials. In the near term, as the clinical cancer chemoprevention field advances, it will be important to understand how preventive agents act and when they should be administered for primary or secondary cancer chemoprevention.

Acknowledgments
This work was supported in part by NIH RO-1-CA8756 (E.D.), RO1-CA62275 (E.D.), RO1-CA78814 (M.B.S.), the Department of Defense Grants DAMD17-99-1-9168 and DAMD17- 98-1-8604, the American Cancer Society Grant RPG-90-019- 10-DDC (E.D.), the National Foundation for Cancer Research (M.B.S.), and the Oliver and Jennie Donaldson Trust. M.B.S. is the Oscar M. Cohn Professor. We thank Dr. Nanjoo Suh, Dartmouth Medical School, for helpful consultation and Ms. Ann Frost for expert editorial assistance.

Ethan Dmitrovsky
Michael B. Sporn
Dartmouth Medical School

See Also
CELLULAR RESPONSES TO DNA DAMAGE ; CHEMOPREVENTION TRIALS ; ESTROGENS AND ANTIESTROGENS ; MOLECULAR EPIDEMIOLOGY AND CANCER RISK ; MOLECULAR MECHANISMS OF CANCER INVASION ; MULTISTAGE CARCINOGENESIS ; NUTRITIONAL SUPPLEMENTS AND DIET AS CHEMOPREVENTIVE AGENTS ; TUMOR CELL MOTILITY AND INVASION

GLOSSARY
biomarkers and intermediate end points Markers of the carcinogenesis process that highlight cells or tissues at risk for malignant conversion; these may serve as surrogates of response in clinical cancer chemoprevention trials.

cancer chemoprevention Use of dietary, nutritional, or pharmacological interventions to inhibit development of invasive cancer by blocking DNA damage that initiates carcinogenesis or by arresting or reversing the progression of premalignant cells that have already acquired genomic damage.

premalignancy Cells or tissues that are at an intermediate step in the carcinogenesis process and have acquired some, but not all, features of transformation; these cells are diagnosed based on histopathologic features and often exhibit genetic changes.

primary prevention Therapeutic interventions to prevent primary cancers from arising in high-risk individuals.

secondary prevention Therapeutic interventions to prevent second cancers from arising in patients cured of a primary cancer.

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