CORRESPONDENCE

RESPONSE: Re: Selenium Supplementation and Secondary Prevention of Nonmelanoma Skin Cancer in a Randomized Trial

James Marshall, Mary Reid, Anna Duffield-Lillico

Affiliations of authors: Division of Cancer Prevention & Population Sciences, Roswell Park Cancer Institute, Buffalo, NY (JM, MR); Memorial Sloan-Kettering Cancer Center, Department of Epidemiology & Biostatistics, New York, NY (ADL).

Correspondence to: James Marshall, PhD, Division of Cancer Prevention & Population Sciences, Roswell Park Cancer Institute, Carlton House Bldg., Rm. 304, Elm & Carlton Streets, Buffalo, NY 14263 (e-mail: james.marshall{at}roswellpark.org)

We are grateful to Dr. Huff for his comments.

The biologic activity of selenium is very much dependent on its chemical form (13). Elemental selenium, for example, has virtually no biologic activity. Selenite and selenate, inorganic forms, are toxic at fairly low doses. In the Nutritional Prevention of Cancer (NPC) trial, selenium was administered in selenized yeast. The major form of selenium in the selenized yeast most commonly available today is selenomethionine, an organic form; the form that predominated in the selenized yeast used in the NPC trial was also selenomethionine, although a number of other selenium compounds were recently identified (4). Selenomethionine, now being tested in two ongoing prostate cancer chemoprevention trials (5,6), has low toxicity and is absorbed by the body in the same manner as methionine. Catabolism of selenomethionine initiates a cascade of metabolites, including selenocysteine, hydrogen selenide (which is an active oxidant), and methylselenol (which may be most directly protective against cancer). Methylselenocysteine, a possibly important compound now under investigation, is metabolized to methylselenol in a single-step cleavage (13).

The toxicity, the carcinogenicity, and, conversely, the anticancer activity of selenium compounds likely vary widely. The form of selenium mentioned by Huff, selenium disulfide, may well be carcinogenic in a number of applications. Nonetheless, the fact that one selenium compound has deleterious effects does not mean all others do. The hazard of extrapolating from nonhumans to humans also bears emphasizing. The NPC trial has, on average, 7.9 years of follow-up on human subjects. It is fair to question whether the results for the NPC participants are fully generalizable, but it must be qualitatively less difficult to generalize from these subjects to other humans than from Fischer or B6C3F1 rats or ICR Swiss mice to humans.

The primary end point of the NPC study was nonmelanoma skin cancer (NMSC); NPC tested selenium supplementation as a means of preventing NMSC recurrence among high-risk individuals and found that it increased risk. Nonetheless, the enthusiastic response to the first presentation of the NPC results emphasized secondary end points. The editorial that accompanied that first NPC report cautioned that the results demanded replication before they could be regarded as in any sense definitive or confirmed (7). Our finding is that selenium increased the risk of our primary end point, a finding that requires additional testing in other clinical trials. Huff's comments are a useful reminder of the high standard necessary for chemoprevention: Trials of selenium in men with an average risk, whose results will figure prominently in decisions about chemopreventive strategies, should attend carefully to the clinical trial evidence that selenium may increase the risk of NMSC.

REFERENCES

1 Ip C, Ganther HE. Activity of methylated forms of selenium in cancer prevention. Cancer Res 1990;50:1206–11.[Abstract]

2 Ip C, Hayes C, Budnick RM, Ganther HE. Chemical form of selenium, critical metabolites, and cancer prevention. Cancer Res 1991;51:595–600.[Abstract]

3 Ip C, Lisk DJ, Ganther H, Thompson HJ. Triphenylselenonium and diphenylselenide in cancer chemoprevention: comparative studies of anticarcinogenic efficacy, tissue selenium levels and excretion profile. Anticancer Res 1997;17:3195–9.[ISI][Medline]

4 Uden PC, Boakye HT, Kahakachchi C, Hafezi R, Nolibos P, Block E, et al. Element selective characterization of stability and reactivity of selenium species in selenized yeast. J Anal At Spectrom 2003;18:1–10.[CrossRef][ISI]

5 Clark LC, Marshall JR. Randomized, controlled chemoprevention trials in populations at very high risk for prostate cancer: elevated prostate-specific antigen and high-grade prostatic intraepithelial neoplasia. Urology 2001;57(4 Suppl 1):185–7.[CrossRef][ISI][Medline]

6 Klein EA, Thompson IM, Lippman SM, Goodman PJ, Albanes D, Taylor PR, et al. SELECT: the Selenium and Vitamin E Cancer Prevention Trial: rationale and design. Prostate Cancer Prostatic Dis 2000;3:145–51.[CrossRef][ISI][Medline]

7 Colditz GF. Selenium and cancer prevention: promising results indicate further trials required. JAMA 1996;276:1984–5.[CrossRef][ISI][Medline]



             
Copyright © 2004 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement