Phase III Study of <i>N,N</i>-Diethyl-2-[4-(Phenylmethyl) Phenoxy]Ethanamine (BMS-217380-01) Combined With Doxorubicin Versus Doxorubicin Alone in Metastatic/Recurrent Breast Cancer: National Cancer Institute of Canada Clinical Trials Group Study MA.19

Reyno, Leonard; Seymour, Lesley; Tu, Dongsheng; Dent, Susan; Gelmon, Karen; Walley, Barbara; Płużańska, A; Gorbunova, Vera; Garin, A.; Jassem, Jacek; Pieńkowski, Tadeusz; Dancey, Janet; Pearce, Laura; MacNeil, Mary; Marlin, S.; Lebwohl, David; Voi, Maurizio; Pritchard, Kathleen I.

doi:10.1200/jco.2003.04.075

Cited by 57 publications

(24 citation statements)

References 13 publications

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“…In aggregate, our data suggest that DPPE directly targets TICs. This model may explain the significant improvement in overall survival and progression-free survival observed in the doxorubicin plus DPPE arm despite no objective difference in tumor response (38), as targeted killing of rare TICs may reduce additional metastasis and improve overall survival without significantly affecting the bulk of metastatic tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Our results suggest that DPPE-based therapies should involve continuous or frequent administration of the drug. This is notably a challenge given the side effect of the drugs at the current dose (38), but may be overcome with a better understanding of the pharmacokinetics of DPPE. Alternatively, more potent DPPE derivatives with better specificity may be developed.…”

Section: Discussionmentioning

confidence: 99%

“…In a phase III randomized trial for metastatic breast cancer using doxorubicin with or without DPPE, it was observed that the addition of the latter resulted in a significant improvement in overall survival and a trend toward a difference in progression-free survival but, paradoxically, no difference in objective tumor response (38). The effect of adding DPPE was not reproduced in the most recent trial of epirubicin plus cyclophosphamide +/-DPPE in naBve, previously untreated patients with metastatic breast cancer, possibly because of the excellent response by the EC arm alone, 6 although results from long-term follow-up are not yet available.…”

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confidence: 99%

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Preferential Killing of Breast Tumor Initiating Cells by N,N-Diethyl-2-[4-(Phenylmethyl)Phenoxy]Ethanamine/Tesmilifene

Deng

Liu²,

Pritchard³

et al. 2008

Clinical Cancer Research

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Purpose: N,N-Diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine (DPPE; tesmilifene) is thought to potentiate the antineoplastic effect of cytotoxic drugs. In a phase III randomized trial for metastatic breast cancer using doxorubicin with or without DPPE, addition of the latter resulted in a significant improvement in overall survival and a trend toward a difference in progression-free survival but, paradoxically, no difference in objective tumor response. Here we tested the hypothesis that DPPE targets breast tumor-initiating cells (TICs). Experimental Design: Human breast TICs from pleural effusions were identified as CD44 + :CD24 -/low cells by flow cytometry and functionally by their ability to form nonadherent spheres in culture. Mouse mammary TICs from two different models of breast cancer were identified as cells capable of initiating spheres in culture and secondary tumors following transplantation into the mammary gland of syngeneic mice. Results: We show that at physiologically attainable concentrations, treatment with DPPE alone reduced tumorsphere formation and viability of CD44 +

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Preferential Killing of Breast Tumor Initiating Cells by N,N-Diethyl-2-[4-(Phenylmethyl)Phenoxy]Ethanamine/Tesmilifene

Deng

Liu²,

Pritchard³

et al. 2008

Clinical Cancer Research

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“…Tesmilifene (DPPE) is a structural analogue of PBPE that was brought up to a phase III clinical trial in association with cytotoxic drugs for breast cancer treatment (38). The rationale for this combination was the observation that tesmilifene sensitized tumor cells to chemotherapy by reversing their multidrug-resistant phenotype (39).…”

Section: Discussionmentioning

confidence: 99%

Microsomal antiestrogen-binding site ligands induce growth control and differentiation of human breast cancer cells through the modulation of cholesterol metabolism

Payré

Médina

Boubekeur

et al. 2008

Molecular Cancer Therapeutics

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The microsomal antiestrogen-binding site (AEBS) is a highaffinity membranous binding site for the antitumor drug tamoxifen that selectively binds diphenylmethane derivatives of tamoxifen such as PBPE and mediates their antiproliferative properties. The AEBS is a hetero-oligomeric complex consisting of 3B-hydroxysterol-# 8 -# 7 -isomerase and 3B-hydroxysterol-# 7 -reductase. High-affinity AEBS ligands inhibit these enzymes leading to the massive intracellular accumulation of zymostenol or 7-dehydrocholesterol (DHC), thus linking AEBS binding to the modulation of cholesterol metabolism and growth control. The aim of the present study was to gain more insight into the control of breast cancer cell growth by AEBS ligands. We report that PBPE and tamoxifen treatment induced differentiation in human breast adenocarcinoma cells MCF-7 as indicated by the arrest of cells in the G 0 -G 1 phase of the cell cycle, the increase in the cell volume, the accumulation and secretion of lipids, and a milk fat globule protein found in milk. These effects were observed with other AEBS ligands and with zymostenol and DHC. Vitamin E abrogates the induction of differentiation and reverses the control of cell growth produced by AEBS ligands, zymostenol, and DHC, showing the importance of the oxidative processes in this effect. AEBS ligands induced differentiation in estrogen receptor-negative mammary tumor cell lines SKBr-3 and MDA-MB-468 but with a lower efficiency than observed with MCF-7. Together, these data show that AEBS ligands exert an antiproliferative effect on mammary cancer cells by inducing cell differentiation and growth arrest and highlight the importance of cholesterol metabolism in these effects.

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“…We therefore asked whether we could screen for TFU inhibitory drugs. Primary tumorspheres were dissociated into single cells and treated with Adriamycin (doxorubicin), an anthracycline used in single-agent treatment of breast cancer (36,37). The ability of the cells to form secondary tumorspheres in the absence of the drug was determined by counting spheres 2 weeks later.…”

Section: When Sca1mentioning

confidence: 99%

Identification of Tumorsphere- and Tumor-Initiating Cells in HER2/Neu-Induced Mammary Tumors

Liu

Deng²,

Lehal³

et al. 2007

Cancer Research

149

144

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A variety of human malignancies, including breast cancer, are thought to be organized in a hierarchy, whereby a relatively minor population of tumor initiating cells (TIC) is responsible for tumor growth and the vast majority of remaining cells is nontumorigenic. Analysis of TICs in model systems of breast cancer would offer uniform and accessible source of tumor cells and the power of mouse genetics to dissect these rare cells. The HER2/Neu proto-oncogene is overexpressed in an aggressive form of human breast cancer. Mouse mammary tumor virus (MMTV)-Neu transgenic mice develop mammary tumors that mimic human HER2 subtype breast cancer. Here, we report on the functional identification of mouse HER2/Neu TICs that can induce tumors after transplantation into the mammary gland of recipient mice. Secondary tumors formed after injecting MMTV-Neu TICs resemble primary tumors in the original transgenic mice and are organized in a hierarchy containing TICs as well as their nontumorigenic descendants. To study MMTV-Neu TICs in vitro, we grew tumorspheres under nonadherent culture conditions. Tumorsphere forming units (TFU) capable of producing tumorspheres retained tumorigenic potential and were indistinguishable by several criteria from TICs. Interestingly, MMTV-Neu TICs and TFUs were committed to the luminal cell fate when induced to differentiate in vitro. Our data define reproducible characteristics of the MMTV-Neu TIC and TFU, which help to explain marker expression profiles of HER2-positive breast cancer. In addition, the similarity between TICs and TFUs in this system provides a rationale for TFU-based screens to target tumor-initiating cells in HER2 + breast cancer. [Cancer Res 2007; 67(18):8671-81]

show abstract

Phase III Study of N,N-Diethyl-2-[4-(Phenylmethyl) Phenoxy]Ethanamine (BMS-217380-01) Combined With Doxorubicin Versus Doxorubicin Alone in Metastatic/Recurrent Breast Cancer: National Cancer Institute of Canada Clinical Trials Group Study MA.19

Abstract: This study demonstrated no advantage in RR, RD, or PFS but significantly superior OS for DPPE plus DOX. Additional studies of DPPE are warranted.

Cited by 57 publications

References 13 publications

Preferential Killing of Breast Tumor Initiating Cells by N,N-Diethyl-2-[4-(Phenylmethyl)Phenoxy]Ethanamine/Tesmilifene

Preferential Killing of Breast Tumor Initiating Cells by N,N-Diethyl-2-[4-(Phenylmethyl)Phenoxy]Ethanamine/Tesmilifene

Microsomal antiestrogen-binding site ligands induce growth control and differentiation of human breast cancer cells through the modulation of cholesterol metabolism

Identification of Tumorsphere- and Tumor-Initiating Cells in HER2/Neu-Induced Mammary Tumors

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