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      Effectiveness of tocotrienol-rich fraction combined with tamoxifen in the management of women with early breast cancer: a pilot clinical trial

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          Abstract

          Introduction

          Basic research has indicated that tocotrienols have potent antiproliferative and proapoptotic effects that would be expected to reduce the effect of breast cancer.

          Methods

          We conducted a double-blinded, placebo-controlled pilot trial to test the effectiveness of adjuvant tocotrienol therapy in combination with tamoxifen for 5 years in women with early breast cancer. Two-hundred-forty women, aged between 40 and 60 years, with either tumor node metastases (TNM) Stage I or II breast cancer and estrogen receptor (ER)-positive tumors were nonrandomly assigned to two groups. The intervention group received tocotrienol-rich fraction (TRF) plus tamoxifen, whereas the control group received placebo plus tamoxifen, for 5 years.

          Results

          During the 5 years of the study, eight patients died of breast cancer, whereas in 36 patients, a local or systemic recurrence developed. Five-year breast cancer-specific survival was 98.3% (95% confidence interval (CI), 95.9% to 100%) in the intervention group and 95% (95% CI, 91.1% to 98.9%) in the control group, whereas the 5-year disease-free survival was 86.7% (95% CI, 80.6% to 92.8%) and 83.3% (95% CI, 76.6% to 90.0%), respectively. Risk of mortality due to breast cancer was 60% (HR, 0.40; 95% CI, 0.08 to 2.05) lower in the intervention group versus the controls after adjustment for age, ethnicity, stage, and lymph node status, but this was not statistically significant. Adjuvant TRF therapy was not associated with breast cancer recurrence (HR, 0.84; 95% CI, 0.43 to 1.65).

          Conclusions

          From the current study, no association seems to exist between adjuvant tocotrienol therapy and breast cancer-specific survival in women with early breast cancer.

          Trial registration

          ClinicalTrials.gov Identifier: NCT01157026.

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          Most cited references14

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          gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention.

          Q. Jiang, S Christen, M. Shigenaga … (2001)
          gamma-tocopherol is the major form of vitamin E in many plant seeds and in the US diet, but has drawn little attention compared with alpha-tocopherol, the predominant form of vitamin E in tissues and the primary form in supplements. However, recent studies indicate that gamma-tocopherol may be important to human health and that it possesses unique features that distinguish it from alpha-tocopherol. gamma-Tocopherol appears to be a more effective trap for lipophilic electrophiles than is alpha-tocopherol. gamma-Tocopherol is well absorbed and accumulates to a significant degree in some human tissues; it is metabolized, however, largely to 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman (gamma-CEHC), which is mainly excreted in the urine. gamma-CEHC, but not the corresponding metabolite derived from alpha-tocopherol, has natriuretic activity that may be of physiologic importance. Both gamma-tocopherol and gamma-CEHC, but not alpha-tocopherol, inhibit cyclooxygenase activity and, thus, possess antiinflammatory properties. Some human and animal studies indicate that plasma concentrations of gamma-tocopherol are inversely associated with the incidence of cardiovascular disease and prostate cancer. These distinguishing features of gamma-tocopherol and its metabolite suggest that gamma-tocopherol may contribute significantly to human health in ways not recognized previously. This possibility should be further evaluated, especially considering that high doses of alpha-tocopherol deplete plasma and tissue gamma-tocopherol, in contrast with supplementation with gamma-tocopherol, which increases both. We review current information on the bioavailability, metabolism, chemistry, and nonantioxidant activities of gamma-tocopherol and epidemiologic data concerning the relation between gamma-tocopherol and cardiovascular disease and cancer.
          Article 0 comments Cited 59 times – based on 0 reviews     Review now
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            Tocotrienols inhibit the growth of human breast cancer cells irrespective of estrogen receptor status.

