HER2 Support Group Forums - View Single Post - Tamoxifen (ER+, ER-, synergies etc)

Rich66 · 11-03-2009, 09:54 PM

1: Mol Cancer Ther. 2008 Sep;7(9):3056-63. Links: Methylseleninic acid synergizes with tamoxifen to induce caspase-mediated apoptosis in breast cancer cells.

Li Z, Carrier L, Rowan BG.
Department of Structural and Cellular Biology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
Tamoxifen has efficacy as a breast cancer therapy and chemoprevention agent. However, toxicity and resistance to tamoxifen limit its clinical application. There is an urgent need to develop compounds that may be combined with tamoxifen to improve efficacy and overcome toxicity and resistance. We showed previously that the organoselenium compound methylseleninic acid (MSA) increased the growth-inhibitory effect of tamoxifen and reversed tamoxifen resistance in breast cancer cells. In this study, we examined the mechanism for induction of apoptosis by MSA combined with tamoxifen in tamoxifen-sensitive and tamoxifen-resistant breast cancer cells. 4-hydroxytamoxifen (TAM; 10(-7) mol/L) alone resulted in cell cycle arrest but no apoptosis, whereas MSA alone (10 micromol/L) induced apoptosis in tamoxifen-sensitive cells. Combination of MSA with TAM resulted in a synergistic apoptosis in both tamoxifen-sensitive and tamoxifen-resistant breast cancer cells compared with either agent alone. MSA and MSA combined with TAM induced apoptosis through the intrinsic, mitochondrial apoptotic pathway. MSA induced a sequential activation of caspase-9 and then caspase-8. These results indicate that the growth inhibition synergy and reversal of tamoxifen resistance by combination of selenium with tamoxifen occurs via a tamoxifen-induced cell cycle arrest, allowing more cells to enter the intrinsic apoptotic pathway elicited by selenium.
PMID: 18790785 [PubMed - indexed for MEDLINE

http://mct.aacrjournals.org/content/4/8/1239.full 2005
Selenium disrupts estrogen receptor α signaling and potentiates tamoxifen antagonism in endometrial cancer cells and tamoxifen-resistant breast cancer cells

Requests for reprints: Brian G. Rowan, Department of Structural and Cellular Biology, SL49, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112. Phone 504-988-1365; Fax: 504-988-1687. E-mail: browan@tulane.edu

Abstract

Tamoxifen, a selective estrogen receptor (ER) modulator, is the most widely prescribed hormonal therapy treatment for breast cancer. Despite the benefits of tamoxifen therapy, almost all tamoxifen-responsive breast cancer patients develop resistance to therapy. In addition, tamoxifen displays estrogen-like effects in the endometrium increasing the incidence of endometrial cancer. New therapeutic strategies are needed to circumvent tamoxifen resistance in breast cancer as well as tamoxifen toxicity in endometrium. Organic selenium compounds are highly effective chemopreventive agents with well-documented benefits in reducing total cancer incidence and mortality rates for a number of cancers. The present study shows that the organic selenium compound methylseleninic acid (MSA, 2.5 μmol/L) can potentiate growth inhibition of 4-hydroxytamoxifen (10⁻⁷ mol/L) in tamoxifen-sensitive MCF-7 and T47D breast cancer cell lines. Remarkably, in tamoxifen-resistant MCF-7-LCC2 and MCF7-H2Δ16 breast cancer cell lines and endometrial-derived HEC1A and Ishikawa cells, coincubation of 4-hydroxytamoxifen with MSA resulted in a marked growth inhibition that was substantially greater than MSA alone. Growth inhibition by MSA and MSA + 4-hydroxytamoxifen in all cell lines was preceded by a specific decrease in ERα mRNA and protein without an effect on ERβ levels. Estradiol and 4-hydroxytamoxifen induction of endogenous ER-dependent gene expression (pS2 and c-myc) as well as ER-dependent reporter gene expression (ERE₂e1b-luciferase) was also attenuated by MSA in all cell lines before effect on growth inhibition. Taken together, these data strongly suggest that specific decrease in ERα levels by MSA is required for both MSA potentiation of the growth inhibitory effects of 4-hydroxytamoxifen and resensitization of tamoxifen-resistant cell lines.

Carcinogenesis. 2006 Dec;27(12):2424-33. Epub 2006 Jun 19.
The combination of green tea and tamoxifen is effective against breast cancer.

Sartippour MR, Pietras R, Marquez-Garban DC, Chen HW, Heber D, Henning SM, Sartippour G, Zhang L, Lu M, Weinberg O, Rao JY, Brooks MN.
Department of Surgery, Center for Human Nutrition, University of California, Los Angeles, CA 90095-1782, USA.
Epidemiologic data have suggested that green tea may prevent breast cancer. Studies in our laboratory have provided evidence that green tea extract inhibits breast cancer growth by a direct anti-proliferative effect on the tumor cells, as well as by indirect suppressive effects on the tumor-associated endothelial cells. In this study, we asked whether concurrent administration of green tea may add to the anti-tumor effects of standard breast cancer therapy. We observed that green tea increased the inhibitory effect of tamoxifen on the proliferation of the ER (estrogen receptor)-positive MCF-7, ZR75, T47D human breast cancer cells in vitro. This combination regimen was also more potent than either agent alone at increasing cell apoptosis. In animal experiments, mice treated with both green tea and tamoxifen had the smallest MCF-7 xenograft tumor size, and the highest levels of apoptosis in tumor tissue, as compared with either agent administered alone. Moreover, the suppression of angiogenesis in vivo correlated with larger areas of necrosis and lower tumor blood vessel density in treated xenografts. Green tea decreased levels of ER-alpha in tumors both in vitro and in vivo. We also observed that green tea blocked ER-dependent transcription, as well as estradiol-induced phosphorylation and nuclear localization of mitogen-activated protein kinase. To our knowledge, this study is the first to show the interaction of green tea with the ER pathway, as well as provide mechanistic evidence that the combination of green tea and tamoxifen is more potent than either agent alone in suppressing breast cancer growth. These results may lead to future improvements in breast cancer treatment and prevention.

PMID: 16785249 [PubMed - indexed for MEDLINE]

Br J Cancer. 2008 Oct 7;99(7):1056-63. Epub 2008 Sep 16.
A new role for tamoxifen in oestrogen receptor-negative breast cancer when it is combined with epigallocatechin gallate.

Scandlyn MJ, Stuart EC, Somers-Edgar TJ, Menzies AR, Rosengren RJ.
Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
We have previously shown that tamoxifen+epigallocatechin gallate (EGCG) is synergistically cytotoxic towards oestrogen receptor (ER)-negative breast cancer cells. To determine if this response would correlate with significant tumour suppression in vivo, athymic nude female mice were implanted with MDA-MB-231 cells and treated with tamoxifen, EGCG, EGCG+tamoxifen, or vehicle control for 10 weeks. Tumour volume in EGCG- (25 mg kg(-1))+tamoxifen (75 microg kg(-1))-treated mice decreased by 71% as compared with vehicle control (P<0.05), whereas tumour weight was decreased by 80% compared with control (P<0.01). Epigallocatechin gallate treatment did not alter ER protein expression in MDA-MB-231 cells and thus was not a mechanism for the observed tumour suppression. However, western blotting of tumour extracts demonstrated that epidermal growth factor receptor (EGFR; 85% lower than control), pEGFR (78% lower than control), mammalian target of rapamycin (mTOR; 78% lower than control), and CYP1B1 (75% lower than control) were significantly lower after the combination treatment as compared with all other treatments. Nuclear factor-kappaB (NF-kappaB), b-Raf, p-MEK, S6K, 4EBP1, Akt, vascular EGFR-1 (VEGFR-1) and VEGF expressions were decreased in control but not in the individual treatments, whereas MEK, phospholipase D 1/2, TGF alpha, and ERK expressions were not changed after any treatment. The results demonstrate that tamoxifen at realistic doses (75 mug kg(-1)) can suppress the growth of ER-negative breast cancer when combined with EGCG. In addition, the dominant mechanism for tumour suppression is the concomitant decrease in tumour protein expressions of mTOR and the EGFR.

PMID: 18797454 [PubMed - indexed for MEDLINE]

http://www.springerlink.com/content/9n75721824648854/

Cancer Chemother Pharmacol. 2009 May 20. [Epub ahead of print]
Preclinical rationale for combined use of endocrine therapy and 5-fluorouracil but neither doxorubicin nor paclitaxel in the treatment of endocrine-responsive breast cancer.

Kurebayashi J, Nukatsuka M, Sonoo H, Uchida J, Kiniwa M.
Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan, kure@med.kawasaki-m.ac.jp.
PURPOSE: Our previous study indicated that concurrent administration of 4-OH-tamoxifen (TAM) and 5-fluorouracil (5-FU), but not doxorubicin (Dox), resulted in additive antitumor effects on endocrine-responsive breast cancer cells. We further clarified the effects of combined administration of endocrine therapy with chemotherapeutic agents in this study. METHODS: Concurrent treatment with 4-OH-TAM and paclitaxel (Ptx) was investigated in estrogen receptor (ER)-positive breast cancer cells. Additionally, the combined effects of estrogen depletion from culture medium mimicking estrogen ablative therapy with 5-FU, Dox, and Ptx were investigated. RESULTS: Concurrent treatment with 4-OH-TAM and Ptx yielded less than additive antitumor effects in ER-positive breast cancer cells, as observed with Dox in our previous study. More interestingly, estrogen depletion with 5-FU, but with neither Dox nor Ptx, yielded additive antitumor effects on these cells. We also performed preliminary experiments to elucidate the mechanisms of action responsible for the combined antitumor effects observed. Ptx up-regulated the level of expression of one of the molecules related to TAM resistance, Eph-A2, as observed with Dox in our previous study. Estrogen depletion down-regulated the level of expression of one of the molecules related to 5-FU resistance, thymidylate synthase, as observed with 4-OH-TAM in our previous study. CONCLUSIONS: These findings, together with those of our previous study, suggest that concurrent treatment with endocrine therapy, administration of TAM, or estrogen ablative therapy and 5-FU but neither Dox nor Ptx may yield additive antitumor effects on endocrine-responsive breast cancer.

PMID: 19455332 [PubMed - as supplied by publisher]

Cancer Chemother Pharmacol. 2007 Mar;59(4):515-25. Epub 2006 Aug 10.
Additive antitumor effect of concurrent treatment of 4-hydroxy tamoxifen with 5-fluorouracil but not with doxorubicin in estrogen receptor-positive breast cancer cells.

Kurebayashi J, Nukatsuka M, Nagase H, Nomura T, Hirono M, Yamamoto Y, Sugimoto Y, Oka T, Sonoo H.
Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan. kure@med.kawasaki-m.ac.jp
PURPOSE: The sequential addition of tamoxifen (TAM) to chemotherapy seems superior to its concurrent addition in patients with breast cancer. This study was conducted to clarify the hypothesis that there are differential interactions among TAM and chemotherapeutic agents. METHODS: Estrogen receptor (ER)-alpha-positive or -negative breast cancer cells were treated with 4-hydroxy TAM (4OHT), 5-fluorouracil (FU) and/or doxorubicin (Dox). Changes in the expression levels of genes related to sensitivity and resistance to TAM, 5-FU or Dox were tested. RESULTS: Concurrent treatment of 4OHT with 5-FU but not with Dox additively inhibited the growth of ER-alpha-positive cells. 5-FU did not change the expression levels of any tested genes related to either sensitivity or resistance to TAM. Although Dox did not change the expression levels of any genes related to the sensitivity to TAM, Dox significantly increased the expression levels of some genes related to TAM resistance, Eph A-2, ER-beta, Fos and vascular endothelial growth factor. 4OHT significantly decreased thymidilate synthase (TS) activity. CONCLUSIONS: Although the antitumor effect of concurrent 4OHT and 5-FU was additive, that of concurrent 4OHT and Dox was less than additive in ER-alpha-positive cells. The increased expression of genes related to TAM resistance by Dox might be responsible for the interaction. Decreased TS activity by 4OHT might increase the antitumor activity of 5-FU. These findings may provide a preclinical rationale for concurrent use with 5-FU and TAM.

PMID: 16900372 [PubMed - indexed for MEDLINE]

In vivo and in vitro efficacy of capecitabine (X) + tamoxifen (TAM) in breast cancer (BC)

Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 25, No 18S (June 20 Supplement), 2007: 21092

K. Mori, Y. Yamaguchi, N. Sawada, K. Kondoh and S. Hayashi Chugai Pharmaceutical Co, Kamakura, Japan; Saitama Cancer Center, Ina-machi, Japan; School of Medicine, Tohoku University, Sendai, Japan
21092
Background: In vitro studies in BC cell lines suggested antagonismbetween TAM and 5-FU. Thymidine phosphorylase (TP) activatesX to 5-FU in tumors. X activity correlates with tumor TP concentrationsin vivo. Methods: We studied antitumor efficacy of X + TAM invivo and in vitro in human BC models. Nude mice were inoculateds.c. with estradiol, then MCF-7 cells 1 day later. When tumorswere

300 mm³, mice received 6 weeks’ oral vehicle (control),X (d1–14 q21d) at MTD (539 mg/kg) or 2/3 MTD, and/or TAMat 100 or 30 mg/kg/d. We also analyzed impact of 5-FU and doxifluridine(5'-DFUR, an intermediate of X) + TAM on estrogen receptor (ER)signals in an in-vitro culture system. ER signals were monitoredby expression of green fluorescent protein (GFP) in MCF-7 BCcells transfected with the estrogen-responsive element (ERE)-GFPgene (MCF-7-E10). GFP expression was induced in MCF-7-E10 cellsin the presence of estradiol at 3 pM or BC tissue supernatant.Results: X at 2/3 MTD + TAM 30 mg/kg were significantly moreactive than the highest dose of X or TAM alone. Tumor TP concentrationswere significantly higher in TAM- than vehicle-treated mice.In the ER signal system, GFP expression of MCF-7-E10 was reducedby 4-hydroxytamoxifen (4-OHT, active form of TAM) at 0.01 and0.1 nM. When added to 4-OHT, 5-FU 0.3–30 µM or 5'-DFUR3–10 µM reduced GFP expression more than eitheragent alone. In vitro, 5-FU and 5'-DFUR inhibited proliferationof MCF-7-E10 cells regardless of 4-OHT. Additive effects couldnot be confirmed as 4-OHT alone showed only marginal anti- proliferativeactivity at 0.01–0.1 nM. Conclusion: X and TAM are notantagonistic in this model. TAM may augment X activity via TPupregulation in BC tissues. TAM and X intermediates showed noclear antagonism in vitro in an ER signal system. All-oral X+ TAM merits evaluation as combination therapy in breast cancer.

Br J Cancer. 1997;75(6):884-91.
Synergistic antiproliferative activity of tamoxifen and docetaxel on three oestrogen receptor-negative cancer cell lines is mediated by the induction of apoptosis.

FULL TEXT: http://www.ncbi.nlm.nih.gov/pmc/arti...00183-0110.pdf

Ferlini C, Scambia G, Distefano M, Filippini P, Isola G, Riva A, Bombardelli E, Fattorossi A, Benedetti Panici P, Mancuso S.
Department of Obstetrics and Gynecology, Catholic University of Sacred Heart, Rome, Italy.
The taxanes are a promising family of anti-tumour drugs that block cell cycle replication by interfering with the microtubule network. The clinical use of these drugs involves some problems related to their low solubility and occurrence of resistance, which is mainly dependent on the multidrug-resistant (MDR) phenotype. To investigate the possible interaction between docetaxel and tamoxifen (TAM), three oestrogen receptor-negative cancer cell lines, MDR- MDA-MB 231, MDR + CEM-VBLr and MCF-7 ADRr, were used. In all three cell lines, the combination of docetaxel and TAM was more effective in terms of growth inhibition than single drug exposure. Isobolic analysis confirmed the presence of synergism in all cell lines when docetaxel was used at 0.2 microM and TAM at a dose equal to or higher than 1 microM. Flow cytometric DNA analysis performed on the three cell lines showed that TAM was able to increase the G2/M blocking activity of docetaxel. This blocking activity was followed by an increased flow cytometric DNA fragmentation suggestive of the presence of apoptosis, which was confirmed by DNA gel fragmentation and morphological analysis. While an antagonistic effect on P-glycoprotein (P-gp) activity may contribute to the synergistic effect of tamoxifen and docetaxel on CEM-VBLr and MCF-7 ADRr, other mechanisms must be involved, as the synergistic effect is also apparent with a P-gp-negative cell line.

Br J Cancer. 1999 Jan;79(2):257-63.
Tamoxifen induces oxidative stress and apoptosis in oestrogen receptor-negative human cancer cell lines.

Ferlini C, Scambia G, Marone M, Distefano M, Gaggini C, Ferrandina G, Fattorossi A, Isola G, Benedetti Panici P, Mancuso S.
Laboratory of Antineoplastic Pharmacology, Zeneca, Rome, Italy.
Recent data have demonstrated that the anti-oestrogen tamoxifen (TAM) is able to facilitate apoptosis in cancer cells not expressing oestrogen receptor (ER). In an attempt to identify the biochemical pathway for this phenomenon, we investigated the role of TAM as an oxidative stress agent. In two ER-negative human cancer cell lines, namely T-leukaemic Jurkat and ovarian A2780 cancer cells, we have demonstrated that TAM is able to generate oxidative stress, thereby causing thiol depletion and activation of the transcriptional factor NF-kappaB. As described for other oxidative agents, TAM was able to induce either cell proliferation or apoptosis depending on the dose. When used at the lowest dose tested (0.1 microM), a slight proliferative effect of TAM was noticed in terms of cell counts and DNA synthesis rate, whereas at higher doses (10 microM) a consistent occurrence of apoptosis was detected. Importantly, the induction of apoptosis by TAM is not linked to down-regulation or functional inactivation by phosphorylation of the antiapoptotic bcl-2 protein.

PMID: 9888466 [PubMed - indexed for MEDLINE]

1: Biochem Pharmacol. 2005 Sep 1;70(5):725-32. Links: Modulation of epirubicin cytotoxicity by tamoxifen in human breast cancer cell lines. Ebtehal; El-Demerdash: ebtehal_dm@yahoo.com
Azab SS, El-Demerdash E, Abdel-Naim AB, Youssef E, El-Sharkawy N, Osman AM.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Egypt.
: The present study was designed to investigate the modulatory effect of the anti-estrogen, tamoxifen (Tam) on epirubicin (Epi) cytotoxicity in breast cancer cell lines; MCF-7 and NCI-adr. Using sulphorhodamine-B assay, NCI-adr cell line was found to be five-folds more resistant to the cytotoxic effect of Epi as compared to MCF-7 cell line. Pretreatment of cells with Tam was observed to enhance Epi cytotoxicity by 4.3- and 6.5-folds in MCF-7 and NCI-adr cells, respectively. Tam-Epi interaction was found to be additive in MCF-7 cells and synergistic in NCI-adr cells. Flowcytometric DNA ploidy analysis revealed that, Epi induced cell arrest at G2/M phase. Tam pretreatment enhanced the blocking activity of low dose of Epi in MCF-7 and induced nearly two-fold increase in the percentage of S phase in NCI-adr cells. Determination of cellular Epi level revealed that Tam induced a significant increase in intracellular Epi accumulation only in NCI-adr cells after 48 h. However, analysis of P-gp function revealed that Tam failed to modulate P-gp function in both cell lines. Also, assessment of topoisomerae IIalpha gene expression showed that neither Epi nor Tam managed to change its expression level. In conclusion, Tam potentiates Epi cytotoxicity in sensitive and resistant breast cancer cell lines.enhancement of cell accumulation in S and G2/M phase, at which the cells are most sensitive to the cytotoxic effect This potentiation can be explained by an of Epi as well as an increase in the intracellular level of Epi in resistant cell line.
PMID: 16005435 [PubMed - indexed for MEDLINE

1: Cancer Lett. 1996 Nov 12;108(1):7-14. Links: Tamoxifen synergizes the antiproliferative effect of cisplatin in human ovarian cancer cells: enhancement of DNA platination as a possible mechanism.

Ercoli A, Scambia G, De Vincenzo R, Alimonti A, Petrucci F, Fattorossi A, Isola G, Benedetti Panici P, Caroli S, Mancuso S.
Department of Gynecology, Catholic University, Rome, Italy.
We investigated the chemosensitizing activity of tamoxifen (TAM) on estrogen receptor negative ovarian cancer cell lines sensitive (A2780 WT) and resistant to cisplatin (CP) (A2780 CP3). Our results showed that the treatment of both cell lines with the association TAM + CP (concentration range 0.01-1 microN and 0.1-1 microgram/ml, respectively) results in a synergistic antiproliferative activity and a complete reversal of the acquired CP-resistant phenotype. We demonstrated that in A2780 cells the addition of TAM to CP treatment is able to significantly enhance at every tested CP dose (P < 0.001) the amount of platinum (Pt) bound to the DNA. Since Pt-DNA levels in the genome are clearly related to the growth inhibitory effect of CP (correlation value = 0.97, P < 0.001) in our experimental model, we hypothesized that TAM could act synergistically with CP and overcome the acquired CP-resistance by enhancing Pt binding to the DNA. We suggest that, from a clinical point of view, TAM may be usefully included in CP-based chemotherapy regimens for ovarian cancer patients since plasma concentrations of the drug capable of in vitro CP resistance modulation are achievable in vivo. A prospective clinical trial to verify the clinical usefulness of combined TAM + CP treatment in ovarian cancer patients refractory to prior Pt-based chemotherapy is now underway in our department.

Cancer Chemother Pharmacol. 1995;36(5):368-72.
Effect of tamoxifen on mitoxantrone cytotoxicity in drug-sensitive and multidrug-resistant MCF-7 cells.

Desai PB, Bhardwaj R, Damle B.
Division of Medicinal Chemistry and Pharmaceutics, School of Pharmacy, Northeast Louisiana University, Monroe 71209-0470, USA.
The influence of the antiestrogen tamoxifen (TAM) on the activity of mitoxantrone (MXN), was evaluated against wild-type MCF-7/WT and their multidrug-resistant variant MCF-7/ADR cells. Multidrug resistance (MDR) in this cell line which was selected for resistance to Adriamycin (ADR), is associated with increased expression of P-glycoprotein (P-gp). In a clonogenic assay it was observed that TAM (1-10 microM) significantly enhanced the activity of MXN in the MCF-7/ADR but not in the drug-sensitive cell line. Isobologram analysis indicated that the effect of the combination was additive in the parental MCF-7/WT cells and strongly synergistic in the MDR MCF-7/ADR cells. Also, TAM (10 microM) caused a three-fold increase in the steady-state levels (Css) of MXN in MCF-7/ADR cells but did not modulate MXN levels in MCF-7/WT cells. The observed synergism in MCF-7/ADR cells was perhaps due to the increase in Css of MXN that may involve interaction of TAM with P-gp. The combination of MXN and TAM may be useful in the treatment of drug-sensitive and drug-resistant breast cancer.

PMID: 7634377 [PubMed - indexed for MEDLINE]

Anticancer Drugs. 2007 Sep;18(8):923-31.
Enhancement of the antitumor activity of tamoxifen and anastrozole by the farnesyltransferase inhibitor lonafarnib (SCH66336, Sarasar).

Liu G, Marrinan CH, Taylor SA, Black S, Basso AD, Kirschmeier P, Robert Bishop W, Liu M, Long BJ.
Department of Biological Research - Oncology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
Lonafarnib is an orally bioavailable farnesyltransferase inhibitor. Originally developed to block the membrane localization of Ras, subsequent work suggested that farnesyltransferase inhibitors mediate their antitumor activities by altering the biological activities of additional farnesylated proteins. Breast tumor models that express wild-type Ras have been shown to be sensitive to farnesyltransferase inhibitors. We have determined the effects of combining lonafarnib with the antiestrogen 4-hydroxy tamoxifen on hormone-dependent breast cancer cell lines in vitro. The effects of combining lonafarnib with tamoxifen or the aromatase inhibitor anastrozole on the growth of two different MCF-7 breast tumor xenograft models were also evaluated. In four of five human breast cancer cell lines, lonafarnib enhanced the antiproliferative effects of 4-hydroxy tamoxifen. The combination prevented MCF-7 cells from transitioning through the G1 to S phase of the cell cycle and augmented apoptosis. This was associated with reduced expression of E2F-1 and a reduction in hyperphosphorylated retinoblastoma protein. Lonafarnib plus 4-hydroxy tamoxifen also inhibited the mammalian target of rapamycin signal transduction pathway. In nude mice bearing parental MCF-7 or aromatase-transfected MCF-7Ca breast tumor xenografts, lonafarnib enhanced the antitumor activity of both tamoxifen and anastrozole. These studies indicate that lonafarnib enhances the efficacy of endocrine agents clinically used for treating hormone-dependent breast cancer.

Chemo Followed by Tamoxifen Augments Survival in ER+ Breast Cancer

As Reported by HealthDay News. 2009 Dec 11

Postmenopausal women who have estrogen-receptor (ER)−positive breast cancer may be able to improve their survival if they receive treatment with a combination of chemotherapy and tamoxifen. Traditionally, such patients are given tamoxifen, which blocks estrogen receptors. However, researchers have speculated that women with ER-positive breast cancer might benefit from also receiving chemotherapy.
Researchers at Loyola University Chicago Stritch School of Medicine compared the survival benefits of 4 different regimens in 1460 patients, whom they followed for up to 13 years (median, 9 years). The regimens compared were tamoxifen alone, chemotherapy alone, tamoxifen plus chemotherapy given simultaneously, and chemotherapy followed by tamoxifen. All of the patients had positive lymph nodes. Tamoxifen was taken for 5 years. The chemotherapy regimen consisted of cyclophosphamide, doxorubicine (Adriamycin), and 5-fluorouracil.
Compared with tamoxifen alone, the combination of chemotherapy with tamoxifen increased disease-free survival by 24%. Sequential administration of chemotherapy followed by tamoxifen was slightly more beneficial than simultaneous tamoxifen plus chemotherapy. Estimated disease-free survival at 10 years was 48% for the tamoxifen-alone group, as compared with 57% for the group receiving both chemotherapy and tamoxifen.
The research results were published in the December 10 online issue of The Lancet and were presented on December 10 at the San Antonio Breast Cancer Symposium.

Health News
Adding Chemo to Tamoxifen Helps Some Breast Cancer Patients

12/11/2009

THURSDAY, Dec. 10 (HealthDay News) -- Adding chemotherapy to standard cancer-suppressing tamoxifen can boost survival in postmenopausal women with the most common type of breast cancer, known as estrogen receptor-positive, and it's best given before the tamoxifen regimen starts, according to a new study.
"Chemotherapy with Adriamycin adds to your survival benefit over and above what tamoxifen would do if you are postmenopausal and have positive lymph nodes and estrogen receptor-positive cancer [the most common type]," explained Dr. Kathy Albain, the lead researcher and professor of medicine at Loyola University Chicago Stritch School of Medicine.
And in another study, Albain found that screening breast tumors with an available multi-gene test spots patients who may not need this form of chemotherapy, despite fitting the standard profile.
Both studies are published online Dec. 10, the first in the journal The Lancet and the second in The Lancet Oncology. Albain is also due to present her findings Thursday at the annual San Antonio Breast Cancer Symposium in San Antonio, Texas.
In estrogen receptor-positive cancer, tumor cells carry many receptors on their surfaces to which estrogen can attach, fueling tumor growth. Tamoxifen works by blocking the receptors.
Experts have long debated whether women with estrogen receptor-positive cancers -- whose growth is fueled by circulating estrogen -- would get more benefit from having a chemotherapy regimen on top of tamoxifen.
Albain led a research team from multiple centers that followed nearly 1,500 breast cancer patients for up to 13 years, with a median (half longer, half less) of nearly nine years. All were past menopause and had hormone receptor-positive cancer that had spread to at least one lymph node in the armpit area.
Albain's team assigned 381 women to tamoxifen alone, 587 to chemotherapy alone and 590 to both, with some receiving tamoxifen and chemo together and some in a sequential manner.
Tamoxifen was taken daily for five years. The chemo regimen used is called CAF, for "cyclophosphamide, Adriamycin and 5-fluorouracil."
In all, after accounting for study dropouts, 1,460 women received treatment.
The combined treatments of chemo plus tamoxifen increased the women's disease-free survival by 24 percent, Albain found. When her team looked at which delivery protocol worked best -- simultaneous tamoxifen and chemotherapy or chemo followed by tamoxifen -- the sequential approach was found to be better, giving slightly better disease-free survival.
Ten-year disease-free survival estimates were 57 percent for the combination group and 48 percent for the tamoxifen-only group, the researchers found.
However, women receiving chemo were more likely to have drops in white blood cells, important for fighting infections, the team noted. And they were also more prone to blood clots, congestive heart failure and other complications.
In a second study, Albain's team analyzed whether a gene test, called Oncotype DX, could predict which women would benefit from chemotherapy. Genomic Health, which makes the test, helped fund the study, along with the U.S. National Cancer Institute.
The test, which Albain said is already widely used, is done on the tumor itself. "This puts 21 genes together and comes up with a score," she said. The score -- low, intermediate, high -- predicts the risk of recurrence over 10 years if a woman used tamoxifen alone.
When the researchers performed the test on 367 specimens, they found a low score identified those women who may not need the chemo, despite the fact that they have cancer that spread to lymph nodes.
"This is a positive study, there's no question," said Dr. Joanne Mortimer, vice chair of medical oncology for the City of Hope Cancer Center in Duarte, Calif., of the first study. "This study tells us [that] if you have positive lymph nodes [and are postmenopausal with estrogen receptor-positive cancer], you should have both chemo and tamoxifen, because the survival was better."
But, she added, "when you give everyone [who has the estrogen receptor-positive, node-positive breast cancer] chemotherapy, probably there are some who don't need it."
According to Mortimer, that's why the gene test looks promising -- it may spare some women from having to have chemo while ensuring that those who will benefit from the treatment get it.

11-03-2009, 09:54 PM	#4
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Re: Tamoxifen (ER+, ER-, synergies etc) 1: Mol Cancer Ther. 2008 Sep;7(9):3056-63. Links Methylseleninic acid synergizes with tamoxifen to induce caspase-mediated apoptosis in breast cancer cells. Li Z, Carrier L, Rowan BG. Department of Structural and Cellular Biology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA. Tamoxifen has efficacy as a breast cancer therapy and chemoprevention agent. However, toxicity and resistance to tamoxifen limit its clinical application. There is an urgent need to develop compounds that may be combined with tamoxifen to improve efficacy and overcome toxicity and resistance. We showed previously that the organoselenium compound methylseleninic acid (MSA) increased the growth-inhibitory effect of tamoxifen and reversed tamoxifen resistance in breast cancer cells. In this study, we examined the mechanism for induction of apoptosis by MSA combined with tamoxifen in tamoxifen-sensitive and tamoxifen-resistant breast cancer cells. 4-hydroxytamoxifen (TAM; 10(-7) mol/L) alone resulted in cell cycle arrest but no apoptosis, whereas MSA alone (10 micromol/L) induced apoptosis in tamoxifen-sensitive cells. Combination of MSA with TAM resulted in a synergistic apoptosis in both tamoxifen-sensitive and tamoxifen-resistant breast cancer cells compared with either agent alone. MSA and MSA combined with TAM induced apoptosis through the intrinsic, mitochondrial apoptotic pathway. MSA induced a sequential activation of caspase-9 and then caspase-8. These results indicate that the growth inhibition synergy and reversal of tamoxifen resistance by combination of selenium with tamoxifen occurs via a tamoxifen-induced cell cycle arrest, allowing more cells to enter the intrinsic apoptotic pathway elicited by selenium. PMID: 18790785 [PubMed - indexed for MEDLINE http://mct.aacrjournals.org/content/4/8/1239.full 2005 Selenium disrupts estrogen receptor α signaling and potentiates tamoxifen antagonism in endometrial cancer cells and tamoxifen-resistant breast cancer cells Requests for reprints: Brian G. Rowan, Department of Structural and Cellular Biology, SL49, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112. Phone 504-988-1365; Fax: 504-988-1687. E-mail: browan@tulane.edu Abstract Tamoxifen, a selective estrogen receptor (ER) modulator, is the most widely prescribed hormonal therapy treatment for breast cancer. Despite the benefits of tamoxifen therapy, almost all tamoxifen-responsive breast cancer patients develop resistance to therapy. In addition, tamoxifen displays estrogen-like effects in the endometrium increasing the incidence of endometrial cancer. New therapeutic strategies are needed to circumvent tamoxifen resistance in breast cancer as well as tamoxifen toxicity in endometrium. Organic selenium compounds are highly effective chemopreventive agents with well-documented benefits in reducing total cancer incidence and mortality rates for a number of cancers. The present study shows that the organic selenium compound methylseleninic acid (MSA, 2.5 μmol/L) can potentiate growth inhibition of 4-hydroxytamoxifen (10⁻⁷ mol/L) in tamoxifen-sensitive MCF-7 and T47D breast cancer cell lines. Remarkably, in tamoxifen-resistant MCF-7-LCC2 and MCF7-H2Δ16 breast cancer cell lines and endometrial-derived HEC1A and Ishikawa cells, coincubation of 4-hydroxytamoxifen with MSA resulted in a marked growth inhibition that was substantially greater than MSA alone. Growth inhibition by MSA and MSA + 4-hydroxytamoxifen in all cell lines was preceded by a specific decrease in ERα mRNA and protein without an effect on ERβ levels. Estradiol and 4-hydroxytamoxifen induction of endogenous ER-dependent gene expression (pS2 and c-myc) as well as ER-dependent reporter gene expression (ERE₂e1b-luciferase) was also attenuated by MSA in all cell lines before effect on growth inhibition. Taken together, these data strongly suggest that specific decrease in ERα levels by MSA is required for both MSA potentiation of the growth inhibitory effects of 4-hydroxytamoxifen and resensitization of tamoxifen-resistant cell lines. Carcinogenesis. 2006 Dec;27(12):2424-33. Epub 2006 Jun 19. The combination of green tea and tamoxifen is effective against breast cancer. Sartippour MR, Pietras R, Marquez-Garban DC, Chen HW, Heber D, Henning SM, Sartippour G, Zhang L, Lu M, Weinberg O, Rao JY, Brooks MN. Department of Surgery, Center for Human Nutrition, University of California, Los Angeles, CA 90095-1782, USA. Epidemiologic data have suggested that green tea may prevent breast cancer. Studies in our laboratory have provided evidence that green tea extract inhibits breast cancer growth by a direct anti-proliferative effect on the tumor cells, as well as by indirect suppressive effects on the tumor-associated endothelial cells. In this study, we asked whether concurrent administration of green tea may add to the anti-tumor effects of standard breast cancer therapy. We observed that green tea increased the inhibitory effect of tamoxifen on the proliferation of the ER (estrogen receptor)-positive MCF-7, ZR75, T47D human breast cancer cells in vitro. This combination regimen was also more potent than either agent alone at increasing cell apoptosis. In animal experiments, mice treated with both green tea and tamoxifen had the smallest MCF-7 xenograft tumor size, and the highest levels of apoptosis in tumor tissue, as compared with either agent administered alone. Moreover, the suppression of angiogenesis in vivo correlated with larger areas of necrosis and lower tumor blood vessel density in treated xenografts. Green tea decreased levels of ER-alpha in tumors both in vitro and in vivo. We also observed that green tea blocked ER-dependent transcription, as well as estradiol-induced phosphorylation and nuclear localization of mitogen-activated protein kinase. To our knowledge, this study is the first to show the interaction of green tea with the ER pathway, as well as provide mechanistic evidence that the combination of green tea and tamoxifen is more potent than either agent alone in suppressing breast cancer growth. These results may lead to future improvements in breast cancer treatment and prevention. PMID: 16785249 [PubMed - indexed for MEDLINE] Br J Cancer. 2008 Oct 7;99(7):1056-63. Epub 2008 Sep 16. A new role for tamoxifen in oestrogen receptor-negative breast cancer when it is combined with epigallocatechin gallate. Scandlyn MJ, Stuart EC, Somers-Edgar TJ, Menzies AR, Rosengren RJ. Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand. We have previously shown that tamoxifen+epigallocatechin gallate (EGCG) is synergistically cytotoxic towards oestrogen receptor (ER)-negative breast cancer cells. To determine if this response would correlate with significant tumour suppression in vivo, athymic nude female mice were implanted with MDA-MB-231 cells and treated with tamoxifen, EGCG, EGCG+tamoxifen, or vehicle control for 10 weeks. Tumour volume in EGCG- (25 mg kg(-1))+tamoxifen (75 microg kg(-1))-treated mice decreased by 71% as compared with vehicle control (P<0.05), whereas tumour weight was decreased by 80% compared with control (P<0.01). Epigallocatechin gallate treatment did not alter ER protein expression in MDA-MB-231 cells and thus was not a mechanism for the observed tumour suppression. However, western blotting of tumour extracts demonstrated that epidermal growth factor receptor (EGFR; 85% lower than control), pEGFR (78% lower than control), mammalian target of rapamycin (mTOR; 78% lower than control), and CYP1B1 (75% lower than control) were significantly lower after the combination treatment as compared with all other treatments. Nuclear factor-kappaB (NF-kappaB), b-Raf, p-MEK, S6K, 4EBP1, Akt, vascular EGFR-1 (VEGFR-1) and VEGF expressions were decreased in control but not in the individual treatments, whereas MEK, phospholipase D 1/2, TGF alpha, and ERK expressions were not changed after any treatment. The results demonstrate that tamoxifen at realistic doses (75 mug kg(-1)) can suppress the growth of ER-negative breast cancer when combined with EGCG. In addition, the dominant mechanism for tumour suppression is the concomitant decrease in tumour protein expressions of mTOR and the EGFR. PMID: 18797454 [PubMed - indexed for MEDLINE] http://www.springerlink.com/content/9n75721824648854/ Cancer Chemother Pharmacol. 2009 May 20. [Epub ahead of print] Preclinical rationale for combined use of endocrine therapy and 5-fluorouracil but neither doxorubicin nor paclitaxel in the treatment of endocrine-responsive breast cancer. Kurebayashi J, Nukatsuka M, Sonoo H, Uchida J, Kiniwa M. Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan, kure@med.kawasaki-m.ac.jp. PURPOSE: Our previous study indicated that concurrent administration of 4-OH-tamoxifen (TAM) and 5-fluorouracil (5-FU), but not doxorubicin (Dox), resulted in additive antitumor effects on endocrine-responsive breast cancer cells. We further clarified the effects of combined administration of endocrine therapy with chemotherapeutic agents in this study. METHODS: Concurrent treatment with 4-OH-TAM and paclitaxel (Ptx) was investigated in estrogen receptor (ER)-positive breast cancer cells. Additionally, the combined effects of estrogen depletion from culture medium mimicking estrogen ablative therapy with 5-FU, Dox, and Ptx were investigated. RESULTS: Concurrent treatment with 4-OH-TAM and Ptx yielded less than additive antitumor effects in ER-positive breast cancer cells, as observed with Dox in our previous study. More interestingly, estrogen depletion with 5-FU, but with neither Dox nor Ptx, yielded additive antitumor effects on these cells. We also performed preliminary experiments to elucidate the mechanisms of action responsible for the combined antitumor effects observed. Ptx up-regulated the level of expression of one of the molecules related to TAM resistance, Eph-A2, as observed with Dox in our previous study. Estrogen depletion down-regulated the level of expression of one of the molecules related to 5-FU resistance, thymidylate synthase, as observed with 4-OH-TAM in our previous study. CONCLUSIONS: These findings, together with those of our previous study, suggest that concurrent treatment with endocrine therapy, administration of TAM, or estrogen ablative therapy and 5-FU but neither Dox nor Ptx may yield additive antitumor effects on endocrine-responsive breast cancer. PMID: 19455332 [PubMed - as supplied by publisher] Cancer Chemother Pharmacol. 2007 Mar;59(4):515-25. Epub 2006 Aug 10. Additive antitumor effect of concurrent treatment of 4-hydroxy tamoxifen with 5-fluorouracil but not with doxorubicin in estrogen receptor-positive breast cancer cells. Kurebayashi J, Nukatsuka M, Nagase H, Nomura T, Hirono M, Yamamoto Y, Sugimoto Y, Oka T, Sonoo H. Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan. kure@med.kawasaki-m.ac.jp PURPOSE: The sequential addition of tamoxifen (TAM) to chemotherapy seems superior to its concurrent addition in patients with breast cancer. This study was conducted to clarify the hypothesis that there are differential interactions among TAM and chemotherapeutic agents. METHODS: Estrogen receptor (ER)-alpha-positive or -negative breast cancer cells were treated with 4-hydroxy TAM (4OHT), 5-fluorouracil (FU) and/or doxorubicin (Dox). Changes in the expression levels of genes related to sensitivity and resistance to TAM, 5-FU or Dox were tested. RESULTS: Concurrent treatment of 4OHT with 5-FU but not with Dox additively inhibited the growth of ER-alpha-positive cells. 5-FU did not change the expression levels of any tested genes related to either sensitivity or resistance to TAM. Although Dox did not change the expression levels of any genes related to the sensitivity to TAM, Dox significantly increased the expression levels of some genes related to TAM resistance, Eph A-2, ER-beta, Fos and vascular endothelial growth factor. 4OHT significantly decreased thymidilate synthase (TS) activity. CONCLUSIONS: Although the antitumor effect of concurrent 4OHT and 5-FU was additive, that of concurrent 4OHT and Dox was less than additive in ER-alpha-positive cells. The increased expression of genes related to TAM resistance by Dox might be responsible for the interaction. Decreased TS activity by 4OHT might increase the antitumor activity of 5-FU. These findings may provide a preclinical rationale for concurrent use with 5-FU and TAM. PMID: 16900372 [PubMed - indexed for MEDLINE] In vivo and in vitro efficacy of capecitabine (X) + tamoxifen (TAM) in breast cancer (BC) Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 25, No 18S (June 20 Supplement), 2007: 21092 K. Mori, Y. Yamaguchi, N. Sawada, K. Kondoh and S. Hayashi Chugai Pharmaceutical Co, Kamakura, Japan; Saitama Cancer Center, Ina-machi, Japan; School of Medicine, Tohoku University, Sendai, Japan 21092 Background: In vitro studies in BC cell lines suggested antagonismbetween TAM and 5-FU. Thymidine phosphorylase (TP) activatesX to 5-FU in tumors. X activity correlates with tumor TP concentrationsin vivo. Methods: We studied antitumor efficacy of X + TAM invivo and in vitro in human BC models. Nude mice were inoculateds.c. with estradiol, then MCF-7 cells 1 day later. When tumorswere 300 mm³, mice received 6 weeks’ oral vehicle (control),X (d1–14 q21d) at MTD (539 mg/kg) or 2/3 MTD, and/or TAMat 100 or 30 mg/kg/d. We also analyzed impact of 5-FU and doxifluridine(5'-DFUR, an intermediate of X) + TAM on estrogen receptor (ER)signals in an in-vitro culture system. ER signals were monitoredby expression of green fluorescent protein (GFP) in MCF-7 BCcells transfected with the estrogen-responsive element (ERE)-GFPgene (MCF-7-E10). GFP expression was induced in MCF-7-E10 cellsin the presence of estradiol at 3 pM or BC tissue supernatant.Results: X at 2/3 MTD + TAM 30 mg/kg were significantly moreactive than the highest dose of X or TAM alone. Tumor TP concentrationswere significantly higher in TAM- than vehicle-treated mice.In the ER signal system, GFP expression of MCF-7-E10 was reducedby 4-hydroxytamoxifen (4-OHT, active form of TAM) at 0.01 and0.1 nM. When added to 4-OHT, 5-FU 0.3–30 µM or 5'-DFUR3–10 µM reduced GFP expression more than eitheragent alone. In vitro, 5-FU and 5'-DFUR inhibited proliferationof MCF-7-E10 cells regardless of 4-OHT. Additive effects couldnot be confirmed as 4-OHT alone showed only marginal anti- proliferativeactivity at 0.01–0.1 nM. Conclusion: X and TAM are notantagonistic in this model. TAM may augment X activity via TPupregulation in BC tissues. TAM and X intermediates showed noclear antagonism in vitro in an ER signal system. All-oral X+ TAM merits evaluation as combination therapy in breast cancer. Br J Cancer. 1997;75(6):884-91. Synergistic antiproliferative activity of tamoxifen and docetaxel on three oestrogen receptor-negative cancer cell lines is mediated by the induction of apoptosis. FULL TEXT: http://www.ncbi.nlm.nih.gov/pmc/arti...00183-0110.pdf Ferlini C, Scambia G, Distefano M, Filippini P, Isola G, Riva A, Bombardelli E, Fattorossi A, Benedetti Panici P, Mancuso S. Department of Obstetrics and Gynecology, Catholic University of Sacred Heart, Rome, Italy. The taxanes are a promising family of anti-tumour drugs that block cell cycle replication by interfering with the microtubule network. The clinical use of these drugs involves some problems related to their low solubility and occurrence of resistance, which is mainly dependent on the multidrug-resistant (MDR) phenotype. To investigate the possible interaction between docetaxel and tamoxifen (TAM), three oestrogen receptor-negative cancer cell lines, MDR- MDA-MB 231, MDR + CEM-VBLr and MCF-7 ADRr, were used. In all three cell lines, the combination of docetaxel and TAM was more effective in terms of growth inhibition than single drug exposure. Isobolic analysis confirmed the presence of synergism in all cell lines when docetaxel was used at 0.2 microM and TAM at a dose equal to or higher than 1 microM. Flow cytometric DNA analysis performed on the three cell lines showed that TAM was able to increase the G2/M blocking activity of docetaxel. This blocking activity was followed by an increased flow cytometric DNA fragmentation suggestive of the presence of apoptosis, which was confirmed by DNA gel fragmentation and morphological analysis. While an antagonistic effect on P-glycoprotein (P-gp) activity may contribute to the synergistic effect of tamoxifen and docetaxel on CEM-VBLr and MCF-7 ADRr, other mechanisms must be involved, as the synergistic effect is also apparent with a P-gp-negative cell line. Br J Cancer. 1999 Jan;79(2):257-63. Tamoxifen induces oxidative stress and apoptosis in oestrogen receptor-negative human cancer cell lines. Ferlini C, Scambia G, Marone M, Distefano M, Gaggini C, Ferrandina G, Fattorossi A, Isola G, Benedetti Panici P, Mancuso S. Laboratory of Antineoplastic Pharmacology, Zeneca, Rome, Italy. Recent data have demonstrated that the anti-oestrogen tamoxifen (TAM) is able to facilitate apoptosis in cancer cells not expressing oestrogen receptor (ER). In an attempt to identify the biochemical pathway for this phenomenon, we investigated the role of TAM as an oxidative stress agent. In two ER-negative human cancer cell lines, namely T-leukaemic Jurkat and ovarian A2780 cancer cells, we have demonstrated that TAM is able to generate oxidative stress, thereby causing thiol depletion and activation of the transcriptional factor NF-kappaB. As described for other oxidative agents, TAM was able to induce either cell proliferation or apoptosis depending on the dose. When used at the lowest dose tested (0.1 microM), a slight proliferative effect of TAM was noticed in terms of cell counts and DNA synthesis rate, whereas at higher doses (10 microM) a consistent occurrence of apoptosis was detected. Importantly, the induction of apoptosis by TAM is not linked to down-regulation or functional inactivation by phosphorylation of the antiapoptotic bcl-2 protein. PMID: 9888466 [PubMed - indexed for MEDLINE] 1: Biochem Pharmacol. 2005 Sep 1;70(5):725-32. Links Modulation of epirubicin cytotoxicity by tamoxifen in human breast cancer cell lines. Ebtehal El-Demerdash: ebtehal_dm@yahoo.com Azab SS, El-Demerdash E, Abdel-Naim AB, Youssef E, El-Sharkawy N, Osman AM. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Egypt. The present study was designed to investigate the modulatory effect of the anti-estrogen, tamoxifen (Tam) on epirubicin (Epi) cytotoxicity in breast cancer cell lines; MCF-7 and NCI-adr. Using sulphorhodamine-B assay, NCI-adr cell line was found to be five-folds more resistant to the cytotoxic effect of Epi as compared to MCF-7 cell line. Pretreatment of cells with Tam was observed to enhance Epi cytotoxicity by 4.3- and 6.5-folds in MCF-7 and NCI-adr cells, respectively. Tam-Epi interaction was found to be additive in MCF-7 cells and synergistic in NCI-adr cells. Flowcytometric DNA ploidy analysis revealed that, Epi induced cell arrest at G2/M phase. Tam pretreatment enhanced the blocking activity of low dose of Epi in MCF-7 and induced nearly two-fold increase in the percentage of S phase in NCI-adr cells. Determination of cellular Epi level revealed that Tam induced a significant increase in intracellular Epi accumulation only in NCI-adr cells after 48 h. However, analysis of P-gp function revealed that Tam failed to modulate P-gp function in both cell lines. Also, assessment of topoisomerae IIalpha gene expression showed that neither Epi nor Tam managed to change its expression level. In conclusion, Tam potentiates Epi cytotoxicity in sensitive and resistant breast cancer cell lines.enhancement of cell accumulation in S and G2/M phase, at which the cells are most sensitive to the cytotoxic effect This potentiation can be explained by an of Epi as well as an increase in the intracellular level of Epi in resistant cell line. PMID: 16005435 [PubMed - indexed for MEDLINE 1: Cancer Lett. 1996 Nov 12;108(1):7-14. Links Tamoxifen synergizes the antiproliferative effect of cisplatin in human ovarian cancer cells: enhancement of DNA platination as a possible mechanism. Ercoli A, Scambia G, De Vincenzo R, Alimonti A, Petrucci F, Fattorossi A, Isola G, Benedetti Panici P, Caroli S, Mancuso S. Department of Gynecology, Catholic University, Rome, Italy. We investigated the chemosensitizing activity of tamoxifen (TAM) on estrogen receptor negative ovarian cancer cell lines sensitive (A2780 WT) and resistant to cisplatin (CP) (A2780 CP3). Our results showed that the treatment of both cell lines with the association TAM + CP (concentration range 0.01-1 microN and 0.1-1 microgram/ml, respectively) results in a synergistic antiproliferative activity and a complete reversal of the acquired CP-resistant phenotype. We demonstrated that in A2780 cells the addition of TAM to CP treatment is able to significantly enhance at every tested CP dose (P < 0.001) the amount of platinum (Pt) bound to the DNA. Since Pt-DNA levels in the genome are clearly related to the growth inhibitory effect of CP (correlation value = 0.97, P < 0.001) in our experimental model, we hypothesized that TAM could act synergistically with CP and overcome the acquired CP-resistance by enhancing Pt binding to the DNA. We suggest that, from a clinical point of view, TAM may be usefully included in CP-based chemotherapy regimens for ovarian cancer patients since plasma concentrations of the drug capable of in vitro CP resistance modulation are achievable in vivo. A prospective clinical trial to verify the clinical usefulness of combined TAM + CP treatment in ovarian cancer patients refractory to prior Pt-based chemotherapy is now underway in our department. Cancer Chemother Pharmacol. 1995;36(5):368-72. Effect of tamoxifen on mitoxantrone cytotoxicity in drug-sensitive and multidrug-resistant MCF-7 cells. Desai PB, Bhardwaj R, Damle B. Division of Medicinal Chemistry and Pharmaceutics, School of Pharmacy, Northeast Louisiana University, Monroe 71209-0470, USA. The influence of the antiestrogen tamoxifen (TAM) on the activity of mitoxantrone (MXN), was evaluated against wild-type MCF-7/WT and their multidrug-resistant variant MCF-7/ADR cells. Multidrug resistance (MDR) in this cell line which was selected for resistance to Adriamycin (ADR), is associated with increased expression of P-glycoprotein (P-gp). In a clonogenic assay it was observed that TAM (1-10 microM) significantly enhanced the activity of MXN in the MCF-7/ADR but not in the drug-sensitive cell line. Isobologram analysis indicated that the effect of the combination was additive in the parental MCF-7/WT cells and strongly synergistic in the MDR MCF-7/ADR cells. Also, TAM (10 microM) caused a three-fold increase in the steady-state levels (Css) of MXN in MCF-7/ADR cells but did not modulate MXN levels in MCF-7/WT cells. The observed synergism in MCF-7/ADR cells was perhaps due to the increase in Css of MXN that may involve interaction of TAM with P-gp. The combination of MXN and TAM may be useful in the treatment of drug-sensitive and drug-resistant breast cancer. PMID: 7634377 [PubMed - indexed for MEDLINE] Anticancer Drugs. 2007 Sep;18(8):923-31. Enhancement of the antitumor activity of tamoxifen and anastrozole by the farnesyltransferase inhibitor lonafarnib (SCH66336, Sarasar). Liu G, Marrinan CH, Taylor SA, Black S, Basso AD, Kirschmeier P, Robert Bishop W, Liu M, Long BJ. Department of Biological Research - Oncology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. Lonafarnib is an orally bioavailable farnesyltransferase inhibitor. Originally developed to block the membrane localization of Ras, subsequent work suggested that farnesyltransferase inhibitors mediate their antitumor activities by altering the biological activities of additional farnesylated proteins. Breast tumor models that express wild-type Ras have been shown to be sensitive to farnesyltransferase inhibitors. We have determined the effects of combining lonafarnib with the antiestrogen 4-hydroxy tamoxifen on hormone-dependent breast cancer cell lines in vitro. The effects of combining lonafarnib with tamoxifen or the aromatase inhibitor anastrozole on the growth of two different MCF-7 breast tumor xenograft models were also evaluated. In four of five human breast cancer cell lines, lonafarnib enhanced the antiproliferative effects of 4-hydroxy tamoxifen. The combination prevented MCF-7 cells from transitioning through the G1 to S phase of the cell cycle and augmented apoptosis. This was associated with reduced expression of E2F-1 and a reduction in hyperphosphorylated retinoblastoma protein. Lonafarnib plus 4-hydroxy tamoxifen also inhibited the mammalian target of rapamycin signal transduction pathway. In nude mice bearing parental MCF-7 or aromatase-transfected MCF-7Ca breast tumor xenografts, lonafarnib enhanced the antitumor activity of both tamoxifen and anastrozole. These studies indicate that lonafarnib enhances the efficacy of endocrine agents clinically used for treating hormone-dependent breast cancer. Chemo Followed by Tamoxifen Augments Survival in ER+ Breast Cancer As Reported by HealthDay News. 2009 Dec 11 Postmenopausal women who have estrogen-receptor (ER)−positive breast cancer may be able to improve their survival if they receive treatment with a combination of chemotherapy and tamoxifen. Traditionally, such patients are given tamoxifen, which blocks estrogen receptors. However, researchers have speculated that women with ER-positive breast cancer might benefit from also receiving chemotherapy. Researchers at Loyola University Chicago Stritch School of Medicine compared the survival benefits of 4 different regimens in 1460 patients, whom they followed for up to 13 years (median, 9 years). The regimens compared were tamoxifen alone, chemotherapy alone, tamoxifen plus chemotherapy given simultaneously, and chemotherapy followed by tamoxifen. All of the patients had positive lymph nodes. Tamoxifen was taken for 5 years. The chemotherapy regimen consisted of cyclophosphamide, doxorubicine (Adriamycin), and 5-fluorouracil. Compared with tamoxifen alone, the combination of chemotherapy with tamoxifen increased disease-free survival by 24%. Sequential administration of chemotherapy followed by tamoxifen was slightly more beneficial than simultaneous tamoxifen plus chemotherapy. Estimated disease-free survival at 10 years was 48% for the tamoxifen-alone group, as compared with 57% for the group receiving both chemotherapy and tamoxifen. The research results were published in the December 10 online issue of The Lancet and were presented on December 10 at the San Antonio Breast Cancer Symposium. Health News Adding Chemo to Tamoxifen Helps Some Breast Cancer Patients 12/11/2009 THURSDAY, Dec. 10 (HealthDay News) -- Adding chemotherapy to standard cancer-suppressing tamoxifen can boost survival in postmenopausal women with the most common type of breast cancer, known as estrogen receptor-positive, and it's best given before the tamoxifen regimen starts, according to a new study. "Chemotherapy with Adriamycin adds to your survival benefit over and above what tamoxifen would do if you are postmenopausal and have positive lymph nodes and estrogen receptor-positive cancer [the most common type]," explained Dr. Kathy Albain, the lead researcher and professor of medicine at Loyola University Chicago Stritch School of Medicine. And in another study, Albain found that screening breast tumors with an available multi-gene test spots patients who may not need this form of chemotherapy, despite fitting the standard profile. Both studies are published online Dec. 10, the first in the journal The Lancet and the second in The Lancet Oncology. Albain is also due to present her findings Thursday at the annual San Antonio Breast Cancer Symposium in San Antonio, Texas. In estrogen receptor-positive cancer, tumor cells carry many receptors on their surfaces to which estrogen can attach, fueling tumor growth. Tamoxifen works by blocking the receptors. Experts have long debated whether women with estrogen receptor-positive cancers -- whose growth is fueled by circulating estrogen -- would get more benefit from having a chemotherapy regimen on top of tamoxifen. Albain led a research team from multiple centers that followed nearly 1,500 breast cancer patients for up to 13 years, with a median (half longer, half less) of nearly nine years. All were past menopause and had hormone receptor-positive cancer that had spread to at least one lymph node in the armpit area. Albain's team assigned 381 women to tamoxifen alone, 587 to chemotherapy alone and 590 to both, with some receiving tamoxifen and chemo together and some in a sequential manner. Tamoxifen was taken daily for five years. The chemo regimen used is called CAF, for "cyclophosphamide, Adriamycin and 5-fluorouracil." In all, after accounting for study dropouts, 1,460 women received treatment. The combined treatments of chemo plus tamoxifen increased the women's disease-free survival by 24 percent, Albain found. When her team looked at which delivery protocol worked best -- simultaneous tamoxifen and chemotherapy or chemo followed by tamoxifen -- the sequential approach was found to be better, giving slightly better disease-free survival. Ten-year disease-free survival estimates were 57 percent for the combination group and 48 percent for the tamoxifen-only group, the researchers found. However, women receiving chemo were more likely to have drops in white blood cells, important for fighting infections, the team noted. And they were also more prone to blood clots, congestive heart failure and other complications. In a second study, Albain's team analyzed whether a gene test, called Oncotype DX, could predict which women would benefit from chemotherapy. Genomic Health, which makes the test, helped fund the study, along with the U.S. National Cancer Institute. The test, which Albain said is already widely used, is done on the tumor itself. "This puts 21 genes together and comes up with a score," she said. The score -- low, intermediate, high -- predicts the risk of recurrence over 10 years if a woman used tamoxifen alone. When the researchers performed the test on 367 specimens, they found a low score identified those women who may not need the chemo, despite the fact that they have cancer that spread to lymph nodes. "This is a positive study, there's no question," said Dr. Joanne Mortimer, vice chair of medical oncology for the City of Hope Cancer Center in Duarte, Calif., of the first study. "This study tells us [that] if you have positive lymph nodes [and are postmenopausal with estrogen receptor-positive cancer], you should have both chemo and tamoxifen, because the survival was better." But, she added, "when you give everyone [who has the estrogen receptor-positive, node-positive breast cancer] chemotherapy, probably there are some who don't need it." According to Mortimer, that's why the gene test looks promising -- it may spare some women from having to have chemo while ensuring that those who will benefit from the treatment get it. __________________ Mom's treatment history (link)