Selenium and the Prevention of Cancer

1. Selenium and the Prevention of Cancer Mary E. Reid, Ph.D. Department of Epidemiology Roswell Park Cancer Institute Buffalo NY

2. Introduction to Selenium and Cancer Prevention

3. Epidemiology Geographic correlation data in the U.S. and worldwide have noted an inverse association between Se levels in forage crops or diet and cancer mortality rates Lower mortality for lymphomas, GI tumors, peritoneum, lung, breast for people residing in US in areas with moderate or high SE in forage crops1 and for colorectal cancer2 1Shamberger, CRC Crit Rev Clin Lab Sci 1971;2 2Clark, Arch Environ Health 1981;46

4. Epidemiology Several prospective and case control studies confirmed that individuals with a lower Se status had an increased risk of many cancers These results were supported by population based studies in the US and China

5. Animal Studies Showing Se Anticarcinogenic Effect More than 250 animal studies in carcinogen-exposed animals exposed to Se have been reported 2/3 have shown decrease in incidence of tumors and/or preneoplastic endpoints Pubmed shows >2600 entries for selenium and cancer

6. Selenium Metabolism in Humans

7. Relationship of Ingested Forms and Plasma Forms

8. Bioavailability of Different Forms of Selenium Selenomethionine (SeMeth) has the greatest bioavailability. Selenized yeast achieved 73% of the slope for SeMeth. Selenite achieved 60% of the slope for SeMeth.

9. The Evidence for Prevention of Specific Cancers

10. Nutritional Prevention of Cancer Study Design Double-blind, placebo-controlled, randomized of 1312 high risk non-melanoma skin cancer patients from 7 dermatology clinics in the Eastern Coastal Plain of the US. The follow-up period was 1983-1996. 200 ?g selenium was given as selenized yeast or matched yeast placebo. Primary endpoints included: Recurrence of Basal Cell Carcinoma of the Skin Recurrence of Squamous Cell Carcinoma of the Skin Secondary endpoints included: All Cause Mortality Total Cancer Mortality Total Cancer Incidence (excluding NMSC) Lung, Prostate, Colon Cancer Incidence

11. Adjusted1 Risk Ratios for NMSC Recurrence for Selenium Treatment

12. Adjusted Site Specific Cancer Incidence for Treatment Effect

13. Cumulative Hazard Estimates of Total Cancer, by Treatment Group

14. Prostate Cancer

15. Additional Evidence for Prostate Cancer Prevention Selenium, given orally as Se-Meth 200 mcg/d to men with organ-confined prostate cancer, raises serum levels by 15% and preferentially accumulates in the prostate tissue versus the seminal vesicles. (Sabichi AL et al, CCR, 2006) Selenite treated LNCaP cells included apoptosis by increasing superoxide and inducing p53 mitochondrial translocation. (Zhao R et al, Can Res, 2006)

16. Ongoing Trials to Prevent Prostate Cancer SELECT Trial (NCI-Cooperative Groups) >32,000 men without prostate cancer Multifactorial design of selenomethionine (200 mcg/d) and ?-tocopherol Primary endpoint is prostate cancer; secondary endpoints are other internal cancers, genetic and epigenetic changes Negative Biopsy Trial (NBT) University of Arizona, Tucson AZ (PI: F Ahmann) Subjects must have biopsy negative for cancer, PSA > 4.0 Doses of 0, 200, and 400 mcg of selenized yeast per day. Endpoints: cancer incidence, rise in PSA. Sample Size: 700

17. Watchful Waiting Trial (WW) University of Arizona (PI: F Ahmann) Subjects must have biopsy proven prostate cancer within 48 months. Doses of 0, 200, and 800 mcg of selenized yeast. Endpoints: PSA rise, therapy, metastatic disease. Sample Size: 220 High Grade Prostatic Intraepithelial Neoplasia (HGPIN) Trial Roswell Park Cancer Institute (PI: JR Marshall) Men with confirmed HGPIN on repeated prostate biopsies Treated with 200 mcg of L-selenomethionine Endpoint biopsies to determine progression rates to prostate cancer, molecular and morphometric markers of progression Sample size: 420

18. Colon Cancer

21. Pooled Project of Selenium and Colorectal Adenomas Jacobs et al, JNCI, 2004 Pooled data from the Wheat Bran Fiber Trial, Polyp Prevention Trial and the Polyp Prevention Study 1763 participants with baseline selenium levels and prospective follow-up Results comparing highest versus lowest quartiles showed an OR= .66 (95%CI= .50-.87)

22. High Selenium and Reduced Risk of Advanced Colorectal Adenomas Peters et al, CEBP, 2006 Cases (758) with advanced adenomas and matched controls (767) from the PLCO Screening Trial Quintiles of serum selenium. Lowest mean (108.2 ng/ml) versus highest mean (173.8 ng/ml) Results per 50 ng/ml increase in selenium level Overall: 26% reduction, p-trend= .01 > 67 Yrs: 51% reduction, p-trend= .005 In Men: 37% reduction, p-trend= .001

23. Selenoproteins and Colon Cancer Risk Irons et al, Journal of Nutrition, 2006 (Nutrition Science Research Group, NCI) Wild type and transgenic mice (deficient selenoprotein synthesis) had azoxymethane-induced (AOM) aberrant crypt foci (ACF) Mice were fed a standard diet versus supplemental diet with sodium selenite Transgenic mice had lower levels of GPX1 in liver and colon Supplemental selenium reduced ACF in both groups Selenium treatment reduced the preneoplastic colon lesions independent of selenoprotein synthesis

24. Ongoing Study of Selenium and Colorectal Adenoma Prevention Prevention of colorectal adenomatous polyps University of Arizona, Tucson (PI: DS Alberts) Multifactorial design with 200 mcg of selenized yeast and Celecoxib (discontinued arm) Sample size: 400 subjects in each group

25. Lung Cancer

27. Cumulative Mortality Survival Curve for All Lung Cancers by Treatment Group

28. Meta-analysis of Selenium and Lung Cancer Studies 16 studies were included in the analysis, representing US, Netherlands, Finland, China Combined RR: 0.74 (95%CI= .57-.97) Protective effects of selenium were strongest in areas of low selenium Strongest effect when selenium status was assessed in toenails (RR= .46, 95%CI= .24-.87) versus serum or plasma (RR= .80, 95%CI= .58-1.10)

29. Ongoing Studies of Selenium and Lung Cancer University of Colorado (H Thompson) high risk lung cancer patients exposed to asbestos Dose: 200 mcg/day of selenized yeast Endpoints: bronchoepithelial dysplasia and oxidative stress Prevention of Second Primary Tumors (Intergroup Study) Stage IA surgically treated patients with no adjuvant therapy 200 mcg/d of selenized yeast Ongoing recruitment

30. Mechanisms of Action

31. Selenium and Possible Anticarcinogenic Mechanisms Induces apoptosis Inhibits proliferation Inhibits angiogenesis Inhibits Cox-2 expression Promotes DNA repair Antioxidant activity

36. Endoplasmic Reticulum (ER) Stress Mediators are Targets of Selenium Action Induction of ER stress and stress-associated apoptotic response Low dose of selenium preferentially activates the rescue arm of the ER system Higher doses of selenium lead to assembly of the apoptotic machinery Supports the different activities of selenium with damaged versus salvageable cells

37. Selenium Dosing and Toxicity

38. Doses of Selenium Used in Clinical Studies

39. Conclusions There is strong consistent evidence for the chemopreventive potential of selenium, across several major cancer sites and supported by in vitro and in vivo models More information is needed on the mechanisms of action for each cancer site and stage of carcinogenesis, the role of selenium status and determinants of status, including genetic factors, and the effect of the form of selenium on activity There is a wider range of doses used the current ongoing trials with very low toxicity profiles

40. Collaborators James Marshall, Ph.D. Clement Ip, Ph.D. Yan Dong, Ph.D. Lakshmi Pendyala, Ph.D. Marwan Fakih, M.D. Youcef Rustum, M.D. Haitao Zhang, Ph.D.