Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2012

Open Access 01-12-2012 | Research article

Antitumor activity of zoledronic acid in primary breast cancer cells determined by the ATP tumor chemosensitivity assay

Authors: Tanja Fehm, Manfred Zwirner, Diethelm Wallwiener, Harald Seeger, Hans Neubauer

Published in: BMC Cancer | Issue 1/2012

Login to get access

Abstract

Background

The NeoAzure study has demonstrated that the use of the bisphosphonate zoledronic acid (Zol) in the neoadjuvant setting increases the rate of complete response in primary breast cancer and therefore indicates direct antitumor activity. The purpose of this study was to compare the antitumor effect of Zol with standard chemotherapy in primary breast cancer cells using ATP-tumor chemosensitivity assay (ATP-TCA).

Methods

Breast cancer specimens were obtained from patients with breast cancer who underwent primary breast cancer surgery at the Department of Obstetrics and Gynecology, Tübingen, Germany, between 2006 through 2009. Antitumor effects of Zol, TAC (Docetaxel, Adriamycin, Cyclophosphamide) and FEC (5-Fluorouracil, Epirubicin, Cyclophosphamide) were tested in 116 fresh human primary breast cancer specimens using ATP-TCA. ATP-TCA results were analyzed with different cut-off levels for the half maximal inhibitory concentration (IC50), for IC90 and for the sensitivity index (IndexSUM). Each single agent or combination was tested at six doubling dilutions from 6.25, 12.5, 25, 50, 100, and 200% of test drug concentrations (TDC) derived from the plasma peak concentrations determined by pharmacokinetic data. The assay was carried out in duplicate wells with positive and negative controls.

Results

The median IndexSUM value was lower for Zol than for the combined regimen FEC (36.8%) and TAC (12.9%), respectively, indicating increased antitumor activity of Zol in primary breast cancer cells. The difference regarding Zol and FEC was significant (p < 0.05). The median IC50 value for Zol (8.03% TDC) was significantly lower than the IC50 values for FEC (33.5% TDC) and TAC (19.3% TDC) treatment (p < 0.05). However, the median IC90 value for Zol (152.5% TDC) was significantly higher than the IC90 value obtained with TAC (49.5% TDC; p < 0.05), but similar to the IC90 value for FEC (180.9% TDC). In addition a significant positive correlation was observed for the IndexSum of Zol and the ER status (p < 0.01).

