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Old 09-18-2009, 12:17 PM   #21
Rich66
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Re: BPH-715 (revised Zoledronate) A New Weapon Against Tumor Cells

ABCSG-12: Zoledronic Acid (Zometa) Reduces Recurrence of Early Breast Cancer

By bmirtsching The Austrian Breast and Colorectal Cancer Study Group Trial 12 results were reported at the American Society of Clinical Oncology (ASCO) 2008 Annual Meeting. The study compared treatment with zoledronic acid (Zometa) with placeo in premenopausal women who were treated with anti-estrogen therapy following surgery.
Between 1999 and 2006, over 1800 women participated in the study. All were premenopausal, had estrogen receptor (ER)- and/or progesterone receptor (PR)-positive stage I or II (<10 positive nodes) breast cancer, and have received no chemotherapy other than neo-adjuvant (pre-operative) treatment.
Following completion of surgery (with radiotherapy in breast conservation cases), women were treated with 3.6 mg of goserelin (an ovarian suppression LHRH drug) and then randomized to one of four treatment arms: tamoxifen 20 mg/day; tamoxifen 20 mg/day plus zoledronic acid 4 mg given intravenously every 6 months; anastrozole 1 mg/day; or the AI plus the bisphosphonate at the same doses and schedule.
Dr. Gnant of the University of Vienna reported that the disease-free (DFS) and overall survival (OS) rates were very good for the whole cohort, at 94.0% and 98.2%, respectively.
A total of 137 first DFS events were reported. Of these, 72 occurred in patients treated with anastrozole, and the remaining 65 occurred in those treated with tamoxifen. Statistical analysis showed no significant difference in the primary endpoint of DFS according to the type of endocrine treatment used, but there was a significant difference according to whether or not patients had been given the bisphosphonate. Of the 137 DFS events, 54 occurred in women who had received zoledronic acid, with the remaining 83 in those who had not received the drug. This gave a hazard ratio of 0.643 (95% confidence interval: 0.46-0.91), with a p value of 0.011, in favor of bisphosphonate use over no bisphosphonate use. This is a 35% reduction in the number of events.
The reduction in events were not limited to bone metastasis reduction. Reduction in other distant metastases, local recurrence, and contralateral breast cancer events was established.
Zoledronic acid is a bisphosphonate drug which reduces bone resorption and thereby increases bone mineral density. Bisphosphonates are approved therapies for treatment of osteoporosis. The anticancer effect of bisphosphonates has been suggested in prior studies of other bisphosphonate drugs, e.g., oral clodronate (NSABP). The mechanism of the anticancer effect is not known.
These results have been called “practice changing” by some observers, but not all. However, if the effect is confirmed in other large ongoing studies (AZURE, BIG 1-04, NATAN, GAIN, NSABP B-34), then the use of bisphosphonate therapy is likely to have a large impact on practice, as well as the design of future studies.
Access to bisphosphonate therapy for adjuvant therapy of early breast cancer in the US is limited, because the drugs are not FDA-approved yet for breast cancer treatment. For example, Medicare does not pay for coverage for zoledronic acid for breast cancer. Private payors may not pay for zoledronic acid for breast cancer either, since their treatment algorithms heavily rely upon national guideline groups and current FDA approvals. While zoledronic acid is approved for osteoporosis, the dosing of the drug at the approved frequency is yearly, and the dosing that was shown to be effective in the ABCSG study was more frequent, so therapy was more intensive.
Patients may gain access to bisphosphonate therapy for early breast cancer by enrolling in clinical studies, such as the SWOG S0307 Study which is open at CORT. This study compares the efficacy of three different bisphosphonate drugs (IV zoledronic acid, oral clodronate, oral ibandronate) in a randomized fashion. All patients will receive one of the bisphosphonate therapies. Three is no placebo group. This study will also include a broader range of patients, including pre- and post-menopausal women, ER- and ER+ disease, and those who have receive either pre- or post-operative chemotherapy. In addition, the use of adjuvant biologic therapy such as trastuzumab (Herceptin) or bevacizumab (Avastin) is allowed. For more information about this study, visit the CORT website (www.CORTPA.com), or call 972-566-5588 to speak with a Study Coordinator.
Addendum (2/12/09): The ABCSG-12 Study Results were published in the New England Journal of Medicine today. The reference is: Gnant, M. et al., NEJM 2009; 360 (7): 679-691.
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Tags: ABCSG, ABCSG Trial 12, adjuvant therapy, bisphosphonates, Breast Cancer, Clodronate, Ibandronate, S0307, Stage I-III, SWOG, zoledronic acid, zometa
This entry was posted on November 5, 2008 at 7:54 am and is filed under Breast Cancer. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.

