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Detoxifying Cancer Causing Agents to Prevent Cancer

Margaret Hanausek, Zbigniew Walaszek and Thomas J. Slaga Integr Cancer Ther 2003 2: 139 DOI: 10.1177/1534735403002002005 The online version of this article can be found at: http://ict.sagepub.com/content/2/2/139

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Detoxifying Cancer Causing Agents

Detoxifyinget 10.1177/1534735403253305 Hanausek Cancer al Causing Agents

Detoxifying Cancer Causing Agents to Prevent Cancer

Margaret Hanausek, PhD, Zbigniew Walaszek, PhD, and Thomas J. Slaga, PhD

Different vitamins and other micronutrients in vegetables, fruits, and other natural plant products may prevent cancer development (carcinogenesis) by interfering with detrimental actions of mutagens, carcinogens, and tumor promoters. The goal of current studies in cancer prevention is to determine the mechanisms of synergistic action of the natural source compounds known to inhibit one or more stages of carcinogenesis, that is, initiation and promotion/progression. Many natural cancer preventive agents are effective inhibitors of tumor initiation, promotion, and/or progression. The mechanism of action is related to their abilities to prevent critical carcinogen metabolism and to increase detoxification of carcinogens and tumor promoters. The authors review here the potential role of the detoxification system and, in particular, the roles of D-glucaric acid and the enzyme -glucuronidase in early detection and prevention of cancer. There is now growing evidence for the possible control of different stages of the cancer induction by inhibiting glucuronidase with D-glucaric acid derivatives, especially with its salts (D-glucarates). D-Glucaric acid has been found in many vegetables and fruits. Therefore, the consumption of fruits and vegetables naturally rich in D-glucaric acid or self-medication with D-glucaric acid derivatives such as calcium D-glucarate offers a promising cancer prevention approach. Keywords: Carcinogens; detoxification; natural products; cancer prevention

Detoxification System and Chemoprevention of Cancer

Inhibition of the induction of cancer (carcinogenesis) and the prevention of cancer with chemical compounds is usually referred to as chemoprevention. Chemopreventive agents, which prevent cancercausing agents (carcinogens) from reaching or reacting with critical targets (cancer initiation) are called blocking agents, whereas those preventing the evolution of the neoplastic process in cells (cancer promo1 tion and progression) are called suppressing agents. Currently, a number of blocking and suppressing agents are being tested using either pharmacological
DOI: 10.1177/1534735403253305

or, less often, nutritional regimens. Chemopreventive blocking agents can prevent the occurrence of cancer by increasing the detoxification of chemical carcino2 gens, tumor promoters, and tumor progressors. The pathways of detoxification have been divided into 2 major categories: phase I reactions (oxidations, reductions, and hydrolyses) and phase II reactions (conjugations). Both phase I and II reactions are to make the toxin molecule more polar or water soluble and therefore readily excreted. There has been a growing interest in the inhibitors that induce an increase in activity of phase II detoxifying enzymes, with a special emphasis on glutathione S-transferases.2 Glutathione S-transferases conjugate ultimate carcinogens, that is, very reactive electrophilic metabolites of carcinogenic compounds, with glutathione. There is also strong evidence for the detoxification of chemical carcinogens or their metabolites and tumor promoters/progressors by UDP-glucuronosyltransferases,2 which conjugate nucleophilic compounds produced by our bodies (endogenous) as well as foreign chemicals (exogenous), with D-glucuronic acid. Conjugation with D-glucuronic acid, that is, glucuronidation, appears to be the principal conjugation pathway in the tissues of all vertebrate species examined to date.3 The conjugates are excreted in the bile and urine or transported from one tissue (usually liver) to other tissues. UDP-glucuronosyltransferases are found in the endoplasmic reticulum and nuclear membranes and are markedly inducible by xenobiotic inducers (foreign compounds).4 High specific activity of nuclear UDP-glucuronosyltransferase in the nuclear membrane in proximity to genetic material suggests a very important role in the deactivation of both foreign and endogenous compounds such as steroid hormones. Thus, this enzyme could also serve as an important barrier for the nuclear genetic apparatus against mutagenic and carcinogenic or otherwise
MH, ZW, and TJS are at the AMC Cancer Research Center, Denver, Colorado Correspondence: Margaret Hanausek, PhD, AMC Cancer Research Center, 1600 Pierce Street, Denver, CO 80214. E-mail: hanausekm@amc.org.

