Tamoxifen: Cotreatment options:
[updated May, 2005]
Subject: A summary of options to increase the effectiveness of Tamoxifen therapy.
The same question has come up in various versions recently; how does tamoxifen interact with the typical supplements we use in cancer cotreatment? Does the over riding estrogen receptor blockade of tamoxifen cancel out any inhibitory effect of herbal supplements? Is it still worth taking all these pills if I take tamoxifen?
So I've taken a bit of time to rummage through the literature and see if I can answer these questions in one newsletter. It would appear that it is indeed worth the trouble to continue taking cancer specific supplements while taking tamoxifen. Several have a synergistic effect, enhancing the effect of the tamoxifen. Others, although they don't increase tamoxifen's effect appear to continue act on their own unaffected by tamoxifen, so the effects are additive.
The soy isoflavone, genistein, deserves special mention. There is conflicting research: some says it's good and other studies say it's bad. As I mention later, the studies which most closely resemble "human conditions" suggest the effect is not good, that it hinders tamoxifen's effect. Thus we continue our warning about using soy products with breast cancer and now especially with tamoxifen.
1. Avoid Electromagnetic fields : Electromagnetic fields hinder the production of the hormone melatonin. They also decrease the effectiveness of Tamoxifen in inhibiting the growth of breast cancer cells. Avoid sleeping or spending time adjacent to electric currents.  
2. Avoid soy isoflavones : The research is confusing. Although several studies   have demonstrated a synergistic effect on breast cancer inhibition by adding genistein to tamoxifen, the studies using hormones, drugs, and the soy isoflavones at concentrations most closely resembling those in a post menopausal woman on tamoxifen therapy have produced undesirable results. In the studies modeled to resemble a clinical situation, genistein negated the inhibitory effect of tamoxifen.  
3. Add Green Tea and green tea extracts containing epigallocatechin gallate (EGCG). Combining green tea with tamoxifen produces a synergistic increase in cancer growth inhibition. 
4. Add Quercetin: The anti tumor effect of Tamoxifen on prostate cancer cells is potentiated by quercetin.  Quercetin increases the sensitivity of malignant melanoma cells when exposed to hyperthermic treatments if combined with tamoxifen. 
The antitumor effect of quercetin is not dependent on it binding to estrogen receptor binding sites.  Therefore it makes sense that it continues to be effective even though tamoxifen blocks estrogen binding sites.
5. Add Inositol hexaphosphate (IP-6). IP-6 increases the effectiveness of tamoxifen in blocking breast cancer cell growth. 
6. Resveratrol continues to act independent of tamoxifen. The breast cancer inhibition of resveratrol is via a pathway unaffected by tamoxifen. At this point we have no evidence that the two will act synergistically together, only additively. 
7. Add Melatonin in high doses: The inhibitory effect of tamoxifen on liver cancer is “markedly enhanced” by melatonin.  Melatonin enhances the inhibitory effect of tamoxifen on breast cancer cell growth.  Add some Retenoic acid (vitamin A) as well; it increases the inhibitory effect of the melatonin. 
8. Vitamin A: Use retenoic or all trans-retenoic acid if available. Adding retenoic acid to tamoxifen increases the effect on liver cancer cells.  Combine retenoic acid, Vitamin E and tamoxifen is even better. “A combination therapy of all-trans retinoic acid, tamoxifen and vitamin E increases the survival rate and ameliorates the clinical outcome in patients with inoperable” liver cancer. 
9. Use vitamin E, especially the Tocotrienol form: It inhibits breast cancer growth alone and in combination with tamoxifen. 
10. Black Cohosh: Commonly used to reduce menopausal symptoms, this herb increases tamoxifen's effect of inhibition breast cancer cell proliferation.  Using the two together does not increase tamoxifen's potential for stimulating endometrial cancer. 
References: [to view all abstracts click here]
 Bioelectromagnetics. 1997;18(8):555-62
Environmental magnetic fields inhibit the antiproliferative action of tamoxifen and melatonin in a human breast cancer cell line.
Harland JD, Liburdy RP.
 Zhongguo Zhong Yao Za Zhi. 2002 Dec;27(12):936-9
[The inhibiting effect of genistein on the growth of human breast cancer cells in vitro]
He FJ, Wang J, Niu JZ, Wang JF.
 Eur J Obstet Gynecol Reprod Biol. 2002 May 10;102(2):188-94.
Synergistic inhibitory effects of genistein and tamoxifen on human dysplastic and malignant epithelial breast cells in vitro.
Tanos V, Brzezinski A, Drize O, Strauss N, Peretz T.
 Anticancer Res. 1999 May-Jun;19(3A):1657-62
Tamoxifen and genistein synergistically down-regulate signal transduction and proliferation in estrogen receptor-negative human breast carcinoma MDA-MB-435 cells.
Shen F, Xue X, Weber G.
