Re: Selenium >>> Colon Cancer

[Guest guest]

--- In , " Rodney " <perspect1111@y...>

wrote:

>

> Hi folks:

>

> Now it appears that selenium reduces recurrence of colon cancer by

> 34%.

>

> s - Arizona Cancer Center - JNCI, 17 November 2004.

>

> Rodney.

Hi All,

http://tinyurl.com/5sws9 is the paper.

Duffield-Lillico AJ, Shureiqi I, Lippman SM.

Can Selenium Prevent Colorectal Cancer? A Signpost From Epidemiology.

J Natl Cancer Inst. 2004 Nov 17;96(22):1645-1647. No abstract

available.

PMID: 15547171 [PubMed - as supplied by publisher]

is a review of the paper. Both are pdf-available and the latter is

below.

It appears to me to put the paper in a good perspective. This was

not a

meta analysis of trials of selenium supplementation. Rather, the

full

paper being reviewed examined only for an epidemiological

relationship.

It is not even a prospective study meta analysis.

Adenomas represent and minority of colon cancers. The review below

to me presents a fairly harsh criticism of the results. I let the

review do the speaking below.

The limited epidemiology published heretofore on associa-tions

between selenium and colorectal adenomas or cancer has

been mixed, inconclusive, and based predominantly on small

studies. The epidemiology studies have been about evenly split

between those showing a statistically significant (1–5) or sug-gestive

(6,7) protective association and those showing a null

(8 –11) or suggestive harmful (12,13) association between sele-nium

and colorectal adenomas or cancer. The strongest (and

only clinical) previous support for a possible protective effect of

selenium intake came from a large, randomized controlled trial

of selenium in preventing nonmelanoma skin cancer (14). This

trial showed a statistically significant reduction of colorectal

cancer as a secondary endpoint (relative risk [RR] 0.58, 95%

confidence interval [CI] 0.18 to 0.95) that attenuated after

longer follow-up (RR 0.45, 95% CI 0.19 to 1.08) (15). A

marginally statistically significant overall reduction in colorectal

adenomas, which became stronger in association with the lowest

tertile of baseline selenium, was also observed again, as a

secondary endpoint in the trial (16).

In this issue of the Journal, s et al. report their pooled

analysis of three randomized clinical trials of dietary or nutrient

interventions in preventing colorectal adenomas (17). Individual-level

data from each of the Wheat Bran Fiber (WBF) Trial (18),

the Polyp Prevention Trial (PPT) (19), and the Polyp Prevention

Study (PPS) (20) were statistically reanalyzed to provide a more

precise estimate of the association between plasma selenium

concentration and adenoma risk than would be possible from

any of the three studies alone. None of the trials tested selenium

as an intervention. This pooled analysis, the largest epidemio-logic

investigation of the role of selenium in preventing colo-rectal

neoplasia, indicates that individuals in the highest quartile

of plasma selenium concentration (median 150 ng/mL) (plasma

collected at enrollment for PPT and PPS and 1 year after

randomization for WBF) had 34% lower odds (OR 0.66, 95%

CI 0.50 to 0.87, P trend .006) of developing a new adenoma

throughout the follow-up, compared with those in the lowest

quartile of plasma selenium (median 113 ng/mL).

Plasma selenium concentrations were not statistically signif-icantly

associated with adenoma size, location, or histology in

the pooled analysis. There was a trend, however, of fewer

advanced adenomas (1 cm in diameter and/or villous histol-ogy)

in persons within the highest quartile of plasma selenium.

This suggestion of activity in higher– cancer risk, advanced

adenomas supports the promise of selenium for reducing colo-rectal

cancer risk. The association of selenium with colorectal

cancer development (and mortality) will be assessed as a pre-specified

secondary endpoint of the Selenium and Vitamin E

[prostate] Cancer Prevention Trial (SELECT) currently under

way in more than 35 000 men (21).

Although the three source studies were mutually independent

and executed prior to the pooling project, they had similar

designs and outcomes that strengthened the pooled analysis. All

participants were at high adenoma risk after recent colonoscopic

adenoma resection; each of the three trials assessed colorectal

adenoma endpoints in over 85% of its patients, at year 1 and

either year 3 (WBF) or year 4 (PPT and PPS) after randomiza-tion;

and each intervention did not statistically significantly alter

the adenoma risk. The pooled analysis also had limitations,

however, which were adequately discussed by the authors and

included the possibility that some events (new adenomas) de-tected

at year 1 were not actual events but preexisting adenomas

missed at the index colonoscopy, varied blood collection times,

and different methodologies used to determine plasma selenium

concentrations.

The biologic plausibility of the pooled analysis and earlier

secondary clinical data is provided by consistent animal studies

showing the activity of selenium in colorectal neoplasia (22–28)

and by other data that address relevant selenium mechanisms.

Selenium has effects on key cellular events of tumorigenesis,

such as cell proliferation and apoptosis, and the possible com-plex

mechanisms underlying these effects are emerging in

increasing numbers (28 –30). Important relevant selenium mech-anisms

may involve gene promoter methylation and polyunsat-urated

fatty acid metabolism. Cancer cells commonly have aberrant

methylation patterns characterized by global hypomethylation

coupled with hypermethylation of CpG islands that appear to

contribute importantly to tumorigenesis (31). The enzyme DNA

cytosine methyltransferase 1 (DNMT1) is increased in tumor

progression in association with regional hypermethylation (31).

Preclinical studies suggest that selenium inhibits DNMT1 in

various cell lines, including the HCT116 and HT-29 human

colonic carcinoma cell lines (22,32–34).

Oxidative metabolism of the n-6 polyunsaturated fatty acids

arachidonic and linoleic acids contributes importantly to colonic

tumorigenesis (35), and current data suggest that selenium and

arachidonic and linoleic acid metabolism are linked in colonic

tumorigenesis. Selenomethionine inhibited growth in four hu-

man colon cancer cell lines (HCA-7, HT-29, Caco-pcDNA, and

Caco-60) in a time- and concentration-dependent manner (36).

Selenomethionine also decreased cyclooxygenase 2 (COX-2)

protein and prostaglandin E 2 (PGE 2 ) levels in HCA-7 cells, and

the growth inhibition effects of selenomethionine reversed with

PGE 2 treatment, suggesting that selenomethionine-induced cell

growth inhibition may be mediated in part by COX-2–depen-dent

mechanisms (36). The synthetic inorganic selenium com-pound

p-XSC (1,4-phenylene bis[methylene] selenocyanate) sta-tistically

significantly decreased the rate of small-intestine tumor

formation and colon tumors in APC min mice in a dose-dependent

manner and in association with statistically significantly lower

levels of membrane-bound -catenin and COX-2 activity in

polyps (37). Unlike selenomethionine in HCA-7 cells, p-XSC

did not affect COX-2 protein expression, suggesting that p-XSC

modulates COX-2 activity at the posttranslational rather than at

the transcriptional or translational levels. Docosahexaenoic acid

(DHA, an n-3 polyunsaturated fatty acid) appears to act syner-

gistically

with p-XSC in inhibiting COX-2 and the growth of

colon cancer cells in vitro (38).

Recent data indicate that the link between selenium and the

oxidative metabolism of linoleic and arachidonic acids extends

beyond COX-2 to the lipoxygenases (LOXs), another metabolic

enzyme family involved in colorectal tumorigenesis (39 –41).

15-LOX-1, which has anti– colorectal tumorigenic effects, and

COX-2, which has pro– colorectal tumorigenic effects (35), ex-ert

opposing effects on the selenoprotein thioredoxin reductase,

which is overexpressed in colorectal and other human cancers

(42) and inhibited in vivo by selenium supplementation (43), in

modulating cell growth and apoptosis (41).

In an intriguing study involving 11 patients with adenoma-tous

polyps, the expression of the selenoproteins gastrointestinal

glutathione peroxidase (GI-GPX) and selenoprotein-P (SelP),

which are expressed abundantly in the colorectal mucosa of

healthy individuals (44), were regulated differentially during

colorectal carcinogenesis (45). SelP mRNA expression was

markedly reduced, whereas GI-GPX mRNA expression was

increased in colorectal adenomas, compared with the expression

in adjacent normal mucosa (45). Future studies, including inves-

tigations

into the functional relevance of polymorphisms in the

SelP and GI-GPX genes (46), should assess a potential mecha-nistic

relationship of decreased SelP expression with reduced

GI-GPX expression in colorectal adenomas and whether levels

of locally available selenium may affect this relationship. One

interesting hypothesis is that the downregulation of SelP frees up

locally available selenium for binding to GI-GPX, thus strength-ening

a premalignant cell's defense against reactive oxygen

species (ROS)–inducible DNA damage.

The completed randomized, controlled trial of selenium men-tioned

earlier (14,15), which led to the present pooled analysis,

is far better known (to date) for a secondary reduction in prostate

cancer (30) than it is for its secondary data on a selenium-associated

reduction in colorectal cancer. Even though the colo-rectal

association attenuated over time (15), the pooled analysis

reinforces the earlier secondary clinical data on selenium in the

colon–rectum and should intensify interest in ongoing or

planned prospective translational trials of selenium, either alone

or combined with other promising agents, in preventing colo-rectal

adenomas. The correlative laboratory studies within these

trials will advance our understanding of colorectal carcinogen-esis

and selenium mechanisms (e.g., those discussed above),

activity, and pharmacogenomics—and will potentially lead to

the development of new, promising interventions. These trans-lational

trials, combined with the prespecified colorectal analy-ses

of SELECT, are likely to have the greatest impact on our

understanding of the public health role of selenium in colorectal

cancer prevention, since logistics make a phase III trial of

selenium or another agent highly unlikely in this setting.

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Cheers, Al.