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toxic chemical compounds. Carcinogens identified to date, which after metabolic activation are subject to glucuronidation, include polycyclic aromatic hydrocarbons, some nitrosoamines, aromatic amines, and fungal toxins. Certain tumor promoters including steroid hormones also undergo glucuronidation.3 The importance of conjugating enzymes such as UDP-glucuronosyltransferase, which uses nucleophilic substrates instead of reactive electrophiles, has only recently been recognized.2 It has become apparent that nucleophilic metabolites are often intermediates in formation of ultimate carcinogens. Furthermore, it is clear that glucuronides may be highly stable forms of these intermediates, which are subject to further activation after hydrolysis by the enzyme glucuronidase at sites distant from their site of formation.6 In fact, the elimination and or deactivation of potentially damaging chemicals that undergo glucuronidation is limited not only by the rate of conjugation with D-glucuronic acid but also by the rate of de-glucuronidation by this ubiquitous enzyme.3
5

D-Glucaro-1,4-Lactone

CO HC OH H OCH HC O

CH OH HC OH OCH HC O HC OH CO

CO HCOH OCH HCO HCOH CO

HC OH C OOH

COOH H COH HOCH HCOH

COOH HC OH OCH

H COH COOH

D-Glucurono-6,3-Lactone

HC OH HC OH CO

D-Glucaric Acid

D-Glucaro-6,3-Lactone

Figure 1 In vivo formation of the -glucuronidase inhibitor Dglucaro-1,4-lactone by oxidation of D-glucuronic acid lactone.

Novel Biomarkers of Detoxification System: D-Glucaric Acid and -Glucuronidase

The availability of effective chemoprevention agents is only one component of a full chemoprevention program. Another important component is the availability of a marker or markers that can help evaluate the effects of chemopreventive agents early during the prevention trials and evaluate individuals as to the magnitude of general or site-specific risk to cancer. In fact, the development of intermediate biomarkers of cancer risk and the evaluation of efficacy of individual biological or molecular markers as intermediate end points in prevention trials have been considered as important avenues in cancer research. Recently, the potential role of the detoxification system and the roles of D- glucaric acid and glucuronidase in early detection and prevention of cancer have been investigated. D-Glucaric acid is a natural, apparently nontoxic compound produced by some plants, especially in fruits and vegetables, and in small amounts by mammals, including humans.7 DGlucaric acid is an end product of the D-glucuronic acid pathway in mammals.7 Oxidation of D-glucuronic acid or its lactone leads to oxidation products that hydrolyze spontaneously in aqueous solution to give the potent -glucuronidase inhibitor, D-glucaro-1,4lactone, noninhibitory D-glucaro-6,3-lactone, and Dglucaric acid (see Figure 1), all of which are excreted in urine.7 D-Glucaric acid was identified as a normal constituent of urine7 and serum.8 In fact, D-glucaric acid is a major serum organic acid.8 However, significant differences in serum levels and urinary excretion
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of D-glucaric acid have been reported for apparently healthy people. Since urinary excretion of D-glucaric acid increases following exposure to xenobiotics, it was suggested for use as an indirect indicator of hepatic microsomal enzyme induction by xenobiotic 10 agents. D-Glucaric acid urinary excretion in cancer patients and tumor-bearing rats was found11 to be significantly lower than in healthy controls. In mice with experimental tumors and in cancer patients, uninvolved liver had a lowered D-glucaric acid level.7 Cancer tissue itself lacked the D-glucaric acid synthesizing system.7 The physiological function of D-glucaric acid is unclear. Formation of D-glucaro-1,4-lactone, an inhibitor of -glucuronidase, from one of the products of its hydrolytic action (ie, D-glucuronic acid), could be regarded as a negative feedback mechanism. The accumulation in the body of free carcinogens, tumor promoters, and other toxins, normally excreted as glucuronides in the bile or urine, may be aggravated not only by the elevated -glucuronidase activity but also by the depressed synthesis of the -glucuronidase inhibitor D-glucaro-1,4-lactone (Figure 2). D-Glucaro1,4-lactone does not directly affect the UDP-glucuronosyltransferase activity.3 However, by inhibiting -glucuronidase, it does enhance net glucuronidation. Therefore, it has a potential for chemoprevention of cancer. 12,13 There is now growing evidence12-14 from short- and long-term models for the possible control of different stages of the carcinogenic process by D-glucaro-1,4-lactone, and specifically by its precursors such as D-glucaric acid salts (D-glucarates). Recently, D-glucaric acid and has been found in some 15 vegetables and fruits. Thus, the consumption of
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Detoxifying Cancer Causing Agents