Conclusion

Zoledronic acid has a strong antitumor effect on primary breast cancer cells in vitro which is equal or superior to commonly used chemotherapeutic regimens for treating breast cancer.
Appendix
Available only for authorised users
Literature
1.
Lipton A, Theriault RL, Hortobagyi GN, Simeone J, Knight RD, Mellars K, Reitsma DJ, Heffernan M, Seaman JJ: Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer. 2000, 88: 1082-1090. 10.1002/(SICI)1097-0142(20000301)88:5<1082::AID-CNCR20>3.0.CO;2-Z.CrossRefPubMed
2.
3.
Gnant M, Mlineritsch B, Luschin-Ebengreuth G, Kainberger F, Kässmann H, Piswanger-Sölkner JC, Seifert M, Ploner F, Menzel C, Dubsky P, Fitzal F, Bjelic-Radisic V, Steger G, Greil R, Marth C, Kubista E, Samonigg H, Wohlmuth P, Mittlböck M, Jakesz R, Austrian Breast and Colorectal Cancer Study Group (ABCSG): Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with earlystage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy. Lancet Oncol. 2008, 9: 840-849. 10.1016/S1470-2045(08)70204-3.CrossRefPubMed
4.
Aapro M, Abrahamsson PA, Body JJ, Coleman RE, Colomer R, Costa L, Crinò L, Dirix L, Gnant M, Gralow J, Hadji P, Hortobagyi GN, Jonat W, Lipton A, Monnier A, Paterson AH, Rizzoli R, Saad F, Thürlimann B: Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol. 2008, 19 (3): 420-432.CrossRefPubMed
5.
Hadji P, Body JJ, Aapro MS, Brufsky A, Coleman RE, Guise T, Lipton A, Tubiana-Hulin M: Practical guidance for the management of aromatase inhibitor-associated bone loss. Ann Oncol. 2008, 19: 1407-1416. 10.1093/annonc/mdn164.CrossRefPubMed
6.
Rogers MJ, Watts DJ, Russell RG: Overview of bisphosphonates. Cancer. 1997, 80: 1652-1660. 10.1002/(SICI)1097-0142(19971015)80:8+<1652::AID-CNCR15>3.0.CO;2-Z.CrossRefPubMed
7.
Hillner BE, Ingle JN, Chlebowski RT, Gralow J, Yee GC, Janjan NA, Cauley JA, Blumenstein BA, Albain KS, Lipton A, Brown S: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. American Society of Clinical Oncology. J Clin Oncol. 2003, 21: 4042-4057. 10.1200/JCO.2003.08.017.CrossRefPubMed
8.
Costa L: Bisphosphonates: Reducing the risk of skeletal complications from bone metastasis. Breast. 2007, 16: 16-20.CrossRef
9.
Almubarak H, Jones A, Chaisuparat R, Zhang M, Meiller TF, Scheper MA: Zoledronic acid directly suppresses cell proliferation and induces apoptosis in highly tumorigenic prostate and breast cancers. J Carcinog. 2011, 10: 2-10.4103/1477-3163.75723.CrossRefPubMedPubMedCentral
10.
Senaratne SG, Pirianov G, Mansi JL, Arnett TR, Colston KW: Bisphosphonates induce apoptosis in human breast cancer cell lines. Br J Cancer. 2000, 82: 1459-1468. 10.1054/bjoc.1999.1131.CrossRefPubMedPubMedCentral
11.
Jagdev SP, Coleman RE, Shipman CM, Rostami-H A, Croucher PI: The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel. Br J Cancer. 2001, 84: 1126-1134. 10.1054/bjoc.2001.1727.CrossRefPubMedPubMedCentral
12.
Diel IJ, Jaschke A, Solomayer EF, Gollan C, Bastert G, Sohn C, Schuetz F: Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow: a long-term follow-up. Ann Oncol. 2008, 19: 2007-2011. 10.1093/annonc/mdn429.CrossRefPubMedPubMedCentral
13.
Eidtmann H, de Boer R, Bundred NJ, Llombart-Cussac A, Davidson N, Neven P, von Minckwitz G, Miller J, Schenk N, Coleman R: Efficacy of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36-month results of the ZO-FAST Study. Ann Oncol. 2010, 21: 2188-2194. 10.1093/annonc/mdq217.CrossRefPubMed
14.
Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Heck D, Menzel C, Jakesz R, Seifert M, Hubalek M, Pristauz G, Bauernhofer T, Eidtmann H, Eiermann W, Steger G, Kwasny W, Dubsky P, Hochreiner G, Forsthuber EP, Fesl C, Greil R, on behalf of the Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria: Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol. 2011, 12: 631-641. 10.1016/S1470-2045(11)70122-X.CrossRefPubMed
15.
Coleman RE, Winter MC, Cameron D, Bell R, Dodwell D, Keane MM, Gil M, Ritchie D, Passos-Coelho JL, Wheatley D, Burkinshaw R, Marshall SJ, Thorpe H: AZURE (BIG01/04) Investigators: The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer. Br J Cancer. 2010, 102: 1099-1105. 10.1038/sj.bjc.6605604.CrossRefPubMedPubMedCentral
16.
17.
Daubiné F, Le Gall C, Gasser J, Green J, Clézardin P: Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis. J Natl Cancer Inst. 2007, 99: 322-330. 10.1093/jnci/djk054.CrossRefPubMed
18.
Fromigue O, Lagneaux L, Body JJ: Bisphosphonates induce breast cancer cell death in vitro. J Bone Miner Res. 2000, 15: 2211-2221. 10.1359/jbmr.2000.15.11.2211.CrossRefPubMed
19.
Verdijk R, Franke HR, Wolbers F, Vermes I: Differential effects of bisphosphonates on breast cancer cell lines. Cancer Lett. 2007, 246: 308-312. 10.1016/j.canlet.2006.03.011.CrossRefPubMed
20.
Mitrofan LM, Pelkonen J, Mönkkönen J: The level of ATP analog and isopentenyl pyrophosphate correlates with zoledronic acid-induced apoptosis in cancer cells in vitro. Bone. 2009, 45: 1153-1160. 10.1016/j.bone.2009.08.010.CrossRefPubMed
21.
Neville-Webbe HL, Rostami-Hodjegan A, Evans CA, Coleman RE, Holen I: Sequence- and schedule-dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells. Int J Cancer. 2005, 20 (113): 364-371.CrossRef
22.
Brubaker KD, Brown LG, Vessella RL, Corey E: Administration of zoledronic acid enhances the effects of docetaxel on growth of prostate cancer in the bone environment. BMC Cancer. 2006, 6: 15-10.1186/1471-2407-6-15.CrossRefPubMedPubMedCentral