            Kalanithi Nesaretnam, Ruth Stephen, Ray Dils … (1998)
            Potential antiproliferative effects of tocotrienols, the major vitamin E component in palm oil, were investigated on the growth of both estrogen-responsive (ER+) MCF7 human breast cancer cells and estrogen-unresponsive (ER-) MDA-MB-231 human breast cancer cells, and effects were compared with those of alpha-tocopherol (alphaT). The tocotrienol-rich fraction (TRF) of palm oil inhibited growth of MCF7 cells in both the presence and absence of estradiol with a nonlinear dose-response but such that complete suppression of growth was achieved at 8 microg/mL. MDA-MB-231 cells were also inhibited by TRF but with a linear dose-response such that 20 microg/mL TRF was needed for complete growth suppression. Separation of the TRF into individual tocotrienols revealed that all fractions could inhibit growth of both ER+ and ER- cells and of ER+ cells in both the presence and absence of estradiol. However, the gamma- and delta-fractions were the most inhibitory. Complete inhibition of MCF7 cell growth was achieved at 6 microg/mL of gamma-tocotrienol/delta-tocotrienol (gammaT3/deltaT3) in the absence of estradiol and 10 microg/mL of deltaT3 in the presence of estradiol, whereas complete suppression of MDA-MB-231 cell growth was not achieved even at concentrations of 10 microg/mL of deltaT3. By contrast to these inhibitory effects of tocotrienols, alphaT had no inhibitory effect on MCF7 cell growth in either the presence or the absence of estradiol, nor on MDA-MB-231 cell growth. These results confirm studies using other sublines of human breast cancer cells and demonstrate that tocotrienols can exert direct inhibitory effects on the growth of breast cancer cells. In searching for the mechanism of inhibition, studies of the effects of TRF on estrogen-regulated pS2 gene expression in MCF7 cells showed that tocotrienols do not act via an estrogen receptor-mediated pathway and must therefore act differently from estrogen antagonists. Furthermore, tocotrienols did not increase levels of growth-inhibitory insulin-like growth factor binding proteins (IGFBP) in MCF7 cells, implying also a different mechanism from that proposed for retinoic acid inhibition of estrogen-responsive breast cancer cell growth. Inhibition of the growth of breast cancer cells by tocotrienols could have important clinical implications not only because tocotrienols are able to inhibit the growth of both ER+ and ER- phenotypes but also because ER+ cells could be growth-inhibited in the presence as well as in the absence of estradiol. Future clinical applications of TRF could come from potential growth suppression of ER+ breast cancer cells otherwise resistant to growth inhibition by antiestrogens and retinoic acid.
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              Effect of tocotrienols on the growth of a human breast cancer cell line in culture.

              Lori A Chambers, Ronan K Carroll, N Guthrie … (1995)
              The tocotrienol-rich fraction (TRF) of palm oil consists of tocotrienols and some alpha-tocopherol (alpha-T). Tocotrienols are a form of vitamin E having an unsaturated side-chain, rather than the saturated side-chain of the more common tocopherols. Because palm oil has been shown not to promote chemically-induced mammary carcinogenesis, we tested effects of TRF and alpha-T on the proliferation, growth, and plating efficiency (PE) of the MDA-MB-435 estrogen-receptor-negative human breast cancer cells. TRF inhibited the proliferation of these cells with a concentration required to inhibit cell proliferation by 50% of 180 microgram/mL whereas alpha-T had no effect at concentrations up to 1000 microgram/mL as measured by incorporation of [3H]thymidine. The effects of TRF and alpha-T also were tested in longer-term growth experiments, using concentrations of 180 and 500 microgram/mL. We found that TRF inhibited the growth of these cells by 50%, whereas alpha-T did not. Their effect on the ability of these cells to form colonies also was studied, and it was found that TRF inhibited PE, whereas alpha T had no effect. These results suggest that the inhibition is due to the presence of tocotrienols in TRF rather than alpha T.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Breast Cancer Res
                Title: Breast Cancer Research : BCR
                Publisher: BioMed Central
                ISSN (Print): 1465-5411
                ISSN (Electronic): 1465-542X
                Publication date (Print): 2010
                Publication date (Electronic): 8 October 2010
                Volume: 12
                Issue: 5
                Page: R81
                Affiliations
                [1 ]Malaysian Palm Oil Board, 6 Persiaran Institusi, Bandar Baru Bangi, Kajang, 43000 Selangor Darul Ehsan, Malaysia
                [2 ]Kuala Lumpur Hospital, Jalan Pahang, 50586 Kuala Lumpur, Federal Territory, Malaysia
                Article
                Publisher ID: bcr2726
                DOI: 10.1186/bcr2726
                PMC ID: 3096974
                PubMed ID: 20929592
                SO-VID: 92ccdd90-e7b1-4e6b-a29c-5ea5cf7435de
                Copyright © Copyright ©2010 Nesaretnam et al.; licensee BioMed Central Ltd.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 30 June 2010
                Date revision received : 29 September 2010
                Date accepted : 8 October 2010
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Oncology & Radiotherapy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy

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