known to be accompanied by increased excretion of Dglucaric acid include alcoholism, early stage of renal 16 disease in children, and liver diseases. Decreased values of D-glucaric acid excretion have been found to occur in patients with congestive heart failure, starva16 tion, severe burns, and favism. However, intraindividual variations in urinary excretion of D-glucaric acid have been reported.16 Since the total daily urine collection is often impractical and unreliable, it was proposed to determine the blood serum levels of D-glucaric acid in cancer patients. It was found17 that normal levels of Dglucaric acid in the blood serum of healthy people are 1.42 0.5 M in women and 1.50 0.29 M in men. In cancer patients, the blood serum concentration of Dglucaric acid drops significantly, that is, to levels usually lower then 1 M.17 Recently, a Phase I clinical trial was undertaken to begin to explore the potential role of D-glucaric acid in the prevention of cancer in humans.18 Current smokers and nonsmokers, both men and women, were assigned to escalating doses of calcium Dglucarate (from 1.5 to 9.0 gm/day) given over a 6-week period. Blood levels of D- glucaric acid and glucuronidase were determined at baseline and every 2 weeks. In addition, lymphocytes and sputum specimens were collected for K-ras oncogene determination. A consistent suppression of -glucuronidase levels was achieved by increasing doses of calcium D-glucarate, which, in turn, correlated well with increasing Dglucaric acid blood levels. DNA was isolated from the lymphocyte fraction of the blood and sputum obtained from male and female smokers and nonsmokers (baseline). Mutated K-ras, an oncogene linked to lung cancer, was found in the DNA isolated from baseline blood lymphocytes and from sputum of some male smokers. No K-ras mutations were found in nonsmokers. The baseline D-glucaric acid level in the blood of smokers with mutated K-ras was significantly lower (ie, by circa 34%, P < .05) than in other smokers or nonsmokers. No unusual toxicity was encountered in this Phase I study, and calcium D-glucarate was well tolerated, even at the highest dose levels.18 Thus, calcium D-glucarate supplementation has potential for reducing the risk of lung cancer development in tobacco smokers. The results of extensive animal studies12,13 also suggest that calcium D-glucarate may reduce the risk of lung as well as breast, prostate, liver, skin, and colon cancer in humans.

Figure 2 The effect of calcium D-glucarate and D-glucaro-1,4lactone on detoxification of compounds that undergo glucuronidation.

fruits and vegetables naturally rich in D-glucaric acid, or self-medication with D-glucaric acid derivatives such as calcium D-glucarate or potassium hydrogen Dglucarate, offers a promising chemopreventive approach. The ability to inhibit chemical carcinogenesis by inhibiting -glucuronidase activity has some interesting implications. For example, certain subpopulations may be more susceptible to chemical carcinogens because of high -glucuronidase activity. There is good evidence for human subpopulations with high and low -glucuronidase levels. Also, -glucuronidase levels are higher in 25- to 60-year-old males, in pregnant women, and in workers exposed to certain environmental carcinogens. In animal models, glucuronidase activity increases significantly after both tobacco smoke exposure and oral tobacco administration. Although most of this evidence (reviewed earlier12,13) relative to subpopulations, which may be particularly susceptible to carcinogens, is circumstantial, it does suggest that the association between -glucuronidase activity and chemical carcinogenesis in animal models, or cancer incidence in human subpopulations, warrants further study. Because urinary excretion of D- glucaric acid increases following exposure to xenobiotics, including different toxins and environmental carcinogens, urinary excretion of D-glucaric acid is considered useful as a nonspecific parameter for exposure to environmental factors.16 In fact, very often, the results of the D-glucaric acid tests correlate well with the results of bacterial urinary assays for mutagenic activity, that is, the Ames test.16 In relatively small population studies, smoking has been found to have no effect or to cause a significant increase.9 However, the tobacco use extent, that is, light versus heavy tobacco use, has not been clearly stated in the above studies. Disease states
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Importance of Natural Inhibitors of Carcinogenesis

Scores of epidemiologic studies have noted a lower risk of cancer among persons whose diet include a relatively large amount of vegetables, fruits, and other
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plant products. A popular explanation, both within the scientific community and among members of the public, is that different vitamins and other micronutrients in vegetables, fruits, and other natural plant products prevent carcinogenesis by interfering with detrimental actions of mutagens, carcinogens, and tumor promoters. These natural inhibitors of carcinogenesis are apparently nontoxic or markedly less toxic than synthetic chemopreventive agents. Although it is generally accepted that a diet of large amounts of vegetables, fruits, and other plant products lowers cancer incidence, there is still a need to identify the most effective constituents of the diet as well as to elucidate their mechanisms of action. There has been significant progress in the understanding of the multistage nature of carcinogenesis21-23 2,24,25 and the mechanisms of cancer prevention. The mouse skin model, which represents one of the best understood experimental models of multistage carcinogenesis, has permitted the resolution of three distinct stages: initiation, promotion, and progression.21,22 It is now apparent that the cellular evolution to malignancy involves the sequential alteration of proto-oncogenes26 and/or tumor suppressor genes,27 whose gene products participated in critical pathways for the transduction of signals and/or regulation of gene expression. One of the goals of current studies in cancer prevention is to determine the mechanisms of synergistic action of the natural source compounds, known to inhibit one or more stages of carcinogenesis, that is, initiation and promotion/progression.2,24 The basic theory underlying these studies is that concurrent treatment with various natural source inhibitors of different stages of carcinogenesis results in synergistic effects, leading to more efficient prevention of cancer. The mechanisms that focus on initiation events include (a) inhibition or alteration of phase I enzymes responsible for the formation of reactive carcinogenic metabolites ultimately leading to their reduced formation; (b) inhibition or induction of oxidative enzyme pathways that produce products of lower carcinogenic potential; (c) induction of detoxification enzymes (phase II enzymes) and pathways (nonoxidative) for both proximate and ultimate carcinogen; (d) scavenging of reactive, carcinogenic intermediates through direct chemical interaction; (e) inhibition or enhancement of DNA repair mechanisms; and (f ) inhibition of cell proliferation and DNA synthesis. Specifically, one may want to choose compounds that act through one or more different mechanisms (see Table 1). For example, one may chose an agent that appears to work primarily by mechanism (a) above, for example, ellagic acid.2,24 This compound has been shown to block cytochrome P450 enzymes involved in the
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19,20

metabolic activation of polycyclic aromatic hydrocarbons. On the other hand, ellagic acid appears to work also by scavenging electrophilic carcinogenic intermediates.2,19 Thus, such a compound would fall into mechanism (d ) above. One may also want to use proanthocyanidins and green tea polyphenols that fall into the general class of chemicals that possess antioxidant properties. These compounds have been shown to alter specific metabolic pathways, including phase I and phase II enzyme mediated pathways, in bringing about inhibition of carcinogenesis in different tissues.2,24 All these compounds appear to have the common feature that they have been shown to induce the activity of glutathione S-transferases in specific tissues.2,24 Many of these compounds appear to have actions that would place them in mechanism (c) above. This latter property (that is, the ability to induce enzymes involved in detoxification of many carcinogens) may represent the most important property in the ability of some of these compounds to block carcinogenesis by diverse carcinogenic agents. Finally, one may choose to use calcium D-glucarate, an in vivo inhibitor of the glucuronidase enzyme, also involved in detoxification of many carcinogens and tumor promoters (mechanism (c)).12,13 The process of tumor promotion/progression involves a combination of several mechanisms. Among anti-tumor-promoting mechanisms (see Table 1), the ones that are most promising include (a) inhibition of inflammation, (b) inhibition of cell proliferation and hyperplasia, (c) modulation of cell differentiation and apoptosis, (d) scavenging of reactive oxygen species and preventing depletion of antioxidant defense systems, and (e) enhancement of tumor promoter detoxification pathways. The natural cancerpreventive agents that exert their effects against tumor promotion usually inhibit one, more, or even all events involved in the tumor promotion process.2,24,25 It is unclear, however, whether inhibition of one particular event involved in promotion by chemopreventive agents is sufficient and/or necessary to exert their maximum to complete anti-tumor-promoting effects.2,25 Specifically, one may chose, for example, anti-tumor-promoting natural compounds or extracts2,19 that inhibit inflammation (mechanism (a) above, agents such as resveratrol and ursolic acid from rosemary extract); cell proliferation and hyperplasia (mechanism (b) above, agents such as retinoids and Dglucarate); and oxygen free radical formation (mechanism ( d ) above, agents such as lycopene and proanthocyanidins). In addition, one may want to use novel triterpenoid saponins, named avicins, recently shown28 to reduce inflammation and hyperplasia (mechanisms a and b) as well as oxidative damage and nitrosative stress (mechanism d). Finally, one may use
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Table 1. Targeting Specific Stages of Carcinogenesis With Dietary Factors and Chemopreventive Agents

Mechanisms of Prevention
Tumor Initiation a. Inhibition of phase I enzymes to prevent the formation of reactive carcinogenic metabolites b. Inhibition or induction of oxidative enzyme pathways to produce less carcinogenic metabolites c. Enhancement or induction of detoxification enzymes (phase II enzymes) and pathways d. Direct chemical scavenging of carcinogenic intermediates e. Inhibition or enhancement of DNA repair f. Inhibition of cell proliferation and DNA synthesis

Examples of Preventive Agents/Factors

a. Epigallocatechin gallate (EGCG), selenium, phenylisothiocyanate (PEITC), indol-3-carbinol, coumarins, ellagic acid, resveratrol, genistein, 1-ethynylpyrene b. Butylated hydroanisole (BHA), butylated hydroxytoluene (BHT), ethoxyquin, 7,8-benzoflavone, quercetin c. Oltipraz, EGCG, PEITC, diallyl sulfide, resveratrol, Nacetylcysteine, D-glucarate d. Ellagic acid e. Calorie restriction, EGCG, selenium f. Calorie restriction, difluoromethylornithine, selenium, antiestrogens, dehydroepiandrosterone (DHEA), fluasterone, retinoids, Dglucarate a. Nonsteroidal anti-inflammatory drugs, calorie restriction, DHEA, fluasterone, antihistamines, resveratrol, ursolic acid, avicins b. Calorie restriction, difluoromethylornithine, selenium, antiestrogens, DHEA, fluasterone, retinoids, D-glucarate c. Retinoids (all-trans retinoic acid, fenretinide), calorie restriction, monoterpenes (that is, D-limonene), fluasterone, genistein, calcium d. Antioxidants (carotenoids, -tocopherol, ascorbic acid, proanthocyanidins, EGCG, avicins), selenium, calorie restriction e. D-Glucarate, aromatase inhibitors, antiestrogens

Tumor promotion/progression a. Inhibition of inflammation b. Inhibition of cell proliferation and hyperplasia c. Modulation of cell differentiation and apoptosis d. Scavenging of reactive oxygen species and preventing depletion of antioxidant defense systems e. Detoxification of tumor promoters, especially steroid hormones

anti-tumor-promoting compounds such as D12,13 glucarate to reduce the detrimental effects of free steroid hormones in the mammary gland and the prostate gland carcinogenesis (mechanism e). In breast cancer prevention, D-glucarate may potentially be used alone or in combination with antiestrogens or aromatase inhibitors.29 In conclusion, many natural cancer-preventive agents are effective inhibitors of tumor initiation, promotion, and/or progression. In a number of cases, the mechanism(s) of action are related to their abilities to prevent critical carcinogen metabolism, and to increase detoxification pathways for carcinogens and free radicals as well as to their antioxidizing activity. Usually, natural cancer preventive agents inhibit the initiation and promotion/progression stages to a different degree. Therefore, a combination(s) of various natural cancer preventive agents, with different mechanisms of action, will most likely prove to be more effective in inhibiting the development of cancer compared to 1 agent. However, one must take into account that some inducers and inhibitors of phase I, phase II, and related enzymes may affect the metabolism of cancer drugs.30 Making scientifically based decisions30,31 about the use of food and herbal medicines during chemotherapy is very important because of the critical nature of cancer treatment.

References
1. Wattenberg LW. Inhibition of carcinogenesis by minor dietary constituents. Cancer Res. 1992;52:2085s-2091s. 2. Hursting SD, Slaga TJ, Fischer SF, DiGiovanni J, Phang JM. Mechanism-based cancer prevention approaches: targets, examples, and the use of transgenic mice. J Natl Cancer Inst. 1999;91:215-225. 3. Dutton GJ. Glucuronidation of Drugs and Other Compounds. Boca Raton, Fla: CRC Press; 1980. 4. Burchell B, Coughtrie MHW. UDP-Glucuronosyltransferases. Pharm Ther. 1989;43:261-289. 5. Siest G, Magdalou J, Burchell B. Cellular and Molecular Aspects of Glucuronidation. Paris: INSERM; 1988. 6. Reddy BS, Weisburger JH, Wynder EL. Fecal bacterial glucuronidase: control by diet. Science. 1974;183:416-417. 7. Levy G, Conchi J. -Glucuronidase and the hydrolysis of glucuronides. In: Dutton GJ, ed. Glucuronic Acid: Free and Combined. New York: Academic Press; 1966:301-364. 8. Blumenthal HJ, Lucuta VL, Blumenthal DC. Specific enzymic assay for D- glucarate in human serum. Anal Biochem . 1990;185:286-293. 9. Colombi A, Maroni M, Antonini C, Fait A, Zocchetti C, Foa V. Influence of sex, age and smoking habits on the urinary excretion of D-glucaric acid. Clin Chim Acta. 1983;128:349-358. 10. Batt HM, Siest G. Laboratory tests as indirect indications of the activity of drug metabolizing enzymes: use of glucaric acid and gamma-glutamyltranspeptidase. Dev Clin Biochem. 1980;2:178192. 11. Yokoyama M, Matsuoka S, Wakui A. Activation of tegafur and urinary excretion of D-glucaric acid in tumor-bearing hosts. In: Ishigami J, ed. Recent Adv Chemother, Proc Int Congr Chemother, 14th. Tokyo, Japan: University of Tokyo Press; 1985:113-115.

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Hanausek et al
12. Walaszek Z. Potential use of D-glucaric acid derivatives in cancer prevention. Cancer Lett. 1990;54:1-8. 13. Walaszek Z. Chemopreventive properties of D-glucaric acid derivatives. Cancer Bull. 1993;45:453-457. 14. Yoshimi N, Walaszek Z, Mori H, Hanausek M, Szemraj J, Slaga TJ. Inhibition of azoxymethane-induced rat colon carcinogenesis by potassium hydrogen D-glucarate. Int J Oncol. 2000;16:43-48. 15. Walaszek Z, Szemraj J, Hanausek M, Adams AK, Sherman U. DGlucaric acid content of various fruits and vegetables and cholesterol lowering effects of dietary D-glucarate in the rat. Nutr Res. 1996;16:673-682. 16. Brewster MA. Biomarkers of xenobiotics exposure. Ann Clin Lab Sci. 1988;18:306-317. 17. Walaszek Z, Hanausek M, Szemraj J, Adams AK. D-Glucaric acid as a prospective tumor marker. Methods Mol Med . 1998;14:487-495. 18. Walaszek Z, Raich P, Hanausek M, Szemraj J, Narog M, Slaga TJ. Potential role of D-glucaric acid in lung cancer prevention. Proc Am Assoc Cancer Res. 2002;43:306. 19. National Research Council; Committee on Diet and Health, Food and Nutrition Board; Commission on Life Sciences. Diet and Health: Implications for Reducing Chronic Disease Risk. Washington, DC: National Academy Press; 1989. 20. Food, Nutrition and the Prevention of Cancer: A Global Perspective. Washington, DC: World Cancer Research Fund/American Institute for Cancer Research; 1997. 21. Slaga TJ, OConnell J, Rotstein J, et al. Critical genetic determinants and molecular events in multistage skin carcinogenesis. Symp Fundam Cancer Res. 1987;39:31-34. 22. DiGiovanni J. Multistage carcinogenesis in mouse skin. Pharmacol Ther. 1992;47:63-128. 23. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759-767. 24. Slaga TJ. Inhibition of skin tumor initiation, promotion, and progression by antioxidants and related compounds. Crit Rev Food Sci Nutr. 1995;35:51-57. 25. Marks F, Furstenberg G. Cancer chemoprevention through interruption of multistage carcinogenesis: the lessons learnt by comparing mouse skin carcinogenesis and human large bowel cancer. Eur J Cancer. 2000;36:314-329. 26. Bishop JM. Molecular themes in oncogenesis. Cell . 1991;64:235-248. 27. Marshall CJ. Tumor suppressor genes. Cell. 1991;64:313-326. 28. Hanausek M, Ganesh P, Walaszek Z, Slaga TJ, Arntzen C, Gutterman JU. Avicins, a family of triterpenoid saponins from Acacia victoriae (Bentham), suppress H-ras mutations and aneuploidy in a murine skin carcinogenesis model. Proc Natl Acad Sci U S A. 2001;98:11551-11556. 29. Mokbel K. The evolving role of aromatase inhibitors in breast cancer. Int J Clin Oncol. 2002;7:279-278. 30. Block KI, Gyllenhaal C. Clinical corner: herb-drug interaction in cancer chemotherapy: theoretical concerns regarding drug metabolizing enzymes. Int Cancer Ther. 2002;1:83-89. 31. Lippman SM, Hong WK. Cancer prevention science and practice. Cancer Res. 2002;62:5119-5125.

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