23.
Neville-Webbe HL, Evans CA, Coleman RE, Holen I: Mechanisms of the synergistic interaction between the bisphosphonate zoledronic acid and the chemotherapy agent paclitaxel in breast cancer cells in vitro. Tumour Biol. 2006, 27: 92-103. 10.1159/000092489.CrossRefPubMed
24.
Santini D, Vincenzi B, Galluzzo S, Battistoni F, Rocci L, Venditti O, Schiavon G, Angeletti S, Uzzalli F, Caraglia M, Dicuonzo G, Tonini G: Repeated intermittent low-dose therapy with zoledronic acid induces an early, sustained, and long-lasting decrease of peripheral vascular endothelial growth factor levels in cancer patients. Clin Cancer Res. 2007, 13: 4482-4486. 10.1158/1078-0432.CCR-07-0551.CrossRefPubMed
25.
Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Pöstlberger S, Menzel C, Jakesz R, Seifert M, Hubalek M, Bjelic-Radisic V, Samonigg H, Tausch C, Eidtmann H, Steger G, Kwasny W, Dubsky P, Fridrik M, Fitzal F, Stierer M, Rücklinger E, Greil R: ABCSG-12 Trial Investigators, Marth C: Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009, 360: 679-691. 10.1056/NEJMoa0806285.CrossRefPubMed
26.
Lin A, Park J, Melisko M, Goga A, Moasser M, Moore D, Brissaud C, Rugo H: Zoledronic acid as adjuvant therapy for women with early stage breast cancer and occult tumor cells in bone marrow (abstract). Breast Cancer Res Treat. 2007, 106 (S1): 510-
27.
Rack BK, Jueckstock J, Genss EM, Schoberth A, Schindlbeck C, Strobl B, Heinrigs M, Rammel G, Zwingers T, Sommer H, Friese K, Janni W: Effect of zoledronate on persisting isolated tumor cells in the bone marrow of patients without recurrence of early breast cancer (abstract). Breast Cancer Res Treat. 2007, 106 (S1): 511-
28.
Solomayer E, Gebauer G, Hirnle P, Janni W, Luck H, Becker S, Huober J, Kraemer B, Wackwitz B, Fehm T: Influence of zoledronic acid on disseminated tumor cells (DTC) in primary breast cancer patients (abstract). Cancer Res. 2009, 69 (Suppl2): 2048-CrossRef
29.
Aft R, Naughton M, Trinkaus K, Watson M, Ylagan L, Chavez-MacGregor M, Zhai J, Kuo S, Shannon W, Diemer K, Herrmann V, Dietz J, Ali A, Ellis M, Weiss P, Eberlein T, Ma C, Fracasso PM, Zoberi I, Taylor M, Gillanders W, Pluard T, Mortimer J, Weilbaecher K: Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial. Lancet Oncol. 2010, 11: 421-428. 10.1016/S1470-2045(10)70054-1.CrossRefPubMedPubMedCentral
30.
Rachner TD, Singh SK, Schoppet M, Benad P, Bornhäuser M, Ellenrieder V, Ebert R, Jakob F, Hofbauer LC: Zoledronic acid induces apoptosis and changes the TRAIL/OPG ratio in breast cancer cells. Cancer Lett. 2010, 287: 109-116. 10.1016/j.canlet.2009.06.003.CrossRefPubMed
31.
Chlebowski RT, Chen Z, Cauley JA, Anderson G, Rodabough RJ, McTiernan A, Lane DS, Manson JE, Snetselaar L, Yasmeen S, O'Sullivan MJ, Safford M, Hendrix SL, Wallace RB: Oral bisphosphonate use and breast cancer incidence in postmenopausal women. J Clin Oncol. 2010, 28: 3582-3590. 10.1200/JCO.2010.28.2095.CrossRefPubMedPubMedCentral
32.
Mener DJ: Prostate specific antigen reduction following statin therapy: Mechanism of action and review of the literature. IUBMB Life. 2010, 62: 584-590. 10.1002/iub.355.CrossRefPubMed
33.
Chen T, Berenson J, Vescio R, Swift R, Gilchick A, Goodin S, LoRusso P, Ma P, Ravera C, Deckert F, Schran H, Seaman J, Skerjanec A: Pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with bone metastases. J Clin Pharmacol. 2002, 42: 1228-1236. 10.1177/009127002762491316.CrossRefPubMed
34.
Andreotti PE, Cree IA, Kurbacher CM, Hartmann DM, Linder D, Harel G, Gleibermann I, Caruso PA, Ricks SH, Untch M, Sartori C, Bruckner HW: Chemosensitivity testing of human tumors using a microplate adenosine triphosphate luminescence assay: clinical correlation for cisplatin resistance of ovarian carcinoma. Cancer Res. 1995, 55: 5276-5282.PubMed
35.
Neubauer H, Gall C, Vogel U, Hornung R, Wallwiener D, Solomayer E, Fehm T: Changes in tumour biological markers during primary systemic chemotherapy (PST). Anticancer Res. 2008, 28 (3B): 1797-1804.PubMed
Metadata
Title
Antitumor activity of zoledronic acid in primary breast cancer cells determined by the ATP tumor chemosensitivity assay
Authors
Tanja Fehm
Manfred Zwirner
Diethelm Wallwiener
Harald Seeger
Hans Neubauer
Publication date
01-12-2012
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2012
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-12-308

Other articles of this Issue 1/2012

BMC Cancer 1/2012 Go to the issue

Case report

Functioning glucagonoma associated with primary hyperparathyroidism: multiple endocrine neoplasia type 1 or incidental association?

Study protocol

Move more for life: the protocol for a randomised efficacy trial of a tailored-print physical activity intervention for post-treatment breast cancer survivors

Research article

Statins and the risk of gastric cancer in diabetes patients

Research article

Competitive amplification of differentially melting amplicons (CADMA) improves KRAS hotspot mutation testing in colorectal cancer

Case report

Intracranial melanocytic meningeal tumours and melanosis oculi: case report and literature review

Research article

Real-imaging cDNA-AFLP transcript profiling of pancreatic cancer patients: Egr-1 as a potential key regulator of muscle cachexia
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits