HER2 Support Group Forums - View Single Post - Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Cell

Rich66 · 10-03-2009, 07:43 PM

1: Clin Cancer Res. 2009 Jan 1;15(1):119-30. Links: Preferential killing of breast tumor initiating cells by N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine/tesmilifene.

Deng T, Liu JC, Pritchard KI, Eisen A, Zacksenhaus E.
Toronto General Research Institute-University Health Network, Ontario, Canada.
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(+):CD24(-/low) breast cancer cells. The kinetics of killing varied for the different breast tumor cells and required continuous exposure to the drug. Whereas doxorubicin killed CD44(+):CD24(-/low) and CD44(-):CD24(+) cells equally well, DPPE induced apoptosis preferentially in CD44(+):CD24(-/low) cells. Treatment of Her2/Neu(+) mammary tumor cells with DPPE in vitro efficiently killed TICs, as determined by flow cytometry and transplantation assays; DPPE further cooperated with doxorubicin to completely eradicate tumorigenic cells. CONCLUSIONS: Our results show that continuous treatment with DPPE alone directly targets breast TICs, and provide rationale to test for cooperation between DPPE and known drugs with efficacy toward breast cancer subtypes.
PMID: 19118039 [PubMed - indexed for MEDLINE

Tesmilifene is a Tamoxifen derivative.
Please note the significant finding that is so different from the early detectable tumor shrinkage=efficacy paradigm:
"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."

1: Cancer Lett. 2009 Feb 18;274(2):279-89. Epub 2008 Nov 4. Links: Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene.

Ferguson PJ, Brisson AR, Koropatnick J, Vincent MD.
Lawson Health Research Institute, London Health Sciences Centre, 790 Commissioners Road, London, Ontario, Canada. peter.ferguson@uwo.ca
N,N-diethyl-2-[4-(phenylmethyl)phenoxyl]ethanamine (tesmilifene), a tamoxifen derivative with antihistamine activity, greatly enhanced the survival of doxorubicin-treated, advanced stage breast cancer patients in a phase III trial. However, the molecular basis of tesmilifene action is not firmly established. The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma (HNSCC) and breast carcinoma cell lines as a model system. Multidrug resistant (MDR) variants of an HNSCC cell line, HN-5a/V15e, and a breast carcinoma cell line, MCF-7/V25a, both highly overexpressed mdr1 (ABCB1) mRNA and the proteins P-glycoprotein and glutathione transferase-pi. Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect. Tesmilifene had minimal effect on drug cytotoxicity against the parental cell lines. However, the same tesmilifene treatment enhanced cytotoxicity of docetaxel, paclitaxel, epirubicin, doxorubicin, and vinorelbine against both MDR cell lines by up to 50%. Flow cytometric measurement of annexin V/propidium iodide staining demonstrated that tesmilifene increased the killing of HN-5a/V15e cells caused by docetaxel after 24 and 48h exposure. Tesmilifene increased accumulation of radiolabelled vincristine in HN-5a/V15e cells, over 4h, by up to 100%. The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs. The mechanism of enhancement appears to be related to expression of an ABC pump-dependent, MDR phenotype.

1: Hum Exp Toxicol. 2008 Feb;27(2):143-7. Links: N,N-diethyl-2-[4-(phenylmethyl) phenoxy] ethanamine (DPPE; tesmilifene), a chemopotentiating agent with hormetic effects on DNA synthesis in vitro, may improve survival in patients with metastatic breast cancer.

Brandes LJ.
Department of Medicine and Pharmacology/Therapeutics, University of Manitoba and Section of Hematology/Oncology, CancerCare Manitoba, 675 McDermot Avenue, Winnipeg MB R3E0V9, Canada. brandes@cc.umanitoba.ca
N,N-diethyl-2-[4-(phenylmethyl) phenoxy] ethanamine (DPPE; tesmilifene) is a novel anti-histaminic and chemopotentiating agent that has a hormetic effect on DNA synthesis in MCF (Michigan Cancer Foundation)-7 human breast cancer cells in vitro and stimulates the growth of experimental tumors in rodents. In a prospectively randomized phase three trial (NCIC MA.19), 152 patients who were co-administered DPPE and doxorubicin survived 50% longer (P < 0.03) than 153 patients who were administered the same dose and schedule of doxorubicin alone. At clinically relevant in vitro concentrations that do not inhibit the P-glycoprotein (P-gp) pump, DPPE selectively sensitizes the cancer cells that express the multiple drug resistance phenotype, making them more susceptible to the cytotoxic effects of chemotherapeutic agents, including anthracyclines and taxanes. Based on its previously demonstrated interaction with histamine at CYP3A4, a P450 that metabolizes arachidonic acid, and its induction of high levels of prostacyclin in the gut of rodents, modulation by DPPE of the intracellular concentration of arachidonate products, such as hydroxyeicosatetraeinoic acids, implicated in increased cancer cell proliferation and metastasis, is postulated.
PMID: 18480139 [PubMed - indexed for MEDLINE

http://www.ymbiosciences.com/product...ne/science.php

Science

Tesmilifene has an intriguing mechanism of action and has been shown in Phase II clinical trials and in one Phase III clinical trial to enhance the activity of anthracyclines and taxanes, as well as cisplatin and 5-FU in a variety of pre-clinical models.

In clinical studies there is evidence that tesmilifene increases the cytotoxic effects of mitoxantrone and cyclophosphamide in prostate cancer and doxorubicin and taxol in metastatic breast cancer. In a Phase III study of patients with metastatic breast cancer, the addition of tesmilifene to doxorubicin resulted in a 50% increase in survival compared with doxorubicin alone. A second Phase III study of metastatic breast cancer in 723 patients treated with epirubicin/cyclophosphamide +/- tesmilifene failed to demonstrate efficacy with this chemotherapy regimen.

10-03-2009, 07:43 PM	#42
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Re: Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Ce 1: Clin Cancer Res. 2009 Jan 1;15(1):119-30. Links Preferential killing of breast tumor initiating cells by N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine/tesmilifene. Deng T, Liu JC, Pritchard KI, Eisen A, Zacksenhaus E. Toronto General Research Institute-University Health Network, Ontario, Canada. 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(+):CD24(-/low) breast cancer cells. The kinetics of killing varied for the different breast tumor cells and required continuous exposure to the drug. Whereas doxorubicin killed CD44(+):CD24(-/low) and CD44(-):CD24(+) cells equally well, DPPE induced apoptosis preferentially in CD44(+):CD24(-/low) cells. Treatment of Her2/Neu(+) mammary tumor cells with DPPE in vitro efficiently killed TICs, as determined by flow cytometry and transplantation assays; DPPE further cooperated with doxorubicin to completely eradicate tumorigenic cells. CONCLUSIONS: Our results show that continuous treatment with DPPE alone directly targets breast TICs, and provide rationale to test for cooperation between DPPE and known drugs with efficacy toward breast cancer subtypes. PMID: 19118039 [PubMed - indexed for MEDLINE Tesmilifene is a Tamoxifen derivative. Please note the significant finding that is so different from the early detectable tumor shrinkage=efficacy paradigm: "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." 1: Cancer Lett. 2009 Feb 18;274(2):279-89. Epub 2008 Nov 4. Links Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene. Ferguson PJ, Brisson AR, Koropatnick J, Vincent MD. Lawson Health Research Institute, London Health Sciences Centre, 790 Commissioners Road, London, Ontario, Canada. peter.ferguson@uwo.ca N,N-diethyl-2-[4-(phenylmethyl)phenoxyl]ethanamine (tesmilifene), a tamoxifen derivative with antihistamine activity, greatly enhanced the survival of doxorubicin-treated, advanced stage breast cancer patients in a phase III trial. However, the molecular basis of tesmilifene action is not firmly established. The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma (HNSCC) and breast carcinoma cell lines as a model system. Multidrug resistant (MDR) variants of an HNSCC cell line, HN-5a/V15e, and a breast carcinoma cell line, MCF-7/V25a, both highly overexpressed mdr1 (ABCB1) mRNA and the proteins P-glycoprotein and glutathione transferase-pi. Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect. Tesmilifene had minimal effect on drug cytotoxicity against the parental cell lines. However, the same tesmilifene treatment enhanced cytotoxicity of docetaxel, paclitaxel, epirubicin, doxorubicin, and vinorelbine against both MDR cell lines by up to 50%. Flow cytometric measurement of annexin V/propidium iodide staining demonstrated that tesmilifene increased the killing of HN-5a/V15e cells caused by docetaxel after 24 and 48h exposure. Tesmilifene increased accumulation of radiolabelled vincristine in HN-5a/V15e cells, over 4h, by up to 100%. The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs. The mechanism of enhancement appears to be related to expression of an ABC pump-dependent, MDR phenotype. 1: Hum Exp Toxicol. 2008 Feb;27(2):143-7. Links N,N-diethyl-2-[4-(phenylmethyl) phenoxy] ethanamine (DPPE; tesmilifene), a chemopotentiating agent with hormetic effects on DNA synthesis in vitro, may improve survival in patients with metastatic breast cancer. Brandes LJ. Department of Medicine and Pharmacology/Therapeutics, University of Manitoba and Section of Hematology/Oncology, CancerCare Manitoba, 675 McDermot Avenue, Winnipeg MB R3E0V9, Canada. brandes@cc.umanitoba.ca N,N-diethyl-2-[4-(phenylmethyl) phenoxy] ethanamine (DPPE; tesmilifene) is a novel anti-histaminic and chemopotentiating agent that has a hormetic effect on DNA synthesis in MCF (Michigan Cancer Foundation)-7 human breast cancer cells in vitro and stimulates the growth of experimental tumors in rodents. In a prospectively randomized phase three trial (NCIC MA.19), 152 patients who were co-administered DPPE and doxorubicin survived 50% longer (P < 0.03) than 153 patients who were administered the same dose and schedule of doxorubicin alone. At clinically relevant in vitro concentrations that do not inhibit the P-glycoprotein (P-gp) pump, DPPE selectively sensitizes the cancer cells that express the multiple drug resistance phenotype, making them more susceptible to the cytotoxic effects of chemotherapeutic agents, including anthracyclines and taxanes. Based on its previously demonstrated interaction with histamine at CYP3A4, a P450 that metabolizes arachidonic acid, and its induction of high levels of prostacyclin in the gut of rodents, modulation by DPPE of the intracellular concentration of arachidonate products, such as hydroxyeicosatetraeinoic acids, implicated in increased cancer cell proliferation and metastasis, is postulated. PMID: 18480139 [PubMed - indexed for MEDLINE http://www.ymbiosciences.com/product...ne/science.php Science Tesmilifene has an intriguing mechanism of action and has been shown in Phase II clinical trials and in one Phase III clinical trial to enhance the activity of anthracyclines and taxanes, as well as cisplatin and 5-FU in a variety of pre-clinical models. In clinical studies there is evidence that tesmilifene increases the cytotoxic effects of mitoxantrone and cyclophosphamide in prostate cancer and doxorubicin and taxol in metastatic breast cancer. In a Phase III study of patients with metastatic breast cancer, the addition of tesmilifene to doxorubicin resulted in a 50% increase in survival compared with doxorubicin alone. A second Phase III study of metastatic breast cancer in 723 patients treated with epirubicin/cyclophosphamide +/- tesmilifene failed to demonstrate efficacy with this chemotherapy regimen.