anti-#cancer #selenium-cysteine compounds

. this an update of my knol page:
health/cancer prevention/se-msc/
anti-cancer selenium-cysteine compounds:
Se-methylselenocysteine is the most valuable form of selenium
. garlic grown in a selenium-rich medium
can produce Se-methylselenocysteine;
which has been demonstrated
in animal carcinogenesis bioassays
to be a potent cancer chemopreventive agent .
CAVEAT:
. I'm an evangelist for the dieticians I believe in,
but I'm not myself a certified dietician;
I'm simply practicing my freedom to speak
(often against the GRAINS of
the current dietary professionals) .
. don't even bother with checking my references:
you need to see a doctor or certified dietician
before acting on this advice .
. moreover, keep in mind that my highest calling
is to keep finding the most healthful advice;
so, please read with an eye toward helping me
in this open source self-help effort .

Contents [links to knol page]

• introduction

personal experience
Se-msc toxicity study

• the usual selenium, BC

sources of the best selenium
recipe for growing highest-yield selenized garlic

• published studies

supporting se-msc as cancer preventive
medical resources

introduction

. studies have found that certain forms of selenium (CAS#863394-07-4)
can, in animal carcinogenesis bioassays,
induce cancer-specific cell death (apoptosis)
which suggests it may be valuable for
cancer prevention in humans;
it's important that prevention not be confused with cure:
there is no evidence that se in any form
can knock down an advanced, solid tumour .

. the FDA has looked into
making anti-cancer health claims for Se
and has denied that request for unspecified forms of Se .
. in one of their reports, they assert:
"( Although selenium is known to be an essential mineral,
it can also be toxic. );
but, a major point of my evangelism for
 the SeMethyl-Se-Cysteine (se-msc) form of se
 is that it's uniquely non-toxic .

personal experience

. my daily intake is 5doses of  SeMethyl-Se-Cysteine;
and during bouts of thyroiditis in late 2010
 (after withdrawing from a thyroid suppressant)
I was taking 100 doses of se-msc (20mg)
(every other day to give my liver a break)
starting with 20, then 2*20 doses, ...
then 100 doses at a time by March 2011;
bought another 12pack in May, and August .
. I did that dozens of times from worrying that
my inflamed thyroid might be cancer prone .
. the se-msc form is so safe,
that one of the dogs taking the equivalent of 56doses
didn't even get any liver damage after an entire month;
I've taken about double that, but only occasionally .

. ironically, the evidence that se helps thyroiditis
is quite a bit stronger than that for cancer prevention;
-- if you were to ask  the NIH about it:
"( selenium is Possibly effective for...
Autoimmune thyroiditis (Hashimoto's thyroiditis).
Taking selenium along with thyroid hormone
might decrease antibodies in the body
that contribute to this condition.
Selenium might also help improve mood )
... possibly ineffective at preventing cancer ...
their refs:
# Selenium [for] Hashimoto's thyroiditis:
a systematic review and a meta-analysis.
Thyroid 2010;20:1163-73.
# (L-selenomethionine & Hashimoto's thyroiditis)
# (sodium selenite & autoimmune thyroiditis)

. concerning se-msc's potency as a cancer preventive,
keep in mind that se-msc can hardly be expected
to have an impact on cancer risk by itself:
 if the rest of your diet  doesn't
keep your hormones in the optimal zone,
then your extra insulin is cancer rocket fuel,
and high cortisol is suppressing the immune system .

keyword anti-apoptotic:
. toxic forms of selenium kill cells by bursting them;
this can be traumatic to other parts, like kidneys;
se-msc ideally kills cells by apoptosis;
. there is also some necrosis at mega doses:

Se-msc toxicity study

Food Chem Toxicol. 2008 March; 46(3): 1068–1078.
. To characterize Se-methylselenocysteine toxicity,
beagle dogs received daily doses of
0, 0.15, 0.3, or 0.6 mg/kg/day for 28 days.
animal doses on a human scale?
-- normal human dose is 0.2mg/day --
 100lb = 45.36 kg;
 160lb = 73 kg .
# high dose: 0.6 mg/kg/day:
 45.36kg => 27.22 mg/day = 136 doses;
 73kg => 43.8 mg/day = 219 doses;
# low dose: 0.15 mg/kg/day:
 45.36kg => 6.804 mg/day = 34 doses .
 73kg => 10.95 mg/day = 56 doses .
. one bottle of lef.org se-msc contains:
200microgram *100 capsules * mg/1000 mic = 20 mg .

. rats could take much more than dogs,
so I ignored the rat data;
the dogs were getting a lot of liver necrosis;
however, there were no female livers damaged
at any of the tested dosages .
. the study never found a dose at which
none of the male dogs avoided liver damage:
even at the lowest dose (50), only one male
escaped liver damage ( midzonal necrosis ).
. a few high-dose males also suffered from
peliosis hepatis [blood-filled cavities in liver]
and midzonal degeneration [massive necrosis]
--
not unlike alcoholic damage:
a few binges won't drop a liver;
but a month-long intoxication
can be compared to overtraining .
. I've had dozens of 100-dose uses in the past year,
but I rarely abuse in my liver in other ways
(alcohol, fructose, other drugs, ..)
and, I eat a lot of eggs (liver protection).

I recently had a liver test come back normal;
however, liver poisoning by se-msc
isn't causing the sort of blood enzyme changes
that usually alert one to liver intoxication .
. none if the liver damage was detectable
until autopsy .

the usual selenium, BC

. a primary reason for not getting sufficient se
naturally in the diet
is that there's often not much of it in the
 synthetic fertilizer typically used in non-organic farming;
and, while animals can't thrive without it,
(thus insuring that farmers give se supp's to their animals)
it tends to collect only in certain organs
-- not the muscle portion of the animal that we prefer .

. the form commonly sold as a supplement to humans
 is se-methionine, an organically bound form
that is touted as less toxic than
inorganics such as selenate or selenite .
. in fact, it's just as toxic when finally metabolised
( it may never be metabolised, though;
as the body confuses it with sulphur
when building methionine for proteins
-- this confusion can have adverse consequences
on immune function )

. of the fraction that is metabolised,
it gets turned into the same hydrogen sulfide
that makes selenate and selenite toxic .
. it's also touted as being more bioavailable,
but that is just confusion about what to test for:
a good test is how much se raises glutathione peroxidase;
a useless test just sees how much se is in the blood .

. coincidentally, se-methionine is very cheap to make
as it comes from yeast,
which we have a lot of experience with cultivating,
whereas, the form that prevents cancer 
-- Se-methylselenocysteine (se-msc) comes from garlic
 (the processing of which is unfamiliar,
and likely more expensive) .
. se-yeast is not an economical way to promote apoptosis;
and while some studies suggested it prevented cancer,
this would simply be the effect of correcting a selenium deficiency;
se-yeast is no more effective or less toxic
than the much cheaper selenate;
except perhaps in an overdose situation .

sources of the best selenium

. the following are varous sources of Se-cysteine (Se-methylselenocysteine);
 both on-the-shelf products from various sources,
and a recipe for making it yourself . ]

se-msc (Se-methylselenocysteine)

lef.org 200 mcg, 100 capsules (20mg se) / $4.80
[2011.9.18: sale price?]
amazon.com 200 mcg, 100 capsules (20mg se) / $7.66 [2011.9.18]
iherb.com 200 mcg, 100 capsules (20mg se) / $9 [2011.9.18]

wholesale sources:

eburon-organics Se-Methylseleno-L-cysteine (cas#26046-90-2)
sigmaaldrich Se-(Methyl)selenocysteine hydrochloride
(cas#26046-90-2)  (cas#863394-07-4)
Selenium Technologies Inc (806) 784-0104

se-cysteine from garlic

 { gamma-Glutamyl-Se-methylselenocysteine
, γ-glutamyl-Se-methyl-selenocysteine}
{SelenoForce™, GarliSelect®} 100caps * 100mg * 1000 ppm se  (10mg se) / $9.50[2011.9.18]

recipe for growing highest-yield selenized garlic

. Sabinsa appears to have confidence in hydroponics
while Danish Institute for Food and Veterinary Research
uses symbiotic fungus .
. in any case,
the selenate is added when the bulbs are starting to mature,
and not a lot before,
 because selenate is converted by bacteria into something useless,
so you don't want it just sitting in the water
if the garlic isn't ready to absorb it .

a source for selenate

All World Sci & Chem, 5515 186th Pl SW, Lynnwood, WA. 98037
. the above outlet sells to those without a business license;
by phone (1-800-289-6753)
one of their suppliers has an online catalog
to help you select the product number:
(the prices you see below are wholesale -- expect to pay double that)
spectrumchemical.com/ 800-813-1514.
Sodium Selenate, Anhydrous, Crystal cas#13410-01-0 (Na2O4 Se )
S1428-100GMGL  100 g   EA    $148 [2011.9.18]
S1428-500GMGL   500 g  EA    $494 [2011.9.18]
Sodium Selenate, Decahydrate cas#10102-23-5(Na2O4 Se 10 H2O)
S1430-100GM      100 g    EA     $217 [2011.9.18]
S1430-500GM      500 g    EA      $832 [2011.9.18]

se-garlic grown with symbiotic fungi (mycorrhiza)

Uptake and speciation of selenium in garlic cultivated in
soil amended with symbiotic fungi (mycorrhiza) and selenate
Analytical and Bioanalytical Chemistry Volume 385, Number 6 / July, 2006

. addition of mycorrhiza to the natural soil
increased the selenium uptake by garlic tenfold
to 15 μg g−1 (dry mass) -- one part per thousand.
. analysis showed that
 γ-glutamyl-Se-methyl-selenocysteine amounted to 2/3,
 whereas methylselenocysteine, selenomethionine
and selenate each amounted to a few percent
of the total chromatographed selenium in all garlic samples.
 Se-allyl-selenocysteine and
Se-propyl-selenocysteine,  which are selenium analogues of
biologically active sulfur-containing amino acids
 known to occur in garlic,
 were searched for but not detected in any of the extracts.
[where was the other 1/3?
in γ-glutamyl-Se-methyl-selenomethionine ? ]

interesting trivia about {SelenoForce™, GarliSelect®}

-- won the 2006 NBJ Business Summit's Product Merit Award.

Rebranded SelenoForce®
. while Sabinsa tried to promote GarliSelect® as a
selenium supplementation
most of the customers saw GarliSelect® as a garlic product;
and, seeing that enriched garlic has a completely different
connotation to the customers,
GarliSelect® was rebranded as SelenoForce®.

{SelenoForce™, GarliSelect®} is a selenium-enriched garlic product
 manufactured by a patent pending soilless culture process.
Garlic bulbs are naturally enriched with a unique composition of
organic selenium compounds for nutritional supplementation,
using a proprietary hydroponics method.
The selenium enriched bulbs are dried, powdered and standardized,
to yield SelenoForce™ containing 1000 ppm selenium, (1mg/g)
in bioavailable organic form, in a base of natural garlic powder .

Sabinsa Corporation

* Utah Office; 750 South Innovation Circle; Payson, UT 84651 (USA)

Tel: (801) 465-8400 sabinsautah@utw.com

* Corporate Office; 70 Ethel Road West, Suite 6; Piscataway, NJ 08854 (USA)

Tel: (732) 777-1111 info@sabinsa.com

patents
Manufacturing processes for Se-Methyl-LSelenocysteine 
US 6,794,537      MSC
Composition and methods containing
bioavailable Se-methyl-L-Selenochysteine
for human and veterinary use as a nutritional supplement 
US 6,982,273      MSC
Compositions and Methods containing Allium Sativum Linn,
(Garlic) naturally enriched with organic selenium compounds
for nutritional supplementation
US 7,014,874 B1     GarliSelect®
se library

published studies

supporting se-msc as cancer preventive

se-msc needs help against Survivin
(apoptosis inhibitor)

BMC Cancer. 2010; 10: 418.
Survivin is a member of the protein family
that is an inhibitor of apoptosis (IAP)
that is expressed in the majority of human tumours
including prostate cancer,
but is barely detectable in terminally differentiated normal cells.
Downregulation of survivin could
sensitize prostate cancer cells to
chemotherapeutic agents in vitro and in vivo.
Several studies have shown that selenium compounds
inhibit the growth of prostate cancer cells.
The objective of this study is to investigate whether
survivin gene silencing
in conjunction with selenium treatment
could enhance the prostate cancer therapeutic efficacy
and to elucidate the underlying mechanisms.

Several case control studies have demonstrated
an inverse correlation between serum selenium level
and the risk of developing prostate cancer
[ Plasma selenium level before diagnosis
and the risk of prostate cancer development.
J Urol. 2001;166:2034–2038.
Association between alpha-, gamma-tocopherol, selenium,
and subsequent prostate cancer.
J Natl Cancer Inst. 2000;92:2018–2023.
Serum selenium and subsequent risk of prostate cancer.
Cancer Epidemiol Biomarkers Prev. 2000;9:883–887.]

The Nutritional Prevention of Cancer (NPC) trial
demonstrated that supplementation of selenium,
in the form of selenized yeast,
could reduce the incidence of prostate cancer by 50% .
[ Effects of selenium supplementation for cancer prevention
in patients with carcinoma of the skin.
A randomized controlled trial. 
Nutritional Prevention of Cancer Study Group.
JAMA. 1996;276:1957–1963.
Selenium supplementation, baseline plasma selenium status
and incidence of prostate cancer: an analysis of
the complete treatment period of the NPC Trial.]
BJU Int. 2003;91:608–612.

Although the interim analysis of the SELECT
(Selenium and Vitamin E Chemoprevention Trial)
indicated no reduction in prostate cancer risk
associated with selenium supplementation
[JAMA. 2009;301:39–51.]
the finding should not be simply interpreted as
selenium is ineffective against prostate cancer.
In the Discussion,
we provide several potential explanations
for the discrepancy of the findings in
SELECT and the NPC trial.
The negative SELECT finding makes it more important
and imperative to study the efficacy of
new selenium compounds
[ Activity of methylated forms of selenium in cancer prevention.
Cancer Res. 1990;50:1206–1211.
Chemical form of selenium, critical metabolites,
and cancer prevention.
Cancer Res. 1991;51:595–600.
Lessons from basic research in selenium and cancer prevention.
J Nutr. 1998;128:1845–1854.]
including the compounds used in the study for
prostate cancer intervention:
methylseleninic acid (MSA)
and methylselenocysteine (MSC),

MSA and MSC were obtained from PharmaSe (Lubbock, TX).
PharmaSe, Inc. [info according to fda]:
Julian Spallholz, Ph.D. President and CEO
3416 Knoxville Avenue; Lubbock, Texas 79413
New Dietary Ingredient: L-Se-methylselenocysteine
Date Received by FDA: December 6, 1999

. Several potential reasons have been discussed
to explain the discrepancy of the findings
in SELECT and the NPC trial.
One important consideration is the baseline selenium level.
The NPC trial showed that the protective effect of selenium
was limited to patients [with selenium deficiency] .
[Cancer Epidemiol Biomarkers Prev. 2002;11:630–639.]
The average baseline selenium level in SELECT
was much higher than that observed in the NPC study.
In fact, 78% of men in SELECT had baseline selenium
above the range that selenium provided protection
in the NPC trial (<121.6 ng/ml) .
[ SELECT. JAMA. 2009;301:39–51 ]
Another important consideration is how
selenium exerts its anticancer activity.
... selenium might only be effective
in selected subsets of men with
lower selenium levels at baseline.
The formulation and dose of selenium used in the SELECT study
have also been hot topics of debate.
The compounds used in the current study, MSA and MSC,
are monomethylated forms of selenium
-- very different from selenomethionine,
the formulation used in the SELECT.
MSA and MSC can be easily converted to methylselenol,
which is considered to be the critical metabolite
for the anticancer activity of selenium
[ Lessons from basic research in selenium and cancer prevention.
J Nutr. 1998;128:1845–1854
In vitro and in vivo studies of methylseleninic acid:
evidence that a monomethylated selenium metabolite
is critical for cancer chemoprevention.
Cancer Res. 2000;60:2882–2886.]

Studies published prior to and after
the start of the SELECT study
have showed that MSA and MSC have
stronger anticancer activities than selenomethionine
[ Chemical speciation influences comparative activity of
selenium-enriched garlic and yeast in mammary cancer prevention.
J Agric Food Chem. 2000;48:2062–2070.
Superior in vivo inhibitory efficacy of methylseleninic acid
against human prostate cancer over 
selenomethionine or selenite.
Carcinogenesis. 2008;29:1005–1012
Se-methylselenocysteine: a new compound for
chemoprevention of breast cancer.
Nutr Cancer. 2001;40:12–17.]

Several studies have shown that selenium induces
growth arrest and cell death in prostate cancer cells
and inhibits the growth of prostate cancer xenografts
[studies of animal implanted with a human cancer]
[ Methylseleninic acid sensitizes prostate cancer cells
to TRAIL-mediated apoptosis.
Oncogene. 2005;24:5868–5877.
Synergy between selenium and vitamin E
in apoptosis induction ... in human prostate cancer.
Cancer Res. 2003;63:6988–6995.
Prostate specific antigen expression
is down-regulated by selenium
through disruption of androgen receptor signaling.
Cancer Res. 2004;64:19–22.
Androgen receptor signaling intensity
is a key factor in determining the sensitivity
of prostate cancer cells to selenium ...
Mol Cancer Ther. 2005;4:1047–1055 ]

The insensitivity of some cells to selenium
could be related to its inability to
suppress survivin expression in these cells.
In support of the notion,
we found that the effect of selenium was
greatly enhanced when survivin expression was silenced.

Indeed, in a [rodent implanted with a cancer],
survivin knockdown in combination with [se-msc]
stopped tumor growth completely.
. survivin knockdown greatly enhanced the efficacy of
combination therapy by MSA and paclitaxel,[chemotherapy]
converting the interaction between these two agents
from antagonistic to synergistic .

se-msc cancer prevention by altering
Circadian Rhythm

Cancer Prev Res (Phila). 2008 July; 1(2): 119–127.
Chemopreventive Doses of Methylselenocysteine
Alter Circadian Rhythm in Rat Mammary Tissue
. in several breeds of female rat,
dietary MSC (Methylselenocysteine) inhibits
NMU-induced mammary tumour initiation .

. circadian clock genes play a role in
normal differentiation of mouse mammary gland,
so, the disruption of circadian genes
may be increasing risk of mammary tumours .
. some 1960's studies showed that
disruption of circadian endocrine rhythm
accelerates breast epithelial stem-cell proliferation,
induces mammary gland development,
and increases the formation of
spontaneous mammary tumors in rodents .

. a core circadian gene, Per2,
was shown to have tumor suppressor activity.
. estrogen is a promoter of mammary carcinogenesis
in cells expressing ERα (estrogen receptor alpha)
but, Per2 binds to the ERα, and thereby enhancing
 degradation of the ERα protein .

. we found that the chemopreventive levels of MSC
regulated the expression of genes involved in
circadian rhythm in mammary tissue.
Moreover, the Se-induced increases in circadian genes
were suppressed in all tumors that arose in
all NMU-treated animals maintained on the Se enriched diet.
Given the role of Per2 in tumor suppression,
we speculated that selenium may exert its chemopreventive effects
by upregulating Per2, which may subsequently
regulate DNA-damage responses,
cell proliferation and apoptosis  .

methylselenocysteine &
irinotecan's therapeutic index

Biochem Pharmacol. 2007 May 1; 73(9): 1280–1287.
. irinotecan is a cancer chemotherapy;
the therapeutic index measures toxicity
since the cancer-curing dose
can be higher than the lethal dose .
. in this study, se-msc (C4H9NO2Se·HCl from Sigma)
was shown to protect mice from irinotecan toxicity
for the LD50 dose (where 50% of group dies).
. msc also dramatically raised irinotecan's cancer cure rates;
but this depended greatly on the type of cancer .

introduction to msc:
. most anticarcinogenic actions of Se
[beyond those from correcting deficiencies]
involve precursors of methylselenol (CH3SeH);
one is Methylselenocysteine (MSC)

. animal studies and epidemiological work
indicate that Se also can reduce cancer risk
[ Lessons from basic research in selenium and cancer prevention.
Journal of Nutrition. 1998;128:1845–54.
Chemopreventive agents: selenium.
Pharmacology & Therapeutics. 1998;79:179–92]

Several mechanisms have been proposed
for this anti-carcinogenic action:
# regulation of p53 by the Ref1 dependent redox mechanism .
[ Converting p53 from a killer into a healer.
Nature Medicine. 2002;8:1196–8.
Selenomethionine regulation of p53
by a Ref1-dependent redox mechanism.
Proc Nat'l Acad Sci. 2002;99:14548–14553. ]
# induction of apoptosis
associated with increased phosphorylation of p53 MAPK
and dephosphorylation of Akt and ERK-1 and ERK-2
[ .. selenium-induced growth inhibition in human breast cells ...
Cancer Research. 2002;62:708–14.
... selenium-induced growth arrest in human prostate cancer cells ..
Cancer Research. 2003;63:52–9.
Methylselenocysteine modulates proliferation and apoptosis biomarkers ...
Anticancer Research. 2001;21:863–7.]
# inhibiting vascular endothelial growth factors (VEGFs)
[ ... growth inhibitory effects of selenium.
Biochemical Pharmacology. 1995;50:213–9.]

