Avemar and Lymphoma

Oncol Rep. 2009 Mar;21(3):787-91.
 
    Saiko P, Ozsvar-Kozma M, Graser G, Lackner A, Grusch M, Madlener S, Krupitza G,     Jaeger W, Hidvegi M, Agarwal RP, Fritzer-Szekeres M, Szekeres T.

    Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, General Hospital of Vienna, A-1090 Vienna, Austria.

    Avemar (MSC) is a nontoxic fermented wheat germ extract, which has been shown to significantly improve the survival rate in patients suffering from various malignancies. We investigated its effects in sensitive and 5-FdUrd/Ara-C cross-resistant H9 human lymphoma cells. After 48 and 72 h of incubation, Avemar inhibited the growth of sensitive H9 cells with IC50 values of 290 and 200 microg/ml, whereas the growth of 5-FdUrd/Ara-C cross-resistant H9 cells was attenuated with IC50 values of 180 and 145 microg/ml, respectively. Treatment with 300 microg/ml MSC for 48 h caused dose-dependent induction of apoptosis in 48% of sensitive H9 cells. In cross-resistant H9 cells, incubation with 200 microg/ml Avemar for 48 h led to 41% of apoptotic tumor cells. Growth arrest of sensitive H9 cells after exposure to various concentrations of MSC occurred mainly in the S phase of the cell cycle, thereby increasing the cell population from 54 to 73% while depleting cells in the G0-G1 phase from 40 to 19%. Growth arrest in cross-resistant H9 cells occurred also mainly in the S phase, increasing the cell population from 45 to 68% while depleting cells in the G0-G1 phase from 45 to 31%. As MSC treatment likely overcomes 5-FdUrd/Ara-C resistance, further investigations to elucidate the exact mechanisms are warranted. We conclude that Avemar exerts a number of beneficial effects which could support conventional chemotherapy of human malignancies.

    PMID: 19212640 [PubMed - indexed for MEDLINE




The Cell Cycle and Cancer Drugs
Our body's cells -- both normal and cancerous -- make more cells like them through a series of four major steps often depicted as a circle, called the cell cycle.  Most cancer drugs work by interfering with a specific step in the cell cycle, because if the cell cannot make it through the first three steps of the cell cycle, it cannot divide to make two more cells just like it in the fourth step of the cell cycle -- cell division.  In that case, it usually will die, subtracting one cancer cell from the body's burden, and preventing two more from being created.
 
How Cancer Drugs Work -- Or Don't
 
The reason one cancer drug may work well on a particular cancer while a different drug may not is because drugs each typically have different ways of killing cancer cells, referred to as a drug's mechanism of action, and various cancers are more or less vulnerable to being attacked in any particular way.
 
If a patient's cancer doesn't respond to treatment with a particular drug, the cancer is said to be resistant to that drug, and doctors will usually select another drug that may work better.
 
The cancer drug 5-FdUrd is an improved version of the cancer drug 5-FU.  It makes a sort of "counterfeit" uracil, a substance needed to make new RNA necessary for cell division. When cells try to use the counterfeit uracil, it doesn't work, so the cells can't make RNA.  The cell quits moving through the cell cycle, and so it dies.
 
Ara-C is a cancer drug made to resemble a protein cells need to make DNA, but which won't work for that purpose.  When cells take it up, they can't make DNA.  Unable to make DNA, they can't move further through the cell cycle, and they die.
 
Sometimes, a patient's cancer will be resistant to not one, but two different cancer drugs that work in two different ways.  Such a cancer is said to be "cross-resistant", meaning neither drug works, alone or in combination. A cancer like that can be very difficult to treat successfully.
 
Lymphoma is a cancer that starts in lymphocytes, white blood cells of the immune system.  Among lymphoma cell types, some called H9 human lymphoma cells can be killed by FdUrd or Ara-C.  But if they are cross-resistant to both drugs, the H9 lymphoma cells are an example of cancer cells very hard to kill.
 
However, in a recent research study of H9 cells cross-resistant to both drugs, an international team of cancer scientists working together from universities in the US and Europe found that a natural substance earlier shown effective against several other kinds of cancer killed cross-resistant H9 lymhoma cells when neither of the two conventional cancer drugs used against them in the study could do so. 

DHEA and Vaginal Atrophy

The use of Intravaginal DHEA as a suitable treatment for women who suffer from vaginal atrophy and have a history of cancer. These women typically cannot use estrogen-related hormones to provide relief from a very uncomfortable condition that affects about 5% of menopausal women. Besides hampering intercourse vaginal atrophy can progress as to cause pain with common activities such as walking. This group studied the effect that DHEA had on vaginal tissue integrity when applied intravaginally. They found that it improved vaginal skin tone by causing a dramatic increase in Parabasal cells, an increase in superficial  cells and an impressive lowering of ph. Further study showed that the intravaginal DHEA was able to” improve sexual function and caused no or minimal changes in serum sex steroid levels”. This is important because changes in serum sex steroid levels are the concern of women who have had cancer and it is these changes in serum sex steroid levels that prevents women with a history of cancer from using estrogen.




Menopause. 2009 May 8. [Epub ahead of print]
    Intravaginal dehydroepiandrosterone (Prasterone), the physiological and a highly efficient treatment of vaginal atrophy.
    Labrie F, Archer D, Bouchard C, Fortier M, Cusan L, Gomez JL, Girard G, Baron M, Ayotte N, Moreau M, Dubé R, Côté I, Labrie C, Lavoie L, Berger L, Gilbert L, Martel C, Balser J.