2 Responses to “ABCSG-12: Zoledronic Acid (Zometa) Reduces Recurrence of Early Breast Cancer”
  1. treatment of cancer cells Says:
    treatment of cancer cells…
  2. bmirtsching Says:
    No, there was no critieria for low bone density to enter the study. The study was reported in the New England Journal of Medicine on February 12, 2009. That report did not report the changes in bone density in the treatment groups. It did note in the discussion that zoledronic acid effectively prevented bone loss in patients receiving adjuvant therapy with aromatase inhibitors. The detailed information on the bone effects of zoledronic acid in the premenopausal group of women in this study will hopefully be reported separately.
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Old 09-29-2009, 01:06 PM   #22
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Re: BPH-715 (revised Zoledronate) A New Weapon Against Tumor Cells

1: Anticancer Res. 2009 Jun;29(6):1879-88. Links
Alendronate inhibits growth of high-grade chondrosarcoma cells.

Susa M, Morii T, Yabe H, Horiuchi K, Toyama Y, Weissbach L, Hornicek FJ, Morioka H.
Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan. msusa@partners.org
BACKGROUND: Conventional chemotherapy is ineffective for high-grade chondrosarcomas, highlighting the need for improved chemotherapies. Various clinical trials have been initiated using antiapoptotic agents and perifosine, and are truly in the experimental phases. Chondrosarcoma is still therefore considered a surgical disease despite its aggressive features of recurring locally and spreading to the lungs. Bisphosphonates inhibit growth of various cell types, including cancer cells and perhaps chondrosarcoma. MATERIALS AND METHODS: The effect of different concentrations of alendronate on cell proliferation, migration, apoptosis and cytoskeleton reorganization as well as on the regulation of intracellular protein expression were analyzed for the high-grade chondrosarcoma cell line CS-1. Mevalonate pathway intermediates were used in some experiments to assess mechanistic aspects. RESULTS: Alendronate decreased cell viability of CS-1 by inhibiting cell proliferation and cell migration. Alendronate-induced loss of cell viability led to a sequence of events including apoptosis and cytoskeletal rearrangements. Moreover, changes in the expression levels of various proteins involved in cell proliferation, migration, cell cycle, apoptosis and cytoskeleton reorganization were demonstrated. CONCLUSION: Alendronate exerts antiproliferative effects by perturbing various signaling pathways in CS-1 cells. These findings may lead to new treatment options for high-grade chondrosarcoma.
PMID: 19528443 [PubMed - indexed for MEDLINE]



Support Care Cancer. 2010 Feb 12. [Epub ahead of print]
Bone pain reduction in patients with metastatic breast cancer treated with ibandronate-results from a post-marketing surveillance study.

Diel IJ, Kurth AH, Sittig HB, Meden H, Maasberg M, Sandermann A, Bergner R.
Institute for Gynaecological Oncology, CGG-Clinic, P7, 16-18, 68161, Mannheim, Germany, diel@cgg-mannheim.de.
BACKGROUND: Pain relief is an important treatment goal for breast cancer patients with metastatic bone disease and treatment should be associated with a low rate of side effects. This interim analysis of a prospective non-interventional study documents the efficacy and safety of the amino-bisphosphonate ibandronate in the treatment of metastatic bone disease under real-life conditions. PATIENTS AND METHODS: For up to 24 weeks 913 breast cancer patients received IV infusions of 6 mg ibandronate every 3-4 weeks or 50 mg of oral ibandronate once daily. Efficacy variables included pain severity, analgesic use, and skeletal-related events; the major safety parameter was renal function, assessed by serum creatinine levels. Subgroup analyses were performed according to pretreatment with bisphosphonates (none, ibandronate, or other bisphosphonates). RESULTS: At baseline, patients with ibandronate pretreatment tended to have lower mean pain scores and lower serum creatinine levels than those pre-treated with other bisphosphonates. Over the observation period, analgesic use did not increase. Among the 712 patients reporting pain at baseline, 70% achieved an improvement in pain severity during treatment with ibandronate, and there was no evidence to suggest relevant differences in mean pain reductions with IV or oral administration of ibandronate or according to prior bisphosphonate treatment. Skeletal-related events were rare (7%). Changes in serum creatinine levels during ibandronate treatment were small and both formulations of ibandronate were rated as well tolerated by physicians and patients. CONCLUSIONS: Data from this non-interventional study confirm the analgesic efficacy and safety profile of IV and oral ibandronate under real-life conditions.