Although most preclinical chemoprevention studies
 have used inorganic sodium selenite,
the most informative human trial, Clark et al,
used a Selenium-enriched yeast.
[ ... Nutritional Prevention of Cancer Study Group.
JAMA. 1997;276:1957–1963. Erratum in: JAMA 1997;277(19):1520]

Although yeast Se is thought to be 80% se-methionine,
other forms of yeast Se have been reported,
such as se-cysteine, se-msc, and some unidentified species .
In the selenium intervention trial by Clark et al.,
administration of 200 μg of yeast Se was shown to
reduce the incidence of several types of cancer .
[ Natural agents in the prevention of cancer.
Part 1: human chemoprevention trials.
Alternative Medicine Review. 2001;6:7–19.]

. most epidemiological studies, too,
are showing higher Se levels are reducing cancer risk .
[ Prediagnostic serum selenium and risk of cancer.
Lancet. 1983;2:130–4.
Selenium and cancer: some nutritional aspects.
Nutrition. 2000;16:376–83.]

Based on these data, the SELECT study was initiated
(Selenium and Vitamin E Cancer Prevention Trial)
to determine the effects of Se and vitamin E
in preventing prostate cancer
[ SELECT: the next prostate cancer prevention trial.
Selenum and Vitamin E Cancer Prevention Trial.
Journal of Urology. 2001;166:1311–5.]

L-selenocysteine-prodrug approach

for cancer chemopreventive activity without toxicity.
Mutat Res. 2007 March 5; 627(2): 136–145.
Seleno-amino acid derivatives have  been investigated
 for cancer chemopreventive properties
but were not effective against all classes of mutagens tested .
[ four chemical forms of selenium ...
Cancer Lett. 1990;50:39–44.
Chemopreventive activity of selenocysteine ...
J Biochem Mol Toxicol. 2005;19:396–405.
cancer chemoprevention by inorganic and organic selenium: ...
Carcinogenesis. 1987;8:1763–1766.
Chemical form of selenium, critical metabolites, and cancer prevention.
Cancer Res. 1991;51:595–600.
Comparison of selenium and sulfur analogs in cancer prevention.
Carcinogenesis. 1992;13:1167–1170.
Chemoprevention of mammary cancer with Se-allylselenocysteine ...
Anticancer Res. 1999;19:2875–2880.]

. Se-msc was not effective against
2-amino-3-methylimidazole[4,5]quinoline
[ Antimutagenic activity of selenium-enriched green tea
toward the heterocyclic amine ...
Biol Trace Elem Res. 2002;86:177–191]
[but, Se-msc was at least non-toxic
in much higher doses than other se forms,
so, they set about trying new drugs that were
based on that chemical ....]
An L-selenocysteine-prodrug approach was conceived
as a way to non-toxically supply the larger selenium doses
needed by cancer chemopreventive activity.
[ Selenazolidines as novel organoselenium delivery agents.
Bioorg Med Chem Lett. 2001;11:2911–2915.]

. we investigated the antimutagenic properties of
selenazolidine-4-(R)-carboxylic acid (SCA)
and six derivatives
[ variants of SCA that changed things at
the molecule's R-location .]
All seven organoselenium compounds,
were found to have antimutagenic activity.
... there was only 17-18% difference
in their antimutagenic effectiveness
against either B[a]P or acridine orange.
However, the 7 varieties were best at
different types of cancers:
eg, 2-Methyl.SCA was for B[a]P;
2-Cyclohexyl.SCA was for acridine orange.

Status of selenium in prostate cancer prevention

Br J Cancer. 2004 July 19; 91(2): 195–199.
.  a large number of animal studies
have consistently found Se supplements to be
effective in reducing experimental carcinogenesis
in virtually every tumour model investigated
[ Combs GF, Jr, Gray WP. Chemopreventive agents: selenium.
Pharm Exp Ther. 1998;79:179–192..
Combs GF, Jr, Lü J. Selenium as a cancer preventive agent Selenium:
Molecular Biology and Role in Health 2001. (pdf of chapter))

The NPC(nutritional prevention of cancer) Trial:
. that study reported that 10 years of supplementation,
with a daily dose that [merely corrected deficiencies],
could substantially reduce cancer risks .
(Clark et al, 1996)
. analyses of the complete trial results
were presented only recently
(Duffield-Lillico et al, 2002, 2003a, 2003b;
Reid et al, 2002).

. it tested the hypothesis that a dose of Se
 sized to prevent deficiency (200μg/day)
-- in a variety of forms determined by Se-enriched yeast
(typicaly 80% se-methionine) --
could reduce the rate of a certain cancer
(recurrent nonmelanoma skin cancer
in a high-risk group of 1312 older Americans
living along the eastern seaboard)
They showed instead significant reductions in
risks to total cancer incidence (risk ratio (RR)=0.63),
total cancer deaths (RR=0.50)
and to the incidences of carcinomas at sites
other than skin, (RR=0.55) namely,
lung (RR=0.54), prostate (RR=0.37),
and colon–rectum (RR=0.42) .

metabolism of selenium (arrows show conversion steps):

(AC = anti-cancer in cells or animals)
Na2SeO4 selenate AC(toxic) ->
Na2SeO8 selenite AC(toxic) ->
GSSeSG, selenodiglutathione AC; ->
GSSeH, selenoglutathione; ->
H2Se, hydrogen selenide AC(very toxic);

SeMet, selenomethionine; ->
SeCys, selenocysteine; ->
H2Se, hydrogen selenide AC(very toxic) ->
  (either CH3SeH: Se-msc
or SeO2, selenium dioxide;
or the seCys proteins, which include:

GPXs, glutathione peroxidases;
TDIs, iodothyronine 5′-deiodinases;
TRs, thioredoxin reductases,
P, selenoprotein P;
W, selenoprotein W).

. this chain is reversable:
CH3SeH: Se-methylselenocysteine. ->
CH3SeH, methylselenol; ->
( CH3SeCH3, dimethylselenide AC; -> breath excretion
or (CH3)3Se+, trimethylselenonium AC -> urine excretion
) .
Hydrogen selenide's oxidative metabolism
produces superoxide anion (O2−)
and hydrogen peroxide (H2O2),
which appear to induce apoptosis
[ forms that metabolise to hydrogen selenide
also result in  necrosis -- entails liver damage .]

methylselenol (CH3SeH) [as from se-msc]
provides anti-cancer potential via:
# arrests cells in the G1 or early S phase
to induce apoptosis
# inhibits CDK2 and protein kinase C (PKC)
(the cell cycle regulatory enzymes).
# inhibits matrix metallo.protein.ases
in vascular endothelial cells
# inhibits vascular endothelial growth factor
(tumour-initiated blood vessel growth).

. the CH3SeH is excreted too quickly to be therapeutic;
so, one of its precursors are needed:
# selenobetaine (CH3SeO2H)
#  [se-msc] methyl-selenocysteine (CH3SeCys)
-- are each more efficacious than selenite
in reducing a rodent mammary cancer risk .

Duffield-Lillico et al (2003a), (2003b)
found Se-enriched baker's yeast
reduced prostate cancer risks
only in [those who were selenium deficient] .
. they suggest a target blood Se level
of at least 106ngm/l (1.35nmol/l)
and, perhaps, 123ngm/l (1.58nmol/l) plasma.
Although the serum/plasma Se concentrations
of adequately nourished humans
range 70–200ngm/l (0.9–2.55nmol/l),
almost all of that Se is protein-bound
and not readily available for uptake by cells .
Higher Se doses appear to be needed
to make use of the methylselenides
that are rapidly excreted from the body.
[. this is where se-msc can be useful, I'm betting,
with my occasional 100-dose treatments .]

Anti-cancer Agent from Garlic

Characterization of the Biological Activity of
gamma-Glutamyl-Se- methylselenocysteine:
A Novel, Naturally Occurring Anticancer Agent from Garlic
[CANCER RESEARCH 61, 2923–2928, April 1, 2001]
. gamma-Glutamyl-Se-methylselenocysteine (GGMSC)
has recently been identified as the major Se compound
 in natural garlic and selenized garlic.
Our working hypothesis is that GGMSC serves primarily as a
carrier of Se-methylselenocysteine (MSC),
which has been demonstrated in past research
to be a potent cancer chemopreventive agent
in animal carcinogenesis bioassays.
The present study was designed to examine
the in vivo responses to GGMSC or MSC
using a variety of biochemical and biological end points,
including (a) urinary Se excretion as a function of bolus dose;
(b) tissue Se accumulation profile;
(c) anticancer efficacy;
and (d) gene expression changes as determined by cDNA array analysis.
Our results showed that like MSC, GGMSC was well absorbed p.o.,
with urinary excretion as the major route for eliminating excess Se.
When fed chronically, the profile of Se accumulation in various tissues
was very comparable after treatment with either GGMSC or MSC.
In rats that had been challenged with a carcinogen,
supplementation with either GGMSC or MSC resulted in
a lower prevalence of premalignant lesions in the mammary gland,
and fewer mammary carcinomas
when these early lesions were allowed to progress.
More importantly,
we found that a short term GGMSC/MSC treatment schedule of
4 weeks immediately after carcinogen dosing
was sufficient to provide significant cancer protection,
even in the absence of a sustained exposure
past the initial 4-week period.
. we further discovered that the gene expression changes
induced in mammary epithelial cells of rats given either GGMSC or MSC
showed a high degree of concordance.
On the basis of the collective biology, biochemistry,
and molecular biology data,
we conclude that GGMSC is an effective anti-cancer agent
with a mechanism of action very similar to that of MSC.

Prior to its detection in selenized garlic,
GGMSC has been reported to be present in
Astragulus bisulcatus (a Se accumulator weed)
and Melitotus indica L.
(a Se-tolerant grassland legume, yellow sour clover)
Neither is a marketable food product
commonly consumed by humans.
The discovery of GGMSC as a naturally occurring
phytochemical in garlic,
coupled with the early work showing that
selenized garlic has much higher anticancer activity
than regular unenriched garlic,
provided the impetus to the present investigation
of the bioactivity of GGMSC.
Structurally,
there is one distinctive feature about this dipeptide.
Most peptide bonds involving glutamic acid are of the alpha-variety.
With GGMSC, the selenoamino acid is linked to the
gamma-carboxyl group of glutamic acid
Thus, GGMSC is unlikely to be acted on by aminopeptidases,
which are known to liberate an amino acid via scission of the
peptide bond adjacent to the free amino group.
We found that GGMSC, when given as an acute bolus dose,
is quantitatively absorbed from the gastrointestinal tract like MSC.
Urinary excretion is apparently a major route for
eliminating the excess Se from GGMSC.
If biliary excretion is to play an important role in the
metabolic disposition of GGMSC,
we would have seen a marked increase in fecal Se on the 2nd day.
This is clearly not the case.
In fact,
the amount of Se recovered in two consecutive
24-h urine samples of rats given GGMSC
was strikingly similar to that of rats given MSC.
We also found that in rats fed either a GGMSC diet
or a MSC diet for 1 month,
the tissue Se accumulation profile was comparable
between the two groups .

It is noteworthy that treatment with GGMSC or MSC
for just 1month
was able to provide a lasting protection
against subsequent cancer development.
For cells that have sustained irreparable DNA damage,
apoptosis is a means for their elimination.
The appearance of a defined premalignant lesion (e.g., an IDP)
is the net result of cell proliferation minus cell death.
Thus a down-sizing in the population of premalignant lesions
can in effect be achieved by enhancing cell death
either in the absence of
 or in addition to decreasing cell proliferation.
We have preliminary data indicating that MSC is able to induce
 apoptosis in IDP cells in vivo .
We expect GGMSC to be just as effective as MSC in
increasing apoptosis,
although this remains to be confirmed.

medical resources

testing for se-msc

Dietary supplementation with selenomethylselenocysteine [se-msc]
produces a differential proteomic response.
The Journal of nutritional biochemistry 2009,Oct,01;20(10):791-9;

Selenium intake has been traditionally quantified as
glutathion peroxidase activity
or selenium concentration in blood or tissues.
Effect of se-msc on the blood plasma proteome in rats
was investigated in order to detect protein abundance differences
between experimental ([high-dose se-msc])
and controls (minimum selenium dose and sodium selenate)
However, these indexes [of blood plasma proteome]
 do not reflect organic selenium intake.
Four proteins were found to increase their abundance
specifically in response to [the se-msc]:
haptoglobin, alpha-1-antitrypsin,
apolipoprotein E, -- no different than with sodium selenate
transthyretin -- no different than with sodium selenate.
We postulate that these proteins are potential biomarkers of
chemoprotective [se-msc forms of] selenium intake.

Selenium. Nutritional, toxicologic,
and clinical aspects

West J Med. 1990 August; 153(2): 160–167.
. because of the growing public interest in selenium
as a dietary supplement
and the occurrence of environmental selenium contamination,
medical practitioners should be familiar with
the nutritional, toxicologic, and clinical aspects
of this trace element .
[. deals mostly with toxic forms of se .]