2011-09-19

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]

personal experience
Se-msc toxicity study
sources of the best selenium
recipe for growing highest-yield selenized garlic
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 .]