PMID: 20151162 [PubMed - as supplied by publisher]
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Old 09-29-2009, 06:46 PM   #23
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Re: BPH-715 (revised Zoledronate) A New Weapon Against Tumor Cells

I'm in the SWOG 307 trial. My oncologist who recommended it does a lot of clinical trial research and I spoke to 2 other oncologists who also endorsed it. There is no placebo arm (good for patients, maybe not for interpretation of results). The zoledronic acid (Zometa) is considered standard of care but they should all work. I think better bisphosphonates will come along but it is what we have right now and is showing promising results. For those just completing chemo, you may want to check out the links above.
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Old 10-31-2009, 10:17 PM   #24
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Re: BPH-715 (revised Zoledronate) A New Weapon Against Tumor Cells

BMC Cancer. 2009 Jan 28;9:38.
Activity of mevalonate pathway inhibitors against breast and ovarian cancers in the ATP-based tumour chemosensitivity assay.

Knight LA, Kurbacher CM, Glaysher S, Fernando A, Reichelt R, Dexel S, Reinhold U, Cree IA.
Translational Oncology Research Centre, Queen Alexandra Hospital, The Pathology Centre, Portsmouth, UK. knight.louise@googlemail.com
Previous data suggest that lipophilic statins such as fluvastatin and N-bisphosphonates such as zoledronic acid, both inhibitors of the mevalonate metabolic pathway, have anti-cancer effects in vitro and in patients. We have examined the effect of fluvastatin alone and in combination with zoledronic acid in the ATP-based tumour chemosensitivity assay (ATP-TCA) for effects on breast and ovarian cancer tumour-derived cells. Both zoledronic acid and fluvastatin showed activity in the ATP-TCA against breast and ovarian cancer, though fluvastatin alone was less active, particularly against breast cancer. The combination of zoledronic acid and fluvastatin was more active than either single agent in the ATP-TCA with some synergy against breast and ovarian cancer tumour-derived cells.pre-treatment of ovarian tumour cells with fluvastatin resulted in decreased sensitivity to zoledronic acid. Sequential drug experiments showed that Addition of mevalonate pathway components with zoledronic acid with or without fluvastatin showed little effect, while mevalonate did reduced inhibition due to fluvastatin. These data suggest that the combination of zoledronic acid and fluvastatin may have activity against breast and ovarian cancer based on direct anti-cancer cell effects. A clinical trial to test this is in preparation.

PMID: 19175937 [PubMed - indexed for MEDLINE]
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Old 11-15-2009, 05:04 AM   #25
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Re: BPH-715 (revised Zoledronate) A New Weapon Against Tumor Cells

Eur Cytokine Netw. 2009 Sep;20(3):121-30.
Combined gossypol and zoledronic acid treatment results in synergistic induction of cell death and regulates angiogenic molecules in ovarian cancer cells.

Atmaca H, Gorumlu G, Karaca B, Degirmenci M, Tunali D, Cirak Y, Purcu DU, Uzunoglu S, Karabulut B, Sanli UA, Uslu R.
Section of Molecular Biology, Department of Biology, Faculty of Science and Arts, Celal Bayar University, Muradiye, Manisa, Turkey, Division of Medical Oncology, Tulay Aktas Oncology Hospital, School of Medicine, Ege University, Bornova, Izmir, Turkey.
In the present study, we aimed to evaluate the possible synergistic, cytotoxic effects of combination treatment of gossypol and zoledronic acid, in human ovarian cancer cell lines, OVCAR-3 and MDAH-2774, and to elucidate the role of this novel combination treatment on angiogenesis-related molecules in ovarian cancer. The XTT cell viability assay was used for showing cytotoxicity. Both DNA fragmentation by ELISA assay and caspase 3/7 activity measurement were used for demonstrating apoptosis. To elucidate the angiogenic molecules affected by combination treatment, mRNA levels of angiogenic molecules were measured using the Human Angiogenesis RT2 ProfilerTM PCR Array (SuperArray, Frederick, MD) in ovarian cancer cell lines, OVCAR-3 and MDAH-2774.The combined treatment resulted in significant, synergistic cytotoxicity, and induced apoptosis. This effect was observed to happen in a dose- and time-dependent manner. Moreover, the combination treatment of 10 muM gossypol and 5 muM zoledronic acid resulted in significant down-regulation (>/= thee-fold) in mRNA levels of some pivotal angiogenic molecules in OVCAR-3 and MDAH-2774 cells as compared to the untreated control. However, this effect was different in the two ovarian cancer cell lines observed. Gossypol, in combination with zoledronic acid, may provide a rational treatment option for ovarian cancer, not only by direct inhibition of cell proliferation, but also inhibition of angiogenesis-related molecules.

PMID: 19825521 [PubMed - in process]
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Old 11-15-2009, 05:10 AM   #26
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Re: BPH-715 (revised Zoledronate) A New Weapon Against Tumor Cells

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Old 11-17-2009, 01:16 AM   #27
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Re: BPH-715 (revised Zoledronate) A New Weapon Against Tumor Cells

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Old 11-17-2009, 04:27 PM   #28
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Re: BPH-715 (revised Zoledronate) A New Weapon Against Tumor Cells

Cancer Res. 2009 Sep 15;69(18):7243-51. Epub 2009 Sep 8.
Glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via vascular endothelial growth factor and stromal-derived factor 1.

Folkins C, Shaked Y, Man S, Tang T, Lee CR, Zhu Z, Hoffman RM, Kerbel RS.
Department of Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
Cancer stem cells (CSC) are predicted to be critical drivers of tumor progression due to their self-renewal capacity and limitless proliferative potential. An emerging area of research suggests that CSC may also support tumor progression by promoting tumor angiogenesis. To investigate how CSC contribute to tumor vascular development, we used an approach comparing tumor xenografts of the C6 glioma cell line containing either a low or a high fraction of CSC. Compared with CSC-low tumors, CSC-high tumors exhibited increased microvessel density and blood perfusion and induced increased mobilization and tumor recruitment of bone marrow-derived endothelial progenitor cells (EPC). CSC-high C6 cell cultures also induced higher levels of endothelial cell proliferation and tubule organization in vitro compared with CSC-low cultures. CSC-high cultures and tumors expressed increased levels of the proangiogenic factors vascular endothelial growth factor and stromal-derived factor 1, and when signaling by either factor was blocked, all aspects of angiogenesis observed in CSC-high cultures and tumors, including microvessel density, perfusion, EPC mobilization/recruitment, and stimulation of endothelial cell activity, were reduced to levels comparable with those observed in CSC-low cultures/tumors. These results suggest that CSC contribute to tumor angiogenesis by promoting both local endothelial cell activity and systemic angiogenic processes involving bone marrow-derived EPC in a vascular endothelial growth factor-dependent and stromal-derived factor 1-dependent manner.

PMID: 19738068 [PubMed - indexed for MEDLINE]


Biochim Biophys Acta. 2009 Aug;1796(1):33-40. Epub 2009 May 19.
Bone marrow-derived endothelial progenitor cells contribute to the angiogenic switch in tumor growth and metastatic progression.

Gao D, Nolan D, McDonnell K, Vahdat L, Benezra R, Altorki N, Mittal V.
Department of Cardiothoracic Surgery, Lehman Brothers Lung Cancer Research Center, Cornell University Medical Center, New York, NY 10065, USA.
Emerging evidence indicates that bone marrow (BM)-derived endothelial progenitor cells (EPCs) contribute to angiogenesis-mediated growth of certain tumors in mice and human. EPCs regulate the angiogenic switch via paracrine secretion of proangiogenic growth factors and by direct luminal incorporation into sprouting nascent vessels. While the contributions of EPCs to neovessel formation in spontaneous and transplanted tumors and to the metastatic transition have been reported to be relatively low, remarkably, specific EPC ablation in vivo has resulted in severe angiogenesis inhibition and impaired primary and metastatic tumor growth. The existence of a BM reservoir of EPCs, and the selective involvement of EPCs in neovascularization, have attracted considerable interest because these cells represent novel target for therapeutic intervention. In addition, EPCs are also being used as pharmacodynamic surrogate markers for monitoring cancer progression, as well as for optimizing efficacy of anti-angiogenic therapies in the clinic. This review will focus primarily on recent advances and emerging concepts in the field of EPC biology and discuss ongoing debates involving the role of EPCs in tumor neovascularization. For detailed information on the in vitro characterization of EPCs contribution to non-tumor pathologies, the reader is directed towards several excellent reviews and publications [F. Bertolini, Y. Shaked, P. Mancuso and R.S. Kerbel, Nat. Rev., Cancer 6 (2006) 835-845. [1]] [J.M. Hill, T. Finkel and A.A. Quyyumi, Vox Sang. 87 Suppl 2 (2004) 31-37. [2]] [A.Y. Khakoo and T. Finkel, Annu. Rev. Med. 56 (2005) 79-101. [3]] [H.G. Kopp, C.A. Ramos and S. Rafii, Curr. Opin. Hematol. 13 (2006) 175-181. [4]; K.K. Hirschi, D.A. Ingram and M.C. Yoder, Arterioscler. Thromb. Vasc. Biol. 28 (2008) 1584-1595. [5]; F. Timmermans, J. Plum, M.C. Yoder, D.A. Ingram, B. Vandekerckhove and J. Case, J. Cell. Mol. Med. 13 (2009) 87-102. [6]] and reviews by Bertolini, Voest and Yoder in this issue.

PMID: 19460418 [PubMed - indexed for MEDLINE]

Int J Cancer. 2009 Oct 15;125(8):1771-7.
Endothelial progenitor cells do not contribute to tumor endothelium in primary and metastatic tumors.

Wickersheim A, Kerber M, de Miguel LS, Plate KH, Machein MR.
Tumor Angiogenesis Research Group, Department of Neurosurgery, University of Freiburg Medical School, D-79106 Freiburg, Germany.
Despite extensive research, the contribution of bone-marrow-derived endothelial progenitor cells (BM-EPC) to tumor angiogenesis remains controversial. In previous publications, the extent of incorporation of BM-EPCs into the endothelial cell (EC) layer in different tumor models has been reported as significant in some studies but undetectable in others. Here, we studied the differentiation of BM-EPCs and its contribution to tumor vessels in experimental and spontaneous lung metastasis (B16 melanoma and prostate carcinoma), in an autochthonous transgenic model of prostate tumorigenesis, in orthotopically implanted lung tumors [Lewis lung carcinoma (LLC)], in heterotopic subcutaneous models (LLC and C1 prostate carcinoma) growing in green fluorescent protein (GFP)-expressing bone marrow (BM) chimeras. Immunofluorescence was performed with a set of endothelial and hematopoietic markers and confocal microscopy was used to generate 3D reconstruction images. By performing rigorously conducted morphological studies, we found no evidence of BM-EPCs differentiation into tumor endothelium independently of tumor type, grade and organ site in primary and metastatic tumors. The vast majority of GFP(+) cells were trafficking leucocytes or periendothelial myeloid cells. To explore the possibility that local overexpression of vascular endothelial growth factor (VEGF) might increase the numbers of incorporated BM-EPCs, we analyzed tumors genetically manipulated to overexpress VEGF(164). Local VEGF production induces a massive infiltration of bone-marrow-derived cells, but did not lead to vessel wall integration of these cells. Collectively, these findings suggest that during tumor progression vascularization occurs primarily via classical tumor angiogenesis (e.g., sprouting of pre-existing ECs), whereas BM-EPCs do not incorporate into the vessel wall to any significant extent.

PMID: 19582874 [PubMed - indexed for MEDLINE]
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