    From the 1Laval University Hospital Research Center and Laval University, Quebec, Canada; 2Endoceutics Inc., Quebec City, QC, Canada;3Clinical Research Center, Eastern Virginia Medical School, Norfolk, VA; 4Clinique de Recherche en Santé des Femmes, Quebec City, Canada; 5Diex Recherche Inc., Sherbrooke, QC, Canada; 6Rapid Medical Research Inc., Cleveland, OH;7Clinique Gynécologique, Shawinigan, Canada; 8Montreal Clinical Study Center, Montreal, Canada; 9Centre Hospitalier affilié Universitaire de Québec, Quebec City, Canada; 10McGill University Health Center, Royal Victoria Hospital, Montreal, QC, Canada; and 11Veristat Inc., Boston, MA.

    OBJECTIVE:: Because the secretion of dehydroepiandrosterone (DHEA), the exclusive source of sex steroids in postmenopausal women, is already decreased by 60% and continues to decline at the time of menopause, the objective of this study was to examine the effect of intravaginal DHEA on the symptoms and signs of vaginal atrophy. METHODS:: This prospective, randomized, double-blind and placebo-controlled phase III clinical trial studied the effect of Prasterone (DHEA) applied locally in the vagina on the signs and symptoms of vaginal atrophy in 216 postmenopausal women. RESULTS:: All three doses (0.25%, 0.5%, and 1.0%) of DHEA ovules applied daily intravaginally induced a highly significant beneficial change in the percentage of vaginal parabasal and superficial cells and pH as well as in the most bothersome symptom at 2 weeks. At the standard 12-week time interval, 0.5% DHEA caused a 45.9 +/- 5.31 (P < 0.0001 vs placebo) decrease in the percentage of parabasal cells, a 6.8 +/- 1.29% (P < 0.0001) increase in superficial cells, a 1.3 +/- 0.13 unit (P < 0.0001) decrease in vaginal pH, and a 1.5 +/- 0.14 score unit (P < 0.0001) decrease in the severity of the most bothersome symptom. Similar changes were seen on vaginal secretions, color, epithelial surface thickness, and epithelial integrity. Comparable effects were observed at the 0.25% and 1.0% DHEA doses. CONCLUSIONS:: Local Prasterone, through local androgen and estrogen formation, causes a rapid and efficient reversal of all the symptoms and signs of vaginal atrophy with no or minimal changes in serum steroids, which remain well within the normal postmenopausal range. This approach avoids the fear of systemic effects common to all presently available estrogen formulations and adds a novel physiological androgenic component to therapy.

    PMID: 19436225 [PubMed - as supplied by publisher













Menopause. 2009 May 8. [Epub ahead of print]
    Serum steroid levels during 12-week intravaginal dehydroepiandrosterone administration.
    Labrie F, Archer D, Bouchard C, Fortier M, Cusan L, Gomez JL, Girard G, Baron M, Ayotte N, Moreau M, Dubé R, Côté I, Labrie C, Lavoie L, Bérubé R, Bélanger P, Berger L, Gilbert L, Martel C, Balser J.

    From the 1Laval University Hospital Research Center and Laval University, Quebec, Canada; 2Endoceutics Inc., Quebec City, QC, Canada; 3Clinical Research Center, Eastern Virginia Medical School, Norfolk, VA; 4Clinique de Recherche en Santé des Femmes, Quebec City, Canada; 5Diex Recherche Inc., Sherbrooke, QC, Canada; 6Rapid Medical Research Inc.,Cleveland, OH; 7Clinique Gynécologique, Shawinigan, Canada; 8Montreal Clinical Study Center, Montreal, Canada; 9Centre Hospitalier Affilié Universitaire de Québec, Quebec City, Canada; 10McGill University Health Center, Royal Victoria Hospital, Montreal, QC, Canada; and 11Veristat Inc., Boston, MA.

    OBJECTIVE:: Because a previous 1-week study has shown no or minimal changes in the serum levels of dehydroepiandrosterone (DHEA) and its metabolites after up to daily 1.8% (23.4 mg) intravaginal DHEA, the objective of the present study was to investigate the serum steroid levels during a 12-week daily intravaginal administration of 0%, 0.25%, 0.5%, and 1.0% DHEA (Prasterone) 1.3 mL ovules. METHODS:: In a double-blind, placebo-controlled phase III study, 218 postmenopausal women (age range, 42-74 y) were randomized to receive daily one of four DHEA concentrations intravaginally. Serum steroids were measured by a Good Laboratory Practice-validated mass spectrometry technology in samples obtained at time of visit. RESULTS:: The serum levels of DHEA and 11 of its metabolites measured at screening, day 1, and weeks 2, 4, 8, and 12 in women showed no or minimal changes during the whole observation period, with all values remaining well within the limits of normal postmenopausal women. No accumulation of the steroid metabolites nor change in DHEA bioavailability was detected. CONCLUSIONS:: The present data show that local daily intravaginal DHEA administration at DHEA doses of 3.25-13 mg was able to rapidly and efficiently achieve correction of all the signs and symptoms of vaginal atrophy and improve sexual function and caused no or minimal changes in serum sex steroid levels, which all remain within the normal postmenopausal range, thus avoiding the risks of all estrogen formulations.

    PMID: 19436226 [PubMed - as supplied by publisher]