 Am Surg. 2002 Jun;68(6):575-7; discussion 577-8.
Genistein inhibits tamoxifen effects on cell proliferation and cell cycle arrest in T47D breast cancer cells.
Jones JL, Daley BJ, Enderson BL, Zhou JR, Karlstad MD.
 Cancer Res. 2002 May 1;62(9):2474-7
Dietary genistein negates the inhibitory effect of tamoxifen on growth of estrogen-dependent human breast cancer (MCF-7) cells implanted in athymic mice.
Ju YH, Doerge DR, Allred KF, Allred CD, Helferich WG.
 Cancer Res. 1999 Jan 1;59(1):44-7.
Synergistic effects of (--)-epigallocatechin gallate with (--)-epicatechin, sulindac, or tamoxifen on cancer-preventive activity in the human lung cancer cell line PC-9.
Suganuma M, Okabe S, Kai Y, Sueoka N, Sueoka E, Fujiki H.
 Int J Oncol. 2004 May;24(5):1297-304.
Reduction of CWR22 prostate tumor xenograft growth by combined tamoxifen-quercetin treatment is associated with inhibition of angiogenesis and cellular proliferation.
Ma ZS, Huynh TH, Ng CP, Do PT, Nguyen TH, Huynh H.
 Melanoma Res. 2001 Oct;11(5):469-76.
Quercetin and tamoxifen sensitize human melanoma cells to hyperthermia.
Piantelli M, Tatone D, Castrilli G, Savini F, Maggiano N, Larocca LM, Ranelletti FO, Natali PG.
 Melanoma Res. 1998 Aug;8(4):313-22
Sensitivity of human melanoma cells to oestrogens, tamoxifen and quercetin: is there any relationship with type I and II oestrogen binding site expression?
Lama G, Angelucci C, Bruzzese N, Iacopino F, Nori SL, D'Atri S, Turriziani M, Bonmassar E, Sica G.
 Breast Cancer Res Treat. 2003 Jun;79(3):301-12.
Inositol hexaphosphate (IP6) enhances the anti-proliferative effects of adriamycin and tamoxifen in breast cancer.
Tantivejkul K, Vucenik I, Eiseman J, Shamsuddin AM.
 Carcinogenesis. 2003 May;24(5):869-73.
Resveratrol activates adenylyl-cyclase in human breast cancer cells: a novel, estrogen receptor-independent cytostatic mechanism.
El-Mowafy AM, Alkhalaf M.
 J Pineal Res. 2002 Aug;33(1):8-13.
Potentiation of antiproliferative effects of tamoxifen and ethanol on mouse hepatoma cells by melatonin: possible involvement of mitogen-activated protein kinase and induction of apoptosis.
Hermann R, Podhajsky S, Jungnickel S, Lerchl A.
 J Clin Endocrinol Metab. 1992 Aug;75(2):669-70
Melatonin augments the sensitivity of MCF-7 human breast cancer cells to tamoxifen in vitro.
Wilson ST , Blask DE , Lemus-Wilson AM.
 Pol J Pathol. 2002;53(2):59-65.
Effect of melatonin and all-trans retinoic acid on the proliferation and induction of the apoptotic pathway in the culture of human breast cancer cell line MCF-7.
Czeczuga-Semeniuk E, Wolczynski S, Anchim T, Dzieciol J, Dabrowska M, Pietruczuk M.
 Int J Oncol. 2002 Jan;20(1):89-96.
Combined in vitro anti-tumoral action of tamoxifen and retinoic acid derivatives in hepatoma cells.
Herold C, Ganslmayer M, Ocker M, Hermann M, Hahn EG, Schuppan D.
 Anticancer Res. 2004 Mar-Apr;24(2C):1255-60.
Treatment with all-trans retinoic acid plus tamoxifen and vitamin E in advanced hepatocellular carcinoma.
Clerici C, Castellani D, Russo G, Fiorucci S, Sabatino G, Giuliano V, Gentili G, Morelli O, Raffo P, Baldoni M, Morelli A, Toma S.
 J Nutr. 1997 Mar;127(3):544S-548S.
Inhibition of proliferation of estrogen receptor-negative MDA-MB-435 and -positive MCF-7 human breast cancer cells by palm oil tocotrienols and tamoxifen, alone and in combination.
Guthrie N, Gapor A, Chambers AF, Carroll KK.
 Breast Cancer Res Treat. 2002 Nov;76(1):1-10. Influence of Cimicifuga racemosa on the proliferation of estrogen receptor-positive human breast cancer cells.
Bodinet C, Freudenstein J.
 Toxicol Lett. 2004 May 2;150(3):271-5. Concomitant administration of an isopropanolic extract of black cohosh and tamoxifen in the in vivo tumor model of implanted RUCA-I rat endometrial adenocarcinoma cells. Nisslein T, Freudenstein J.